EAU Guidelines 2021 edition

EAU Guidelines on
Management of
Non-Neurogenic
Male Lower Urinary
Tract Symptoms
(LUTS), incl.
Benign Prostatic
Obstruction (BPO)
S. Gravas (Chair), J.N. Cornu, M. Gacci, C. Gratzke,
T.R.W. Herrmann, C. Mamoulakis, M. Rieken,
M.J. Speakman, K.A.O. Tikkinen
Guidelines Associates: M. Karavitakis, I. Kyriazis, S. Malde,
V. Sakalis, R. Umbach
© European Association of Urology 2021
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION
1.1
Aim and objectives
1.2
Panel composition
1.3
Available publications
1.4
Publication history
4
4
4
4
4
2.
METHODS
2.1
Introduction
2.2
Review
2.3
Patients to whom the guidelines apply
4
4
5
5
3.
EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY
5
4.
DIAGNOSTIC EVALUATION
4.1
Medical history
4.2
Symptom score questionnaires
4.2.1
The International Prostate Symptom Score (IPSS)
4.2.2
The International Consultation on Incontinence Questionnaire (ICIQ-MLUTS)
4.2.3
Danish Prostate Symptom Score (DAN-PSS)
4.3
Frequency volume charts and bladder diaries
4.4
Physical examination and digital-rectal examination
4.4.1
Digital-rectal examination and prostate size evaluation
4.5
Urinalysis
4.6
Prostate-specific antigen (PSA)
4.6.1
PSA and the prediction of prostatic volume
4.6.2
PSA and the probability of PCa
4.6.3
PSA and the prediction of BPO-related outcomes
4.7
Renal function measurement
4.8
Post-void residual urine
4.9
Uroflowmetry
4.10 Imaging
4.10.1 Upper urinary tract
4.10.2 Prostate
4.10.2.1 Prostate size and shape
4.10.3 Voiding cysto-urethrogram
4.11 Urethrocystoscopy
4.12 Urodynamics
4.12.1 Diagnosing bladder outlet obstruction
4.12.2 Videourodynamics
4.13 Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS
4.13.1Prostatic configuration/intravesical prostatic protrusion (IPP)
4.13.2Bladder/detrusor wall thickness and ultrasound-estimated bladder weight
4.13.3 Non-invasive pressure-flow testing
4.13.4The diagnostic performance of non-invasive tests in diagnosing bladder
outlet obstruction in men with LUTS compared with pressure-flow studies
DISEASE MANAGEMENT
5.1
Conservative treatment
5.1.1
Watchful waiting (WW)
5.1.2
Behavioural and dietary modifications
5.1.3
Practical considerations
5.2
Pharmacological treatment
5.2.1
α1-Adrenoceptor antagonists (α1-blockers)
5.2.2
5α-reductase inhibitors
5.2.3
Muscarinic receptor antagonists
5.2.4
Beta-3 agonist
5.2.5
Phosphodiesterase 5 inhibitors
5.2.6
Plant extracts - phytotherapy
6
6
7
7
7
7
7
8
8
8
9
9
9
9
9
10
10
11
11
11
11
11
11
12
12
12
13
13
13
14
14
5.
15
15
16
16
16
17
17
18
19
20
22
23
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MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
5.2.7
Combination therapies
5.2.7.1
α1-blockers + 5α-reductase inhibitors
5.2.7.2
α1-blockers + muscarinic receptor antagonists
5.3
Surgical treatment
5.3.1
Resection of the prostate
5.3.1.1
Monopolar and bipolar transurethral resection of the prostate
5.3.1.2
Holmium laser resection of the prostate
5.3.1.3
Thulium:yttrium-aluminium-garnet laser (Tm:YAG) vaporesection
of the prostate Mechanism of action:
5.3.1.4
Transurethral incision of the prostate
5.3.2
Enucleation of the prostate
5.3.2.1
Open prostatectomy
5.3.2.2
Bipolar transurethral enucleation of the prostate (B-TUEP)
5.3.2.3
Holmium laser enucleation of the prostate
5.3.2.4
Thulium:yttrium-aluminium-garnet laser (Tm:YAG) enucleation
of the prostate Mechanism of action:
5.3.2.5
Diode laser enucleation of the prostate
5.3.2.6
Enucleation techniques under investigation
5.3.2.6.1
Minimal invasive simple prostatectomy
5.3.2.6.2
532 nm (‘Greenlight’) laser enucleation of the prostate
5.3.3
Vaporisation of the prostate
5.3.3.1
Bipolar transurethral vaporisation of the prostate
5.3.3.2
532 nm (‘Greenlight’) laser vaporisation of the prostate
5.3.3.3
Vaporisation techniques under investigation
5.3.3.3.1
Diode laser vaporisation of the prostate
5.3.4
Alternative ablative techniques
5.3.4.1
Aquablation – image guided robotic waterjet ablation: AquaBeam
5.3.4.2
Prostatic artery embolisation
5.3.4.3
Alternative ablative techniques under investigation
5.3.4.3.1
Convective water vapour energy (WAVE) ablation:
The Rezum system
5.3.5
Alternative ablative techniques under investigation
5.3.5.1
Prostatic urethral lift
5.3.5.2
Intra-prostatic injections
5.3.5.3
Non-ablative techniques under investigation
5.3.5.3.1
(i)TIND
5.4
Patient selection
5.5
Management of Nocturia in men with lower urinary tract symptoms
5.5.1
Diagnostic assessment
5.5.2
Medical conditions and sleep disorders Shared Care Pathway
5.5.3
Treatment for Nocturia
5.5.3.1
Antidiuretic therapy
5.5.3.2
Medications to treat LUTD
5.5.3.3
Other medications
25
25
26
28
28
28
30
30
31
31
31
32
33
34
35
36
36
36
37
37
38
39
39
40
40
41
42
42
42
42
43
44
44
44
47
47
47
49
49
50
50
6.
FOLLOW-UP
6.1
Watchful waiting (behavioural)
6.2
Medical treatment
6.3
Surgical treatment
51
51
51
52
7.
REFERENCES
52
8.
CONFLICT OF INTEREST
81
9.
CITATION INFORMATION
81
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
3
1.
INTRODUCTION
1.1
Aim and objectives
Lower urinary tract symptoms (LUTS) are a common complaint in adult men with a major impact on quality
of life (QoL), and have a substantial economic burden. The present Guidelines offer practical evidence-based
guidance on the assessment and treatment of men aged 40 years or older with various non-neurogenic
benign forms of LUTS. The understanding of the LUT as a functional unit, and the multifactorial aetiology of
associated symptoms, means that LUTS now constitute the main focus, rather than the former emphasis
on Benign Prostatic Hyperplasia (BPH). The term BPH is now regarded as inappropriate as it is Benign
Prostatic Obstruction (BPO) that is treated if the obstruction is a significant cause of a man’s LUTS. It must
be emphasised that clinical guidelines present the best evidence available to the experts. However, following
guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace
clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions
- also taking personal values and preferences/individual circumstances of patients into account. Guidelines are
not mandates and do not purport to be a legal standard of care.
1.2
Panel composition
The EAU Non-neurogenic Male LUTS Guidelines Panel consists of an international group of experts with
urological and clinical epidemiological backgrounds. All experts involved in the production of this document
have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb:
http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/.
1.3
Available publications
A quick reference document, the Pocket Guidelines, is available in print and as an app for iOS and Android
devices. These are abridged versions which may require consultation together with the full text version. All
documents are accessible through the EAU website Uroweb: http://www.uroweb.org/guideline/treatment-ofnon-neurogenic-male-luts/.
1.4
Publication history
The Non-neurogenic Male LUTS Guidelines was first published in 2000. The 2021 document presents a limited
update of the 2020 publication; the next full update of the Non-neurogenic Male LUTS Guidelines will be
presented in 2022.
2.
METHODS
2.1
Introduction
For the 2021 Management of Non-Neurogenic Male LUTS Guidelines, a detailed review and restructuring of
section 5.3 Surgical Treatment has been undertaken. Section 5.3 has been restructured to reflect surgical
approach rather than specific technologies and is now divided into five sections: resection; enucleation;
vaporisation; alternative ablative techniques; and non-ablative techniques. The literature cut-off date for section
5.3 is April 2019. In addition, a broad and comprehensive literature search related to Serenoa repens in section
5.2.5 Plant extracts – phytotherapy was performed covering the timeframe between the search cut-off date of
the EU monograph on S. repens [1] and April 2020. A detailed search strategy is available online: http://www.
uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/supplementary-material.
For each recommendation within the guidelines there is an accompanying online strength rating form, the
bases of which is a modified GRADE methodology [2, 3]. Each strength rating form addresses a number of key
elements namely:
1.the overall quality of the evidence which exists for the recommendation, references used in
this text are graded according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [4];
2.
the magnitude of the effect (individual or combined effects);
3.the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
4.
the balance between desirable and undesirable outcomes;
5.
the impact of patient values and preferences on the intervention;
6.
the certainty of those patient values and preferences.
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MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
These key elements are the basis which panels use to define the strength rating of each recommendation.
The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [5]. The strength of each
recommendation is determined by the balance between desirable and undesirable consequences of alternative
management strategies, the quality of the evidence (including certainty of estimates), and nature and variability
of patient values and preferences.
Additional information can be found in the general Methodology section of this print, and online at
the EAU website; http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can
also be viewed online at the above address.
2.2
Review
The Non-Neurogenic Male LUTS Guidelines were peer reviewed prior to publication in 2016.
2.3
Patients to whom the guidelines apply
Recommendations apply to men aged 40 years or older who seek professional help for LUTS in various nonneurogenic and non-malignant conditions such as BPO, detrusor overactivity/overactive bladder (OAB), or
nocturnal polyuria. Men with other associated factors relevant to LUT disease (e.g. concomitant neurological
diseases, young age, prior LUT disease or surgery) usually require a more extensive work-up, which is not
covered in these Guidelines, but may include several tests mentioned in the following sections. EAU Guidelines
on Neuro-Urology, Urinary Incontinence, Urological Infections, Urolithiasis, or malignant diseases of the LUT
have been developed by other EAU Guidelines Panels and are available online: www.uroweb.org/guidelines/.
3.
EPIDEMIOLOGY, AETIOLOGY AND
PATHOPHYSIOLOGY
Lower urinary tract symptoms can be divided into storage, voiding and post-micturition symptoms [6], they
are prevalent, cause bother and impair QoL [7-10]. An increasing awareness of LUTS and storage symptoms
in particular, is warranted to discuss management options that could increase QoL [11]. Lower urinary tract
symptoms are strongly associated with ageing [7, 8], associated costs and burden are therefore likely to
increase with future demographic changes [8, 12]. Lower urinary tract symptoms are also associated with a
number of modifiable risk factors, suggesting potential targets for prevention (e.g. metabolic syndrome) [13]. In
addition, men with moderate-to-severe LUTS may have an increased risk of major adverse cardiac events [14].
Most elderly men have at least one LUTS [8]; however, symptoms are often mild or not very
bothersome [10, 11, 15]. Lower urinary tract symptoms can progress dynamically: for some individuals LUTS
persist and progress over long time periods, and for others they remit [8]. Lower urinary tract symptoms
have traditionally been related to bladder outlet obstruction (BOO), most frequently when histological BPH
progresses through benign prostatic enlargement (BPE) to BPO [6, 9]. However, increasing numbers of studies
have shown that LUTS are often unrelated to the prostate [8, 16]. Bladder dysfunction may also cause LUTS,
including detrusor overactivity/OAB, detrusor underactivity/underactive bladder, as well as other structural
or functional abnormalities of the urinary tract and its surrounding tissues [16]. Prostatic inflammation also
appears to play a role in BPH pathogenesis and progression [17, 18]. In addition, many non-urological
conditions also contribute to urinary symptoms, especially nocturia [8].
The definitions of the most common conditions related to male LUTS are presented below:
•
Acute retention of urine is defined as a painful, palpable or percussible bladder, when the patient is
unable to pass any urine [6].
•
Chronic retention of urine is defined as a non-painful bladder, which remains palpable or percussible after
the patient has passed urine. Such patients may be incontinent [6].
•
Bladder outlet obstruction is the generic term for obstruction during voiding and is characterised
by increasing detrusor pressure and reduced urine flow rate. It is usually diagnosed by studying the
synchronous values of flow-rate and detrusor pressure [6].
•
Benign prostatic obstruction is a form of BOO and may be diagnosed when the cause of outlet
obstruction is known to be BPE [6]. In the Guidelines the term BPO or BOO is used as reported by the
original studies.
•
Benign prostatic hyperplasia is a term used (and reserved) for the typical histological pattern, which
defines the disease.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
5
•
•
Detrusor overactivity (DO) is a urodynamic observation characterised by involuntary detrusor contractions
during the filling phase which may be spontaneous or provoked [6]. Detrusor overactivity is usually
associated with overactive bladder syndrome characterised by urinary urgency, with or without urgency
urinary incontinence, usually with increased daytime frequency and nocturia, if there is no proven
infection or other obvious pathology [19].
Detrusor underactivity (DU) during voiding is characterised by decreased detrusor voiding pressure
leading to a reduced urine flow rate. Detrusor underactivity causes underactive bladder syndrome which
is characterised by voiding symptoms similar to those caused by BPO [20].
Figure 1 illustrates the potential causes of LUTS. In any man complaining of LUTS, it is common for more than
one of these factors to be present.
Figure 1: Causes of male LUTS
Overacve
bladder/
Detrusor
overacvity
Benign
prostac
obstrucon
Others
Distal
ureteric
stone
Nocturnal
polyuria
Underacve
bladder/
Detrusor
underacvity
Bladder
tumour
LUTS
Chronic
Pelvic Pain
syndrome
Urethral
stricture
Neurogenic
bladder
dysfuncon
4.
Urinary tract
infecon /
Inflammaon
Foreign
body
DIAGNOSTIC EVALUATION
Tests are useful for diagnosis, monitoring, assessing the risk of disease progression, treatment planning, and
the prediction of treatment outcomes. The clinical assessment of patients with LUTS has two main objectives:
•
to identify the differential diagnoses, since the origin of male LUTS is multifactorial, the relevant EAU
Guidelines on the management of applicable conditions should be followed;
•
to define the clinical profile (including the risk of disease progression) of men with LUTS in order to
provide appropriate care.
4.1
Medical history
The importance of assessing the patient’s history is well recognised [21-23]. A medical history aims to identify
the potential causes and relevant comorbidities, including medical and neurological diseases. In addition,
6
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
current medication, lifestyle habits, emotional and psychological factors must be reviewed. The Panel
recognises the need to discuss LUTS and the therapeutic pathway from the patient’s perspective. This includes
reassuring the patient that there is no definite link between LUTS and prostate cancer (PCa) [24, 25].
As part of the urological/surgical history, a self-completed validated symptom questionnaire (see
section 4.2) should be obtained to objectify and quantify LUTS. Bladder diaries or frequency volume charts are
particularly beneficial when assessing patients with nocturia and/or storage symptoms (see section 4.3). Sexual
function should also be assessed, preferably with validated symptom questionnaires such as the International
Index for Erectile Function (IIEF) [26].
Summary of evidence
A medical history is an integral part of a patient’s medical evaluation.
A medical history aims to identify the potential causes of LUTS as well as any relevant comorbidities
and to review the patient’s current medication and lifestyle habits.
Recommendation
Take a complete medical history from men with LUTS.
4.2
LE
4
4
Strength rating
Strong
Symptom score questionnaires
All published guidelines for male LUTS recommend using validated symptom score questionnaires [21, 23].
Several questionnaires have been developed which are sensitive to symptom changes and can be used to
monitor treatment [27-33]. Symptom scores are helpful in quantifying LUTS and in identifying which type of
symptoms are predominant; however, they are not disease-, gender-, or age-specific. A systematic review (SR)
evaluating the diagnostic accuracy of individual symptoms and questionnaires, compared with urodynamic
studies (the reference standard), for the diagnosis of BOO in males with LUTS found that individual symptoms
and questionnaires for diagnosing BOO were not significantly associated with one another [34].
4.2.1
The International Prostate Symptom Score (IPSS)
The IPSS is an eight-item questionnaire, consisting of seven symptom questions and one QoL question [28].
The IPSS score is categorised as ‘asymptomatic’ (0 points), ‘mildly symptomatic’ (1-7 points), ‘moderately
symptomatic’ (8-19 points), and ‘severely symptomatic’ (20-35 points). Limitations include lack of assessment
of incontinence, post-micturition symptoms, and bother caused by each separate symptom.
4.2.2
The International Consultation on Incontinence Questionnaire (ICIQ-MLUTS)
The ICIQ-MLUTS was created from the International Continence Society (ICS) Male questionnaire. It is a widely
used and validated patient completed questionnaire including incontinence questions and bother for each
symptom [29]. It contains thirteen items, with subscales for nocturia and OAB, and is available in seventeen
languages.
4.2.3
Danish Prostate Symptom Score (DAN-PSS)
The DAN-PSS [32] is a symptom score used mainly in Denmark and Finland. The DAN-PSS also has questions
on incontinence and measures the bother of each individual LUTS.
Summary of evidence
LE
Symptom questionnaires are sensitive to symptom changes.
3
Symptom scores can quantify LUTS and identify which types of symptoms are predominant; however, 3
they are not disease-, gender-, or age-specific.
Recommendation
Use a validated symptom score questionnaire including bother and quality of life
assessment during the assessment of male LUTS and for re-evaluation during and/or after
treatment.
4.3
Strength rating
Strong
Frequency volume charts and bladder diaries
The recording of volume and time of each void by the patient is referred to as a frequency volume chart (FVC).
Inclusion of additional information such as fluid intake, use of pads, activities during recording, or which grades
of symptom severity and bladder sensation is termed a bladder diary [6]. Parameters that can be derived from
the FVC and bladder diary include: day-time and night-time voiding frequency, total voided volume, the fraction
of urine production during the night (nocturnal polyuria index), and volume of individual voids.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
7
The mean 24-hour urine production is subject to considerable variation. Likewise, circumstantial
influence and intra-individual variation cause FVC parameters to fluctuate, though there is comparatively little
data [35, 36]. The FVC/bladder diary is particularly relevant in nocturia, where it underpins the categorisation
of underlying mechanism(s) [37-39]. The use of FVCs may cause a ‘bladder training effect’ and influence the
frequency of nocturnal voids [40].
The duration of the FVC/bladder diary needs to be long enough to avoid sampling errors, but short
enough to avoid non-compliance [41]. A SR of the available literature recommended FVCs should continue for
three or more days [42]. The ICIQ-Bladder diary (ICIQ-BD) is the only diary that has undergone full validation [43].
Summary of evidence
Frequency volume charts and bladder diaries provide real-time documentation of urinary function and
reduce recall bias.
Three and seven day FVCs provide reliable measurement of urinary symptoms in patients with LUTS.
LE
3
2b
Recommendations
Strength rating
Use a bladder diary to assess male LUTS with a prominent storage component or nocturia. Strong
Tell the patient to complete a bladder diary for at least three days.
4.4
Strong
Physical examination and digital-rectal examination
Physical examination particularly focusing on the suprapubic area, the external genitalia, the perineum and
lower limbs should be performed. Urethral discharge, meatal stenosis, phimosis and penile cancer must be
excluded.
4.4.1
Digital-rectal examination and prostate size evaluation
Digital-rectal examination (DRE) is the simplest way to assess prostate volume, but the correlation to prostate
volume is poor. Quality-control procedures for DRE have been described [44]. Transrectal ultrasound (TRUS)
is more accurate in determining prostate volume than DRE. Underestimation of prostate volume by DRE
increases with increasing TRUS volume, particularly where the volume is > 30 mL [45]. A model of visual aids
has been developed to help urologists estimate prostate volume more accurately [46]. One study concluded
that DRE was sufficient to discriminate between prostate volumes > or < 50 mL [47].
Summary of evidence
Physical examination is an integral part of a patient’s medical evaluation.
Digital-rectal examination can be used to assess prostate volume; however, the correlation to actual
prostate volume is poor.
Recommendation
Perform a physical examination including digital rectal examination in the assessment of
male LUTS.
4.5
LE
4
3
Strength rating
Strong
Urinalysis
Urinalysis (dipstick or sediment) must be included in the primary evaluation of any patient presenting with LUTS
to identify conditions, such as urinary tract infections (UTI), microhaematuria and diabetes mellitus. If abnormal
findings are detected further tests are recommended according to other EAU Guidelines, e.g. Guidelines on
urinary tract cancers and urological infections [48-51].
Urinalysis is recommended in most Guidelines in the primary management of patients with LUTS
[52, 53]. There is limited evidence, but general expert consensus suggests that the benefits outweigh the costs
[54]. The value of urinary dipstick/microscopy for diagnosing UTI in men with LUTS without acute frequency
and dysuria has been questioned [55].
Summary of evidence
Urinalysis (dipstick or sediment) may indicate a UTI, proteinuria, haematuria or glycosuria requiring
further assessment.
The benefits of urinalysis outweigh the costs.
8
LE
3
4
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Recommendation
Use urinalysis (by dipstick or urinary sediment) in the assessment of male LUTS.
4.6
Strength rating
Strong
Prostate-specific antigen (PSA)
4.6.1
PSA and the prediction of prostatic volume
Pooled analysis of placebo-controlled trials of men with LUTS and presumed BPO showed that PSA has a
good predictive value for assessing prostate volume, with areas under the curve (AUC) of 0.76-0.78 for various
prostate volume thresholds (30 mL, 40 mL, and 50 mL). To achieve a specificity of 70%, whilst maintaining
a sensitivity between 65-70%, approximate age-specific criteria for detecting men with prostate glands
exceeding 40 mL are PSA > 1.6 ng/mL, > 2.0 ng/mL, and > 2.3 ng/mL, for men with BPH in their 50s, 60s, and
70s, respectively [56].
A strong association between PSA and prostate volume was found in a large community-based
study in the Netherlands [57]. A PSA threshold value of 1.5 ng/mL could best predict a prostate volume of
> 30 mL, with a positive predictive value (PPV) of 78%. The prediction of prostate volume can also be based on
total and free PSA. Both PSA forms predict the TRUS prostate volume (± 20%) in > 90% of the cases [58, 59].
4.6.2
PSA and the probability of PCa
The role of PSA in the diagnosis of PCa is presented by the EAU Guidelines on Prostate Cancer [60]. The
potential benefits and harms of using serum PSA testing to diagnose PCa in men with LUTS should be
discussed with the patient.
4.6.3
PSA and the prediction of BPO-related outcomes
Serum PSA is a stronger predictor of prostate growth than prostate volume [61]. In addition, the PLESS study
showed that PSA also predicted the changes in symptoms, QoL/bother, and maximum flow-rate (Qmax) [62].
In a longitudinal study of men managed conservatively, PSA was a highly significant predictor of clinical
progression [63, 64]. In the placebo arms of large double-blind studies, baseline serum PSA predicted the
risk of acute urinary retention (AUR) and BPO-related surgery [65, 66]. An equivalent link was also confirmed
by the Olmsted County Study. The risk for treatment was higher in men with a baseline PSA of > 1.4 ng/mL
[67]. Patients with BPO seem to have a higher PSA level and larger prostate volumes. The PPV of PSA for the
detection of BPO was recently shown to be 68% [68]. Furthermore, in an epidemiological study, elevated free
PSA levels could predict clinical BPH, independent of total PSA levels [69].
Summary of evidence
Prostate-specific antigen has a good predictive value for assessing prostate volume and is a strong
predictor of prostate growth.
Baseline PSA can predict the risk of AUR and BPO-related surgery.
Recommendations
Measure prostate-specific antigen (PSA) if a diagnosis of prostate cancer will change
management.
Measure PSA if it assists in the treatment and/or decision making process.
4.7
LE
1b
1b
Strength rating
Strong
Strong
Renal function measurement
Renal function may be assessed by serum creatinine or estimated glomerular filtration rate (eGFR).
Hydronephrosis, renal insufficiency or urinary retention are more prevalent in patients with signs or symptoms
of BPO [70]. Even though BPO may be responsible for these complications, there is no conclusive evidence on
the mechanism [71].
One study reported that 11% of men with LUTS had renal insufficiency [70]. Neither symptom score
nor QoL was associated with the serum creatinine level. Diabetes mellitus or hypertension were the most
likely causes of the elevated creatinine concentration. Comiter et al. [72] reported that non-neurogenic voiding
dysfunction is not a risk factor for elevated creatinine levels. Koch et al. [73] concluded that only those with an
elevated creatinine level require investigational ultrasound (US) of the kidney.
In the Olmsted County Study community-dwelling men there was a cross-sectional association
between signs and symptoms of BPO (though not prostate volume) and chronic kidney disease (CKD) [74].
In 2,741 consecutive patients who presented with LUTS, decreased Qmax, a history of hypertension and/or
diabetes were associated with CKD [75]. Another study demonstrated a correlation between Qmax and eGFR in
middle-aged men with moderate-to-severe LUTS [76]. Patients with renal insufficiency are at an increased risk
of developing post-operative complications [77].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
9
Summary of evidence
Decreased Qmax and a history of hypertension and/or diabetes are associated with CKD in patients
who present with LUTS.
Patients with renal insufficiency are at an increased risk of developing post-operative complications.
Recommendation
Assess renal function if renal impairment is suspected based on history and clinical
examination, or in the presence of hydronephrosis, or when considering surgical treatment
for male LUTS.
4.8
LE
3
3
Strength rating
Strong
Post-void residual urine
Post-void residual (PVR) urine can be assessed by transabdominal US, bladder scan or catheterisation.
Post-void residual is not necessarily associated with BOO, since high PVR volumes can be
a consequence of obstruction and/or poor detrusor function (DU) [78, 79]. Using a PVR threshold of
50 mL, the diagnostic accuracy of PVR measurement has a PPV of 63% and a negative predictive value
(NPV) of 52% for the prediction of BOO [80]. A large PVR is not a contraindication to watchful waiting (WW)
or medical therapy, although it may indicate a poor response to treatment and especially to WW. In both
the MTOPS and ALTESS studies, a high baseline PVR was associated with an increased risk of symptom
progression [65, 66].
Monitoring of changes in PVR over time may allow for identification of patients at risk of AUR [81].
This is of particular importance for the treatment of patients using antimuscarinic medication. In contrast,
baseline PVR has little prognostic value for the risk of BPO-related invasive therapy in patients on α1-blockers
or WW [82]. However, due to large test-retest variability and lack of outcome studies, no PVR threshold for
treatment decision has yet been established; this is a research priority.
Summary of evidence
The diagnostic accuracy of PVR measurement, using a PVR threshold of 50 mL, has a PPV of 63%
and a NPV of 52% for the prediction of BOO.
Monitoring of changes in PVR over time may allow for identification of patients at risk of AUR.
Recommendation
Measure post-void residual in the assessment of male LUTS.
4.9
LE
3
3
Strength rating
Weak
Uroflowmetry
Urinary flow rate assessment is a widely used non-invasive urodynamic test. Key parameters are Qmax and
flow pattern. Uroflowmetry parameters should preferably be evaluated with voided volume > 150 mL. As Qmax
is prone to within-subject variation [83, 84], it is useful to repeat uroflowmetry measurements, especially if the
voided volume is < 150 mL, or Qmax or flow pattern is abnormal.
The diagnostic accuracy of uroflowmetry for detecting BOO varies considerably and is substantially
influenced by threshold values. A threshold Qmax of 10 mL/s has a specificity of 70%, a PPV of 70% and a
sensitivity of 47% for BOO. The specificity using a threshold Qmax of 15 mL/s was 38%, the PPV 67% and the
sensitivity 82% [85]. If Qmax is > 15 mL/s, physiological compensatory processes mean that BOO cannot be
excluded. Low Qmax can arise as a consequence of BOO [86], DUA or an under-filled bladder [87]. Therefore,
it is limited as a diagnostic test as it is unable to discriminate between the underlying mechanisms. Specificity
can be improved by repeated flow rate testing. Uroflowmetry can be used for monitoring treatment outcomes
[88] and correlating symptoms with objective findings.
Summary of evidence
The diagnostic accuracy of uroflowmetry for detecting BOO varies considerably and is substantially
influenced by threshold values. Specificity can be improved by repeated flow rate testing.
LE
2b
Recommendations
Perform uroflowmetry in the initial assessment of male LUTS.
Strength rating
Weak
Perform uroflowmetry prior to medical or invasive treatment.
Strong
10
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
4.10
Imaging
4.10.1
Upper urinary tract
Men with LUTS are not at increased risk for upper tract malignancy or other abnormalities when compared to
the overall population [73, 89-91]. Several arguments support the use of renal US in preference to intravenous
urography. Ultrasound allows for better characterisation of renal masses, the possibility of investigating the liver
and retroperitoneum, and simultaneous evaluation of the bladder, PVR and prostate, together with a lower cost,
radiation dose and less side effects [89]. Ultrasound can be used for the evaluation of men with large PVR,
haematuria, or a history of urolithiasis.
Summary of evidence
Men with LUTS are not at increased risk for upper tract malignancy or other abnormalities when
compared to the overall population.
Ultrasound can be used for the evaluation of men with large PVR, haematuria, or a history of
urolithiasis.
Recommendation
Perform ultrasound of the upper urinary tract in men with LUTS.
LE
3
4
Strength rating
Weak
4.10.2
Prostate
Imaging of the prostate can be performed by transabdominal US, TRUS, computed tomography (CT),
and magnetic resonance imaging (MRI). However, in daily practice, prostate imaging is performed by
transabdominal (suprapubic) US or TRUS [89].
4.10.2.1 Prostate size and shape
Assessment of prostate size is important for the selection of interventional treatment, i.e. open prostatectomy
(OP), enucleation techniques, transurethral resection, transurethral incision of the prostate (TUIP), or minimally
invasive therapies. It is also important prior to treatment with 5α-reductase inhibitors (5-ARIs). Prostate volume
predicts symptom progression and the risk of complications [91].
Transrectal US is superior to transabdominal volume measurement [92, 93]. The presence of a
median lobe may guide treatment choice in patients scheduled for a minimally invasive approach since medial
lobe presence can be a contraindication for some minimally invasive treatments (see section 5.3).
Summary of evidence
Assessment of prostate size by TRUS or transabdominal US is important for the selection of
interventional treatment and prior to treatment with 5-ARIs.
Recommendations
Perform imaging of the prostate when considering medical treatment for male LUTS, if it
assists in the choice of the appropriate drug.
Perform imaging of the prostate when considering surgical treatment.
LE
3
Strength rating
Weak
Strong
4.10.3
Voiding cysto-urethrogram
Voiding cysto-urethrogram (VCUG) is not recommended in the routine diagnostic work-up of men with LUTS,
but it may be useful for the detection of vesico-ureteral reflux, bladder diverticula, or urethral pathologies.
Retrograde urethrography may additionally be useful for the evaluation of suspected urethral strictures.
4.11
Urethrocystoscopy
Patients with a history of microscopic or gross haematuria, urethral stricture, or bladder cancer, who present
with LUTS, should undergo urethrocystoscopy during diagnostic evaluation. The evaluation of a prostatic
middle lobe with urethrocystocopy should be performed when considering interventional treatments for which
the presence of middle lobe is a contraindication.
A prospective study evaluated 122 patients with LUTS using uroflowmetry and urethrocystoscopy
[94]. The pre-operative Qmax was normal in 25% of 60 patients who had no bladder trabeculation, 21% of
73 patients with mild trabeculation and 12% of 40 patients with marked trabeculation on cystoscopy. All 21
patients who presented with diverticula had a reduced Qmax.
Another study showed that there was no significant correlation between the degree of bladder
trabeculation (graded from I to IV), and the pre-operative Qmax value in 39 symptomatic men aged 53-83 years
[95]. The largest study published on this issue examined the relation of urethroscopic findings to urodynamic
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
11
studies in 492 elderly men with LUTS [96]. The authors noted a correlation between cystoscopic appearance
(grade of bladder trabeculation and urethral occlusion) and urodynamic indices, DO and low compliance. It
should be noted, however, that BOO was present in 15% of patients with normal cystoscopic findings, while
8% of patients had no obstruction, even in the presence of severe trabeculation [96].
Summary of evidence
Patients with a history of microscopic or gross haematuria, urethral stricture, or bladder cancer, who
present with LUTS, should undergo urethrocystoscopy during diagnostic evaluation.
None of the studies identified a strong association between the urethrocystoscopic and urodynamic
findings.
Recommendation
Perform urethrocystoscopy in men with LUTS prior to minimally invasive/surgical therapies
if the findings may change treatment.
4.12
LE
3
3
Strength rating
Weak
Urodynamics
In male LUTS, the most widespread invasive urodynamic techniques employed are filling cystometry and
pressure flow studies (PFS). The major goal of urodynamics is to explore the functional mechanisms of LUTS,
to identify risk factors for adverse outcomes and to provide information for shared decision-making. Most
terms and conditions (e.g. DO, low compliance, BOO/BPO, DUA) are defined by urodynamic investigation.
4.12.1
Diagnosing bladder outlet obstruction
Pressure flow studies (PFS) are used to diagnose and define the severity of BOO, which is characterised by
increased detrusor pressure and decreased urinary flow rate during voiding. Bladder outlet obstruction/BPO
has to be differentiated from DUA, which exhibits decreased detrusor pressure during voiding in combination
with decreased urinary flow rate [6].
Urodynamic testing may also identify DO. Studies have described an association between BOO and
DO [97, 98]. In men with LUTS attributed to BPO, DO was present in 61% and independently associated with
BOO grade and ageing [97].
The prevalence of DUA in men with LUTS is 11-40% [99, 100]. Detrusor contractility does not
appear to decline in long-term BOO and surgical relief of BOO does not improve contractility [101, 102]. There
are no published RCTs in men with LUTS and possible BPO that compare the standard practice investigation
(uroflowmetry and PVR measurement) with PFS with respect to the outcome of treatment; however, a study has
been completed in the UK, but the final results have not yet been published [103, 104]. Once available they will
be included in the next edition of the Guidelines.
A Cochrane meta-analysis was done to determine whether performing invasive urodynamic
investigation reduces the number of men with continuing symptoms of voiding dysfunction. Two trials with 350
patients were included. Invasive urodynamic testing changed clinical decision making. Patients who underwent
urodynamics were less likely to undergo surgery; however, no evidence was found to demonstrate whether
this led to reduced symptoms of voiding dysfunction after treatment [105]. A more recent meta-analysis of
retrospective studies showed that pre-operative urodynamic DOA has no diagnostic role in the prediction of
surgical outcomes in patients with male BOO [106].
Due to the invasive nature of the test, a urodynamic investigation is generally only offered if
conservative treatment has failed. The Guidelines Panel attempted to identify specific indications for PFS
based on age, findings from other diagnostic tests and previous treatments. The Panel allocated a different
degree of obligation for PFS in men > 80 years and men < 50 years, which reflects the lack of evidence. In
addition, there was no consensus whether PFS should or may be performed when considering surgery in men
with bothersome predominantly voiding LUTS and Qmax > 10 mL/s, although the Panel recognised that with a
Qmax < 10 mL/s, BOO is likely and PFS is not necessarily needed.
Patients with neurological disease, including those with previous radical pelvic surgery, should be
assessed according to the EAU Guidelines on Neuro-Urology [107].
4.12.2
Videourodynamics
Videourodynamics provides additional anatomical and functional information and may be recommended if the
clinician considers this is needed to understand the pathophysiological mechanism of an individual patient’s
LUTS.
12
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Summary of evidence
Within the literature cut-off dates of the 2021 edition of the Guidelines there were no RCTs in men
with LUTS and possible BPO that compare the standard practice investigation (uroflowmetry and
PVR measurement) with PFS with respect to the outcome of treatment. All subsequent RCTs will be
evaluated for inclusion in the next edition of the Guidelines.
Recommendations
LE
3
Strength rating
Perform pressure-flow studies (PFS) only in individual patients for specific indications prior Weak
to invasive treatment or when further evaluation of the underlying pathophysiology of LUTS
is warranted.
Perform PFS in men who have had previous unsuccessful (invasive) treatment for LUTS.
Weak
Perform PFS in men considering invasive treatment who cannot void > 150 mL.
Weak
Perform PFS when considering surgery in men with bothersome predominantly voiding
LUTS and Qmax > 10 mL/s.
Perform PFS when considering invasive therapy in men with bothersome, predominantly
voiding LUTS with a post void residual > 300 mL.
Perform PFS when considering invasive treatment in men with bothersome, predominantly
voiding LUTS aged > 80 years.
Perform PFS when considering invasive treatment in men with bothersome, predominantly
voiding LUTS aged < 50 years.
Weak
4.13
Weak
Weak
Weak
Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS
4.13.1
Prostatic configuration/intravesical prostatic protrusion (IPP)
Prostatic configuration can be evaluated with TRUS, using the concept of the presumed circle area ratio
(PCAR) [108]. The PCAR evaluates how closely the transverse US image of the prostate approaches a circular
shape. The ratio tends toward one as the prostate becomes more circular. The sensitivity of PCAR was 77% for
diagnosing BPO when PCAR was > 0.8, with 75% specificity [108].
Ultrasound measurement of IPP assesses the distance between the tip of the prostate median
lobe and bladder neck in the midsagittal plane, using a suprapubically positioned US scanner, with a bladder
volume of 150-250 mL; grade I protrusion is 0-4.9 mm, grade II is 5-10 mm and grade III is > 10 mm.
Intravesical prostatic protrusion correlates well with BPO (presence and severity) on urodynamic
testing, with a PPV of 94% and a NPV of 79% [109]. Intravesical prostatic protrusion may also correlate with
prostate volume, DO, bladder compliance, detrusor pressure at maximum urinary flow, BOO index and PVR,
and negatively correlates with Qmax [110]. Furthermore, IPP also appears to successfully predict the outcome
of a trial without catheter after AUR [111, 112]. However, no information with regard to intra- or inter-observer
variability and learning curve is yet available. Therefore, whilst IPP may be a feasible option to infer BPO in men
with LUTS, the role of IPP as a non-invasive alternative to PFS in the assessment of male LUTS remains under
evaluation.
4.13.2
Bladder/detrusor wall thickness and ultrasound-estimated bladder weight
For bladder wall thickness (BWT) assessment, the distance between the mucosa and the adventitia is
measured. For detrusor wall thickness (DWT) assessment, the only measurement needed is the detrusor
sandwiched between the mucosa and adventitia [113].
A correlation between BWT and PFS parameters has been reported. A threshold value of 5 mm
at the anterior bladder wall with a bladder filling of 150 mL was best at differentiating between patients with
or without BOO [114]. Detrusor wall thickness at the anterior bladder wall with a bladder filling > 250 mL
(threshold value for BOO > 2 mm) has a PPV of 94% and a specificity of 95%, achieving 89% agreement with
PFS [73]. Threshold values of 2.0, 2.5, or 2.9 mm for DWT in patients with LUTS are able to identify 81%, 89%,
and 100% of patients with BOO, respectively [115].
All studies found that BWT or DWT measurements have a higher diagnostic accuracy for detecting
BOO than Qmax or Qave of free uroflowmetry, measurements of PVR, prostate volume, or symptom severity. One
study could not demonstrate any difference in BWT between patients with normal urodynamics, BOO or DO.
However, the study did not use a specific bladder filling volume for measuring BWT [116]. Disadvantages of the
method include the lack of standardisation, and lack of evidence to indicate which measurement (BWT/DWT) is
preferable [117]. Measurement of BWT/DWT is therefore not recommended for the diagnostic work-up of men
with LUTS.
Ultrasound-estimated bladder weight (UEBW) may identify BOO with a diagnostic accuracy of 86%
at a cut-off value of 35 g [118, 119]. Severe LUTS and a high UEBW (> 35 g) are risk factors for prostate/BPH
surgery in men on α-blockers [120].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
13
4.13.3
Non-invasive pressure-flow testing
The penile cuff method, in which flow is interrupted to estimate isovolumetric bladder pressure, shows
promising data, with good test repeatability [121] and interobserver agreement [122]. A nomogram has also
been derived [123] whilst a method in which flow is not interrupted is also under investigation [124].
The data generated with the external condom method [125] correlates with invasive PFS in a high
proportion of patients [126]. Resistive index [127] and prostatic urethral angle [128] have also been proposed,
but are still experimental.
The diagnostic performance of non-invasive tests in diagnosing bladder outlet obstruction in
men with LUTS compared with pressure-flow studies
The diagnostic performance of non-invasive tests in diagnosing BOO in men with LUTS compared with PFS
has been investigated in a SR [129]. A total of 42 studies were included is this review. The majority were
prospective cohort studies, and the diagnostic accuracy of the following non-invasive tests were assessed:
penile cuff test; uroflowmetry; detrusor/bladder wall thickness; bladder weight; external condom catheter
method; IPP; Doppler US; prostate volume/height; and near-infrared spectroscopy. Overall, although the
majority of studies have a low risk of bias, data regarding the diagnostic accuracy of these non-invasive tests
is limited by the heterogeneity of the studies in terms of the threshold values used to define BOO, the different
urodynamic definitions of BOO used across different studies and the small number of studies for each test. It
was found that specificity, sensitivity, PPV and NPV of the non-invasive tests were highly variable. Therefore,
even though several tests have shown promising results regarding non-invasive diagnosis of BOO, invasive
urodynamics remains the modality of choice.
4.13.4
Summary of evidence
Data regarding the diagnostic accuracy of non-invasive tests is limited by the heterogeneity of the
studies as well as the small number of studies for each test.
Specificity, sensitivity, PPV and NPV of the non-invasive tests were highly variable.
Recommendation
Do not offer non-invasive tests as an alternative to pressure-flow studies for diagnosing
bladder outlet obstruction in men.
14
LE
1a
1a
Strength rating
Strong
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Figure 2: Assessment algorithm of LUTS in men aged 40 years or older
Readers are strongly recommended to read the full text that highlights the current position of each test in detail.
Male LUTS
History (+ sexual function)
Symptom score questionnaire
Urinalysis
Physical examination
PSA (if diagnosis of PCa will change the
management – discuss with patient)
Measurement of PVR
Abnormal DRE
Suspicion of
neurological disease
High PSA
Abnormal urinalysis
Evaluate according to
relevant guidelines or
clinical standard
Treat underlying
condition
(if any, otherwise
return to initial
assessment)
Manage according to
EAU mLUTS
treatment algorithm
No
Bothersome
symptoms
Yes
Significant PVR
US of kidneys
+/- Renal function
assessment
FVC in cases of predominant
storage LUTS/nocturia
US assessment of prostate
Uroflowmetry
Medical treatment
according to treatment
algorithm
Benign conditions of
bladder and/or prostate
with baseline values
PLAN TREATMENT
Endoscopy (if test would alter the
choice of surgical modality)
Pressure flow studies (see text for
specific indications)
Surgical treatment according
to treatment algorithm
DRE = digital-rectal examination; FVC = frequency volume chart; LUTS = lower urinary tract symptoms;
PCa = prostate cancer; PSA = prostate specific antigen; PVR = post-void residual; US = ultrasound.
5.
DISEASE MANAGEMENT
5.1
Conservative treatment
5.1.1
Watchful waiting (WW)
Many men with LUTS are not troubled enough by their symptoms to need drug treatment or surgical
intervention. All men with LUTS should be formally assessed prior to any allocation of treatment in order
to establish symptom severity and to differentiate between men with uncomplicated (the majority) and
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
15
complicated LUTS. Watchful waiting is a viable option for many men with non-bothersome LUTS as few will
progress to AUR and complications (e.g. renal insufficiency or stones) [130, 131], whilst others can remain
stable for years [132]. In one study, approximately 85% of men with mild LUTS were stable on WW at one year
[133].
A study comparing WW and transurethral resection of the prostate (TURP) in men with moderate
LUTS showed the surgical group had improved bladder function (flow rates and PVR volumes), especially
in those with high levels of bother; 36% of WW patients crossed over to surgery within five years, leaving
64% doing well in the WW group [134, 135]. Increasing symptom bother and PVR volumes are the strongest
predictors of WW failure. Men with mild-to-moderate uncomplicated LUTS who are not too troubled by their
symptoms are suitable for WW.
5.1.2
Behavioural and dietary modifications
It is customary for this type of management to include the following components:
•
education (about the patient’s condition);
•
reassurance (that cancer is not a cause of the urinary symptoms);
•
periodic monitoring;
•
lifestyle advice [132, 133, 136, 137] such as::
oo
reduction of fluid intake at specific times aimed at reducing urinary frequency when most
inconvenient (e.g. at night or when going out in public);
oo
avoidance/moderation of intake of caffeine or alcohol, which may have a diuretic and irritant effect,
thereby increasing fluid output and enhancing frequency, urgency and nocturia;
oo
use of relaxed and double-voiding techniques;
oo
urethral milking to prevent post-micturition dribble;
oo
distraction techniques such as penile squeeze, breathing exercises, perineal pressure, and mental
tricks to take the mind off the bladder and toilet, to help control OAB symptoms;
oo
bladder retraining that encourages men to hold on when they have urgency to increase their bladder
capacity and the time between voids;
oo
reviewing the medication and optimising the time of administration or substituting drugs for others
that have fewer urinary effects (these recommendations apply especially to diuretics);
oo
providing necessary assistance when there is impairment of dexterity, mobility, or mental state;
oo
treatment of constipation.
There now exists evidence that self-management as part of WW reduces both symptoms and progression
[136, 137]. Men randomised to three self-care management sessions in addition to standard care had better
symptom improvement and QoL than men treated with standard care only, for up to a year [136].
5.1.3
Practical considerations
The components of self-care management have not been individually studied. The above components of
lifestyle advice have been derived from formal consensus methodology [138]. Further research in this area is
required.
Summary of evidence
Watchful waiting is usually a safe alternative for men who are less bothered by urinary difficulty or
who wish to delay treatment. The treatment failure rate over a period of five years was 21%; 79% of
patients were clinically stable.
An additional study reported 81% of patients were clinically stable on WW after a mean follow-up of
seventeen months.
Men randomised to three self-management sessions in addition to standard care had better
symptom improvement and QoL than men treated with standard care alone at up to a year. Self-care
management as part of WW reduces both symptoms and progression.
Recommendations
Offer men with mild/moderate symptoms, minimally bothered by their symptoms, watchful
waiting.
Offer men with LUTS lifestyle advice and self-care information prior to, or concurrent with,
treatment.
16
LE
1b
2
1b
Strength rating
Strong
Strong
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
5.2
Pharmacological treatment
5.2.1
α1-Adrenoceptor antagonists (α1-blockers)
Mechanism of action: α1-blockers aim to inhibit the effect of endogenously released noradrenaline on smooth
muscle cells in the prostate and thereby reduce prostate tone and BOO [139]. However, α1-blockers have little
effect on urodynamically determined bladder outlet resistance [140], and treatment-associated improvement of
LUTS correlates poorly with obstruction [141]. Thus, other mechanisms of action may also be relevant.
Alpha 1-adrenoceptors located outside the prostate (e.g. urinary bladder and/or spinal cord)
and α1-adrenoceptor subtypes (α1B- or α1D-adrenoceptors) may play a role as mediators of effects. Alpha
1-adrenoceptors in blood vessels, other non-prostatic smooth muscle cells, and the central nervous system
may mediate adverse events.
Currently available α1-blockers are: alfuzosin hydrochloride (alfuzosin); doxazosin mesylate
(doxazosin); silodosin; tamsulosin hydrochloride (tamsulosin); terazosin hydrochloride (terazosin); and
naftopidil. Alpha 1-blockers exist in different formulations. Although different formulations result in different
pharmacokinetic and tolerability profiles, the overall difference in clinical efficacy between the difference
formulations seems modest.
Efficacy: Indirect comparisons and limited direct comparisons between α1-blockers demonstrate that all
α1-blockers have a similar efficacy in appropriate doses [142]. Clinical effects take a few weeks to develop
fully, but significant efficacy over placebo can occur within hours to days [141].
Controlled studies show that α1-blockers typically reduce IPSS by approximately 30-40%
and increase Qmax by approximately 20-25%. However, considerable improvements also occurred in the
corresponding placebo arms [63, 143]. In open-label studies, an IPSS improvement of up to 50% and Qmax
increase of up to 40% were documented [63, 143]. A recent SR and meta-analysis suggested that Qmax
variation underestimates the real effect of α1-blockers on BPO, as small improvements in Qmax correspond to
relevant improvements in BOO index in PFS [144].
Alpha 1-blockers can reduce both storage and voiding LUTS. Prostate size does not affect
α1-blocker efficacy in studies with follow-up periods of less than one year, but α1-blockers do seem to be
more efficacious in patients with smaller prostates (< 40 mL) in longer-term studies [65, 145-148]. The efficacy
of α1-blockers is similar across age groups [143]. In addition, α1-blockers neither reduce prostate size nor
prevent AUR in long-term studies [146-148]; however, recent evidence suggests that the use of α1-blockers
(alfuzosin and tamsulosin) may improve resolution of AUR [149]. Nonetheless, IPSS reduction and Qmax
improvement during α1-blocker treatment appears to be maintained over at least four years.
Tolerability and safety: Tissue distribution, subtype selectivity, and pharmacokinetic profiles of certain
formulations may contribute to the tolerability profile of specific drugs. The most frequent adverse events of
α1-blockers are asthenia, dizziness and (orthostatic) hypotension. Vasodilating effects are most pronounced
with doxazosin and terazosin, and are less common with alfuzosin and tamsulosin [150]. Patients with
cardiovascular comorbidity and/or vaso-active co-medication may be susceptible to α1-blocker-induced
vasodilatation [151]. In contrast, the frequency of hypotension with the α1A-selective blocker silodosin is
comparable with placebo [152]. In a large retrospective cohort analysis of men aged > 66 years treated with
α1-blockers the risks of falling (odds ratio [OR] 1.14) and of sustaining a fracture (OR 1.16) was increased, most
likely as a result of induced hypotension [153].
An adverse ocular event termed intra-operative floppy iris syndrome (IFIS) was reported in 2005,
affecting cataract surgery [154]. A meta-analysis on IFIS after alfuzosin, doxazosin, tamsulosin or terazosin
exposure showed an increased risk for all α1-blockers [155]. However, the OR for IFIS was much higher for
tamsulosin. It appears prudent not to initiate α1-blocker treatment prior to scheduled cataract surgery, and the
ophthalmologist should be informed about α1-blocker use.
A SR concluded that α1-blockers do not adversely affect libido, have a small beneficial effect on
erectile function, but can cause abnormal ejaculation [156]. Originally, abnormal ejaculation was thought to be
retrograde, but more recent data demonstrate that it is due to a decrease or absence of seminal fluid during
ejaculation, with young age being an apparent risk factor. In a recent meta-analysis ejaculatory dysfunction
(EjD) was significantly more common with α1-blockers than with placebo (OR 5.88). In particular, EjD was
significantly more commonly related with tamsulosin or silodosin (OR 8.57 and 32.5) than placebo, while
both doxazosin and terazosin (OR 0.80 and 1.78) were associated with a low risk of EjD [157]. In the metaregression, the occurrence of EjD was independently associated with the improvement of urinary symptoms
and flow rate, suggesting that the more effective the α1-blocker is the greater the incidence of EjD.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
17
Practical considerations: α1-blockers are usually considered the first-line drug treatment for male LUTS
because of their rapid onset of action, good efficacy, and low rate and severity of adverse events. However,
α1-blockers do not prevent occurrence of urinary retention or need for surgery. Ophthalmologists should be
informed about α1-blocker use prior to cataract surgery. Elderly patients treated with non-selective α1-blockers
should be informed about the risk of orthostatic hypotension. Sexually active patients treated with selective
α1-blockers should be counselled about the risk of EjD.
Summary of evidence
α1-blockers are effective in reducing urinary symptoms (IPSS) and increasing the peak urinary flow
rate (Qmax) compared with placebo.
Alfuzosin, terazosin and doxazosin showed a statistically significant increased risk of developing
vascular-related events compared with placebo.
Alfuzosin, doxazosin, tamsulosin or terazosin exposure has been associated with an increased risk of
IFIS.
Ejaculatory dysfunction is significantly more common with α1-blockers than with placebo, particularly
with more selective α1-blockers such as tamsulosin and silodosin.
Recommendation
Offer α1-blockers to men with moderate-to-severe LUTS.
LE
1a
1a
1a
1a
Strength rating
Strong
5.2.2
5α-reductase inhibitors
Mechanism of action: Androgen effects on the prostate are mediated by dihydrotestosterone (DHT), which is
converted from testosterone by the enzyme 5α-reductase [158], which has two isoforms:
•
5α-reductase type 1: predominant expression and activity in the skin and liver.
•
5α-reductase type 2: predominant expression and activity in the prostate.
Two 5-ARIs are available for clinical use: dutasteride and finasteride. Finasteride inhibits only 5α-reductase
type 2, whereas dutasteride inhibits both 5α-reductase types (dual 5-ARI). The 5-ARIs induce apoptosis of
prostate epithelial cells [159] leading to prostate size reduction of about 18-28% and a decrease in circulating
PSA levels of about 50% after six to twelve months of treatment [160]. Mean prostate volume and PSA
reduction may be even more pronounced after long-term treatment. Continuous treatment reduces the serum
DHT concentration by approximately 70% with finasteride and 95% with dutasteride. However, prostate DHT
concentration is reduced to a similar level (85-90%) by both 5-ARIs.
Efficacy: Clinical effects relative to placebo are seen after treatment of at least six months. After two to four
years of treatment 5-ARIs improve IPSS by approximately 15-30%, decrease prostate volume by 18-28%, and
increase Qmax by 1.5-2.0 mL/s in patients with LUTS due to prostate enlargement [65, 147, 148, 161-167]. An
indirect comparison and one direct comparative trial (twelve months duration) indicate that dutasteride and
finasteride are equally effective in the treatment of LUTS [160, 168]. Symptom reduction depends on initial
prostate size.
Finasteride may not be more efficacious than placebo in patients with prostates < 40 mL [169].
However, dutasteride seems to reduce IPSS, prostate volume, and the risk of AUR, and to increase Qmax even
in patients with prostate volumes of between 30 and 40 mL [170, 171]. A long-term trial with dutasteride in
symptomatic men with prostate volumes > 30 mL and increased risk for disease progression showed that
dutasteride reduced LUTS at least as much as the α1-blocker tamsulosin [147, 167, 172]. The greater the
baseline prostate volume (or serum PSA level), the faster and more pronounced the symptomatic benefit of
dutasteride as compared to tamsulosin.
5α-reductase inhibitors, but not α1-blockers, reduce the long-term (> 1 year) risk of AUR or need
for surgery [65, 165, 173]. In the PLESS study, finasteride reduced the relative risk of AUR by 57% and need
for surgery by 55% (absolute risk reduction 4% and 7%, respectively) at four years, compared with placebo
[165]. In the MTOPS study, finasteride reduced the relative risk of AUR by 68% and need for surgery by
64% (absolute risk reduction 2% and 3%, respectively), also at four years [65]. A pooled analysis of three
randomised trials with two-year follow-up data, reported that treatment with finasteride decreased the relative
risk of AUR by 57%, and surgical intervention by 34% (absolute risk reduction 2% for both) in patients with
moderately symptomatic LUTS [174]. Dutasteride has also demonstrated efficacy in reducing the risks for AUR
and BPO-related surgery. Open-label trials have demonstrated relevant changes in urodynamic parameters
[175, 176]. Furthermore, finasteride might reduce blood loss during transurethral prostate surgery, probably due
to its effects on prostatic vascularisation [177, 178].
18
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Tolerability and safety: The most common adverse events are reduced libido, erectile dysfunction (ED) and less
frequently, ejaculation disorders such as retrograde ejaculation, ejaculation failure, or decreased semen volume
[65, 148, 160, 179]. Gynaecomastia (with breast or nipple tenderness) develops in 1-2% of patients. Two
studies have suggested that treatment with 5-ARIs is associated with a higher incidence of high-grade cancers
although no causal relationship has been proven [180, 181]. There is a long-standing debate regarding potential
cardiovascular side effects of 5-ARIs, in particular dutasteride [182]. Population-based studies in Taiwan and
Ontario did not find an association between the use of 5-ARIs and increased cardiovascular side effects [182,
183].
Practical considerations: Treatment with 5-ARIs should be considered in men with moderate-to-severe LUTS
and an enlarged prostate (> 40 mL) and/or elevated PSA concentration (> 1.4-1.6 ng/mL). They can reduce the
risk of AUR and need for surgery. Due to the slow onset of action, they are not suitable for short-term use. Their
effect on PSA needs to be considered in relation to PCa screening.
Summary of evidence
After two to four years of treatment, 5-ARIs improve IPSS by approximately 15-30%, decrease
prostate volume by 18-28%, and increase Qmax by 1.5-2.0 mL/s in patients with LUTS due to prostate
enlargement.
5α-reductase inhibitors can prevent disease progression with regard to AUR and the need for surgery.
Due to 5-ARIs slow onset of action, they are suitable only for long-term treatment (years).
The most relevant adverse effects of 5-ARIs are related to sexual function, and include reduced libido,
ED and less frequently, ejaculation disorders such as retrograde ejaculation, ejaculation failure, or
decreased semen volume.
Recommendations
Use 5α-reductase inhibitors in men who have moderate-to-severe LUTS and an increased
risk of disease progression (e.g. prostate volume > 40 mL).
Counsel patients about the slow onset of action of 5α-reductase inhibitors.
LE
1b
1a
1b
Strength rating
Strong
Strong
5.2.3
Muscarinic receptor antagonists
Mechanism of action: The detrusor is innervated by parasympathetic nerves whose main neurotransmitter
is acetylcholine, which stimulates muscarinic receptors (M-cholinoreceptors) on the smooth muscle cells.
Muscarinic receptors are also present on other cell types, such as bladder urothelial cells and epithelial cells
of the salivary glands. Five muscarinic receptor subtypes (M1-M5) have been described, of which M2 and
M3 are predominant in the detrusor. The M2 subtype is more numerous, but the M3 subtype is functionally
more important in bladder contractions [184, 185]. Antimuscarinic effects might also be induced or modulated
through other cell types, such as the bladder urothelium or by the central nervous system [186, 187].
The following muscarinic receptor antagonists are licensed for treating OAB/storage symptoms:
darifenacin hydrobromide (darifenacin); fesoterodine fumarate (fesoterodine); oxybutynin hydrochloride
(oxybutynin); propiverine hydrochloride (propiverine); solifenacin succinate (solifenacin); tolterodine tartrate
(tolterodine); and trospium chloride. Transdermal preparations of oxybutynin have been formulated and
evaluated in clinical trials [188, 189].
Efficacy: Antimuscarinics were mainly tested in females in the past, as it was believed that LUTS in men were
caused by the prostate, so should be treated with prostate-specific drugs. However, there is no scientific
data for this assumption [190]. A sub-analysis of an open-label trial of OAB patients showed that age, but
not gender had an impact on urgency, frequency, or urgency incontinence [191]. In a pooled analysis, which
included a sub-analysis of male patients, fesoterodine 8 mg was superior to tolterodine extended release (ER) 4
mg for the improvement of severe urgency episodes/24 hours and the OAB-q Symptom Bother score at week
twelve, the urinary retention rate was around 2% [192].
The efficacy of antimuscarinics as single agents in men with OAB in the absence of BOO have been tested
[193-198]. Most trials lasted only twelve weeks. Four post hoc analyses of large RCTs on the treatment of
OAB in women and men without presumed BOO were performed focusing only on the men [190, 194, 199].
Tolterodine can significantly reduce urgency incontinence, daytime or 24-hour frequency and urgency-related
voiding whilst improving patient perception of treatment benefit. Solifenacin significantly improved mean
patient perception of bladder condition scores, mean OAB questionnaire scores, and overall perception of
bladder problems. Fesoterodine improved micturition frequency, urgency episodes, and urgency urinary
incontinence (UUI) episodes. In open-label trials with tolterodine, daytime frequency, nocturia, UUI, and
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
19
IPSS were significantly reduced compared with baseline values after 12-25 weeks [195, 198]. The TIMES
RCT reported that tolterodine ER monotherapy significantly improved UUI episodes per 24 hours compared
to placebo, at week twelve. Tolterodine ER did not significantly improve urgency, IPSS total or QoL score
compared with placebo. A significantly greater proportion of patients in the tolterodine ER plus tamsulosin
group reported treatment benefit compared with the other three treatment groups [197].
A further analysis showed that men with PSA levels of < 1.3 ng/mL (smaller prostates) might benefit
more from antimuscarinics [200]. Two other studies found a positive effect of antimuscarinics in patients with
OAB and concomitant BPO [198, 201]. In a small RCT propiverine improved frequency and urgency episodes
[201].
Tolerability and safety: Antimuscarinic drug trials generally show approximately 3-10% withdrawals, which
is similar to placebo. Drug-related adverse events include dry mouth (up to 16%), constipation (up to 4%),
micturition difficulties (up to 2%), nasopharyngitis (up to 3%), and dizziness (up to 5%).
Increased PVR in men without BOO is minimal and similar to placebo. Nevertheless, fesoterodine
8 mg showed higher PVRs (+20.2 mL) than placebo (-0.6 mL) or fesoterodine 4 mg (+9.6 mL) [195]. Incidence
of urinary retention in men without BOO was similar to placebo for tolterodine (0-1.3% vs. 0-1.4%). With
fesoterodine 8 mg, 5.3% had symptoms, which was higher than placebo or fesoterodine 4 mg (both 0.8%).
These symptoms appeared during the first two weeks of treatment and mainly affected men aged 66 years or
older.
Theoretically antimuscarinics might decrease bladder strength, and hence might be associated with
PVR urine or urinary retention. A twelve week safety study on men with mild-to-moderate BOO showed that
tolterodine increased the PVR (49 mL vs. 16 mL) but not AUR (3% in both arms) [202]. The urodynamic effects
included larger bladder volumes at first detrusor contraction, higher maximum cystometric capacity, and
decreased bladder contractility index, Qmax was unchanged. This trial indicated that short-term treatment with
antimuscarinics in men with BOO is safe [190].
Practical considerations: Not all antimuscarinics have been tested in elderly men, and long-term studies on
the efficacy of muscarinic receptor antagonists in men of any age with LUTS are not yet available. In addition,
only patients with low PVR volumes at baseline were included in the studies. These drugs should therefore be
prescribed with caution, and regular re-evaluation of IPSS and PVR urine is advised. Men should be advised to
discontinue medication if worsening voiding LUTS or urinary stream is noted after initiation of therapy.
Summary of evidence
LE
Antimuscarinic monotherapy can significantly improve urgency, UUI, and increased daytime frequency. 2
Antimuscarinic monotherapy can be associated with increased PVR after therapy, but acute retention 2
is a rare event in men with a PVR volume of < 150 mL at baseline.
Recommendations
Use muscarinic receptor antagonists in men with moderate-to-severe LUTS who mainly
have bladder storage symptoms.
Do not use antimuscarinic overactive bladder medications in men with a post-void residual
volume > 150 mL.
Strength rating
Strong
Weak
5.2.4
Beta-3 agonist
Mechanism of action: Beta-3 adrenoceptors are the predominant beta receptors expressed in the smooth
muscle cells of the detrusor and their stimulation is thought to induce detrusor relaxation. The mode of action
of beta-3 agonists is not fully elucidated [203].
Efficacy: Mirabegron 50 mg is the first clinically available beta-3 agonist with approval for use in adults with
OAB. Mirabegron has undergone extensive evaluation in RCTs conducted in Europe, Australia, North America
and Japan [204-208]. Mirabegron demonstrated significant efficacy in treating the symptoms of OAB, including
micturition frequency, urgency and UUI and also patient perception of treatment benefit. These studies had a
predominantly female study population. A meta-analysis of eight RCTS including 10,248 patients (27% male)
found that mirabegron treatment resulted in reduced frequency, urgency and UUI rates, as well as an improved
voided volume with a statistically significant improvement of nocturia as compared with both placebo and
tolterodine [209].
Mirabegron has been evaluated in male patients with OAB in the context of LUTS either associated
with or not associated with BPO confirmed by urodynamics [210]. Mirabegron 25 mg daily led to increased
satisfaction and improved QoL, but symptoms assessed by validated questionnaires (IPSS and OAB-SS), only
20
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
improved in non-obstructed patients. Mirabegron as an add-on therapy has been studied in OAB patients with
incontinence despite antimuscarinic therapy [211], again in a predominantly female study population. An Asian
study with a higher proportion of male subjects (approximately one third) reported superiority over placebo in
reducing frequency of micturition, but did not report the results separately for the genders [212].
In a study of more than 1,000 patients of whom approximately 30% were male, combination therapy
of mirabegron 25/50 mg and solifenacin 5/10 mg was associated with statistically significant improvements
in patient outcomes and health related QoL vs. solifenacin 5 mg and placebo; however, they did not separate
out the effects in men and women [213]. In another study, in which 28% patients were male, mirabegron
significantly improved patient reported perception of their condition and QoL whether or not patients were
incontinent [214]. A phase IV study, with a small proportion of male subjects, reported addition of mirabegron in
people with persisting urgency despite solifenacin in a Japanese population [215].
In an RCT evaluating add-on therapy with mirabegron for OAB symptoms remaining after treatment
with tamsulosin 0.2 mg daily in men with BPO, combination therapy was associated with greater improvements
in OAB symptom score, in the urinary urgency and daytime frequency part and storage subscore of the IPSS,
and in the QoL index compared to monotherapy with tamsulosin [216]. A prospective analysis of 50 elderly
men showed that mirabegron add-on therapy was effective for patients whose persistent LUTS and OAB
symptoms were not controlled with α1-blocker monotherapy, without causing negative effects on voiding
function [217].
An RCT compared the efficacy of mirabegron 50 mg or fesoterodine 4 mg add-on therapy to
silodosin in LUTS patients with persisting OAB symptoms [218]. At three months, fesoterodine add-on therapy
showed a significantly greater improvement then mirabegron add-on therapy in OAB symptom score-total
(-2.8 vs. -1.5, p = 0.004), IPSS-QoL (-1.5 vs. -1.1, p = 0.04), and OAB symptom score-urgency score (-1.5 vs.
-0.9, p = 0.008). Fesoterodine was also superior in alleviating detrusor overactivity (52.6% vs. 28.9%, p = 0.03).
Tolerability and safety: The most common treatment-related adverse events in the mirabegron groups were
hypertension, UTI, headache and nasopharyngitis [204-207]. Mirabegron is contraindicated in patients with
severe uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg,
or both). Blood pressure should be measured before starting treatment and monitored regularly during treatment.
A combination of thirteen clinical studies including 13,396 patients, 25% of whom were male, showed that
OAB treatments (anticholinergics or mirabegron) were not associated with an increased risk of hypertension or
cardiovascular events compared to placebo [219]. The proportion of patients with dry mouth and constipation
in the mirabegron groups was notably lower than reported in RCTs of other OAB agents or of the active control
tolterodine [204]. Evaluation of urodynamic parameters in men with combined BOO and OAB concluded that
mirabegron did not adversely affect voiding urodynamic parameters compared to placebo in terms of Qmax,
detrusor pressure at maximum flow and bladder contractility index [220]. The overall change in PVR with
mirabegron is small [220].
A small prospective study (mainly focused on males) has shown that mirabegron 25 mg is safe
in patients aged 80 years or more with multiple comorbidities [221]. A pooled analysis of three trials each of
twelve weeks and a one year trial showed, in patients aged > 65 years, a more favourable tolerability profile for
mirabegron than antimuscarinics [222]. In an eighteen week study of 3,527 patients (23% male), the incidence
of adverse events were higher in the combination (solifenacin 5 mg plus mirabegron 25 mg) group (40%) than
the mirabegron 25 mg alone group (32%). Events recorded as urinary retention were low (< 1%), but were
reported slightly more frequently in the combined group when compared with the monotherapy and placebo
groups. The PVR volume was slightly increased in the combined group compared with solifenacin 5 mg, and
the mirabegron monotherapy and placebo groups. Combined therapy with solifenacin 5 mg plus mirabegron 25
mg and solifenacin 5 mg plus mirabegron 50 mg provided improvements in efficacy generally consistent with
an additive effect [223].
In a retrospective analysis of persistence and adherence in 21,996 patients, of whom 30% were
male, the median time to discontinuation was significantly longer for mirabegron (169 days) compared to
tolterodine (56 days) and other antimuscarinics (30-78 days) (p < 0.0001). There was no statistical difference
between men and women [224]. Data on the safety of combination therapy at twelve months are awaited from
the SYNERGY II trial.
Practical considerations: Long-term studies on the efficacy and safety of mirabegron in men of any age with
LUTS are not yet available. Studies on the use of mirabegron in combination with other pharmacotherapeutic
agents for male LUTS are pending. However, pharmacokinetic interaction upon add-on of mirabegron or
tamsulosin to existing tamsulosin or mirabegron therapy does not cause clinically relevant changes in safety
profiles [225]. Available studies on mirabegron in combination with antimuscarinics in OAB patients had a
predominantly female study population, while further trials are still pending.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
21
Summary of evidence
Mirabegron improves the symptoms of OAB, including micturition frequency, urgency and UUI.
Patients prescribed mirabegron remained on treatment longer than those prescribed antimuscarinics.
Recommendation
Use beta-3 agonists in men with moderate-to-severe LUTS who mainly have bladder
storage symptoms.
LE
2
3
Strength rating
Weak
5.2.5
Phosphodiesterase 5 inhibitors
Mechanism of action: Phosphodiesterase 5 inhibitors (PDE5Is) increase intracellular cyclic guanosine
monophosphate, thus reducing smooth muscle tone of the detrusor, prostate and urethra. Nitric oxide and
PDE5Is might also alter reflex pathways in the spinal cord and neurotransmission in the urethra, prostate, or
bladder [226]. Moreover, chronic treatment with PDE5Is seems to increase blood perfusion and oxygenation
in the LUT [227]. Phosphodiesterase 5 inhibitors could also reduce chronic inflammation in the prostate and
bladder [228]. The exact mechanism of PDE5Is on LUTS remains unclear.
Although clinical trials of several selective oral PDE5Is have been conducted in men with LUTS, only
tadalafil (5 mg once daily) has been licensed for the treatment of male LUTS.
Efficacy: Several RCTs have demonstrated that PDE5Is reduce IPSS, storage and voiding LUTS, and improve
QoL. However, Qmax did not significantly differ from placebo in most trials.
A recent Cochrane review included a total of sixteen randomised trials that examined the effects
of PDE5Is compared to placebo and other standard of care drugs (α1-blockers and 5-ARIs) in men with LUTS
[229]. Phosphodiesterase 5 inhibitors led to a small reduction (mean difference (MD) 1.89 lower, 95% CI 2.27
lower to 1.50 lower) in IPSS compared to placebo. There was no difference between PDE5Is and α1-blockers
in IPSS. Most evidence was limited to short-term treatment up to twelve weeks and of moderate or low
certainty. In earlier [230] and more recent [231] meta-analysis, PDE5Is were also found to improve IPSS and
IIEF score, but not Qmax.
Tadalafil 5 mg reduces IPSS by 22-37% and improvement may be seen within a week of initiation
of treatment [232]. A three point or greater total IPSS improvement was observed in 60% of tadalafil treated
men within one week and in 80% within four weeks [233]. The maximum trial (open label) duration was 52
weeks [234]. A subgroup analysis of pooled data from four RCTs demonstrated a significant reduction in LUTS,
regardless of baseline severity, age, previous use of α-blockers or PDE5Is, total testosterone level or predicted
prostate volume [235]. In a recent post hoc analysis of pooled data from four RCTs, tadalafil was shown to also
be effective in men with cardiovascular risk factors/comorbidities, except for patients receiving more than one
antihypertensive medication. The use of diuretics may contribute to patients’ perception of a negated efficacy
[236]. Among sexually active men > 45 years with comorbid LUTS/BPH and ED, tadalafil improved both
conditions [235].
An integrated data analyses from four placebo controlled clinical studies showed that total IPSS
improvement was largely attributed to direct (92.5%, p < 0.001) vs. indirect (7.5%, p = 0.32) treatment effects
via IIEF-EF improvement [237]. Another analysis showed a small but significant increase in Qmax without any
effect on PVR [238]. An integrated analysis of RCTs showed that tadalfil was not superior to placebo for IPSS
improvement at twelve weeks in men ≥ 75 years (with varied effect size between studies), but was for men < 75
years [239]. An open label urodynamic study of 71 patients showed improvements in both voiding and storage
symptoms, confirmed by improvements in BOO index (61.3 to 47.1; p < 0.001), and resolution of DO in 15 (38%)
of 38 patients. Flow rate improved from 7.1 to 9.1 mL/s (p < 0.001) and mean IPSS from 18.2 to 13.4 [240].
A combination of PDE5Is and α-blockers has also been evaluated. A meta-analysis of five RCTs
(two studies with tadalafil 20 mg, two with sildenafil 25 mg, and one with vardenafil 20 mg), showed that
combination therapy significantly improved IPSS score (-1.8), IIEF score (+3.6) and Qmax (+1.5 mL/s) compared
with α-blockers alone [230]. A Cochrane review found similar findings [229]. The effects of tadalafil 5 mg
combined with finasteride 5 mg were assessed in a 26-week placebo-controlled RCT [241]. The combination
of tadalafil and finasteride provided an early improvement in urinary symptoms (p < 0.022 after 4, 12 and 26
weeks), with a significant improvement of storage and voiding symptoms and QoL. Combination therapy
was well tolerated and improved erectile function [241]. However, only tadalafil 5 mg has been licensed in the
context of LUTS management while data on combinations of PDE5Is and other LUTS medications is emerging.
Tolerability and safety: Reported adverse effects in RCTs comparing the effect of all PDE5Is vs. placebo in men
with LUTS include flushing, gastroesophageal reflux, headache, dyspepsia, back pain and nasal congestion
[230]. The discontinuation rate due to adverse effects for tadalafil was 2.0% [242] and did not differ by age,
LUTS severity, testosterone levels, or prostate volume in the pooled data analyses [235].
22
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Phosphodiesterase 5 inhibitors are contraindicated in patients using nitrates, the potassium channel
opener nicorandil, or the α1-blockers doxazosin and terazosin. They are also contraindicated in patients
who have unstable angina pectoris, have had a recent myocardial infarction (< three months) or stroke (< six
months), myocardial insufficiency (New York Heart Association stage > 2), hypotension, poorly controlled blood
pressure, significant hepatic or renal insufficiency, or if anterior ischaemic optic neuropathy with sudden loss of
vision is known or was reported after previous use of PDE5Is.
Practical considerations: To date, only tadalafil 5 mg once daily has been officially licensed for the treatment of
male LUTS with or without ED. The meta-regression suggested that younger men with low body mass index
and more severe LUTS benefit the most from treatment with PDE5Is [230]. Long-term experience with tadalafil
in men with LUTS is limited to one trial with a one year follow-up [234]; therefore, conclusions about its efficacy
or tolerability greater than one year are not possible. There is limited information on reduction of prostate size
and no data on disease progression.
Summary of evidence
LE
1a
Phosphodiesterase 5 inhibitors improve IPSS and IIEF score, but not Qmax .
A three point or greater total IPSS improvement was observed in 59.8% of tadalafil treated men within 1b
one week and in 79.3% within four weeks.
Recommendation
Use phosphodiesterase type 5 inhibitors in men with moderate-to-severe LUTS with or
without erectile dysfunction.
Strength rating
Strong
5.2.6
Plant extracts - phytotherapy
Potential mechanism of action: Herbal drug preparations are made of roots, seeds, pollen, bark, or fruits. There
are single plant preparations (mono-preparations) and preparations combining two or more plants in one pill
(combination preparations) [243].
Possible relevant compounds include phytosterols, ß-sitosterol, fatty acids, and lectins [243]. In
vitro, plant extracts can have anti-inflammatory, anti-androgenic and oestrogenic effects; decrease sexual
hormone binding globulin; inhibit aromatase, lipoxygenase, growth factor-stimulated proliferation of prostatic
cells, α-adrenoceptors, 5 α-reductase, muscarinic cholinoceptors, dihydropyridine receptors and vanilloid
receptors; and neutralise free radicals [243-245]. The in vivo effects of these compounds are uncertain, and the
precise mechanisms of plant extracts remain unclear.
Efficacy: The extracts of the same plant produced by different companies do not necessarily have the same
biological or clinical effects; therefore, the effects of one brand cannot be extrapolated to others [246]. In
addition, batches from the same producer may contain different concentrations of active ingredients [247].
A review of recent extraction techniques and their impact on the composition/biological activity of available
Serenoa repens based products showed that results from different clinical trials must be compared strictly
according to the same validated extraction technique and/or content of active compounds [248], as the
pharmacokinetic properties of the different preparations can vary significantly.
Heterogeneity and a limited regulatory framework characterise the current status of
phytotherapeutic agents. The European Medicines Agency (EMA) has developed the Committee on Herbal
Medicinal Products (HMPC). European Union (EU) herbal monographs contain the HMPC’s scientific opinion on
safety and efficacy data about herbal substances and their preparations intended for medicinal use. The HMPC
evaluates all available information, including non-clinical and clinical data, whilst also documenting longstanding use and experience in the EU. European Union monographs are divided into two sections: a) Well
established use (marketing authorisation): when an active ingredient of a medicine has been used for more than
ten years and its efficacy and safety have been well established (including a review of the relevant literature);
and b) Traditional use (simplified registration): for herbal medicinal products which do not fulfil the requirements
for a marketing authorisation, but there is sufficient safety data and plausible efficacy on the basis of longstanding use and experience. Table 1 lists the available EU monographs for herbal medicinal products.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
23
Table 2: European Union monographs for herbal medicinal products
Herbal substance
HMPC evaluation
Therapeutic
Indication by HMPC
Symptomatic
treatment of BPH
Date of monograph
Serenoa repens, fructus (saw
palmetto, fruit)
Extraction solvent: hexane [1]
Serenoa repens, fructus (saw
palmetto, fruit)
Extraction solvent: ethanol [1]
Cucurbita pepo L, semen (pumpkin
seed)
Preparation as defined in the
monograph [249]
Prunus africana (Hook f.) Kalkm.,
cortex (pygeum africanum bark)
Preparation as defined in the
monograph [250]
Urtica dioica L., Urtica urens L., their
hybrids or their mixtures, radix
Preparation as defined in the
monograph [251]
Epilobium angustifolium L. and/or
Epilobium parviflorum Schreb., herba
(Willow herb)
Preparation as defined in the
monograph [252]
Well established use
Traditional use
LUTS related to BPH*
14/01/2016
Traditional use
LUTS related to BPH
or related to an OAB*
25/03/2013
Traditional use
LUTS related to BPH*
01/09/2017
Traditional use
LUTS related to BPH*
05/11/2012
Traditional use
LUTS related to BPH*
13/01/2016
14/01/2016
*After serious conditions have been excluded by a medical doctor.
Panel interpretation: Only hexane extracted Serenoa repens (HESr) has been recommended for wellestablished use by the HMPC. Based on this a detailed scoping search covering the timeframe between the
search cut-off date of the EU monograph and April 2020 was conducted for HESr.
A large meta-analysis of 30 RCTs with 5,222 men and follow-up ranging from 4 to 60 weeks, demonstrated
no benefit of treatment with S. repens in comparison to placebo for the relief of LUTS [253]. It was concluded
that S. repens was not superior to placebo, finasteride, or tamsulosin with regard to IPSS improvement, Qmax,
or prostate size reduction; however, the similar improvement in IPSS or Qmax compared with finasteride or
tamsulosin could be interpreted as treatment equivalence. Importantly, in the meta-analysis all different brands
of S. repens were included regardless or not of the presence of HESr as the main ingredient in the extract.
Another SR focused on data from twelve RCTs on the efficacy and safety of HESr [254]. It was
concluded that HESr was superior to placebo in terms of improvement of nocturia and Qmax in patients with
enlarged prostates. Improvement in LUTS was similar to tamsulosin and short-term use of finasteride. An
updated SR analysed fifteen RCTs and also included twelve observational studies. It confirmed the results of
the previous SR on the efficacy of HESr [255]. Compared with placebo, HESr was associated with 0.64 (95%
CI 0.98 to 0.31) fewer voids/night and an additional mean increase in Qmax of 2.75 mL/s (95% CI 0.57 to 4.93),
both were significant. When compared with α-blockers, HESr showed similar improvements in IPSS (WMD
0.57, 95% CI 0.27 to 1.42) and a comparable increase in Qmax when compared to tamsulosin (WMD 0.02, 95%
CI 0.71 to 0.66). Efficacy assessed using IPSS was similar after six months of treatment between HESr and
5-ARIs. Analysis of all available published data for HESr showed a mean significant improvement in IPSS from
baseline of 5.73 points (95% CI 6.91 to 4.54) [255].
A network meta-analysis tried to compare the clinical efficacy of S. repens (HESr and non-HESr)
against placebo and α1-blockers in men with LUTS. Interestingly, only two RCTs on HESr were included in
the analysis. It was found that S. repens achieved no clinically meaningful improvement against placebo or
α1-blockers in short-term follow-up. However, S. repens showed a clinical benefit after a prolonged period of
treatment, and HESr demonstrated a greater improvement than non-HESr in terms of IPSS [256].
With respect to safety and tolerability, data from the SRs showed that HESr had a favourable safety profile with
gastrointestinal disorders being the most frequent adverse effects (mean incidence 3.8%) while HESr had very
limited impact on sexual function.
24
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
A cross-sectional study compared the combination of HESr with silodosin to silodosin monotherapy
in patients treated for at least twelve months (mean duration 13.5 months) [257]. It was reported that 69.9%
of the combination therapy patients achieved the predefined clinically meaningful improvement (improvement
more than three points in baseline IPSS) compared to 30.1% of patients treated only with silodosin. In addition,
a greater than 25% improvement in IPSS was found in 68.8% and 31.2% of the patients in the combination
and the monotherapy groups, respectively. These data suggest that combination of a α1-blocker with HESr
may result in greater clinically meaningful improvements in LUTS compared to α1-blocker monotherapy [257].
Practical considerations: Available RCTs do not use the same endpoints (e.g. IPSS). More studies on the use
of HESr in combination with other pharmacotherapeutic agents for male LUTS are pending. There is a need to
define the subpopulation of patients who will benefit most from therapy with HESr.
Summary of evidence
HESr improves Qmax and results in fewer voids/night [0.64 (95% CI 0.98 to 0.31)] compared to
placebo.
HESr has a very limited negative impact on sexual function.
Recommendations
Offer hexane extracted Serenoa repens to men with LUTS who want to avoid any potential
adverse events especially related to sexual function.
Inform the patient that the magnitude of efficacy may be modest.
LE
2
2
Strength rating
Weak
Strong
5.2.7
Combination therapies
5.2.7.1
α1-blockers + 5α-reductase inhibitors
Mechanism of action: Combination therapy consists of an α1-blocker (Section 5.2.1) together with a 5-ARI
(Section 5.2.2). The α1-blocker exhibits clinical effects within hours or days, whereas the 5-ARI needs several
months to develop full clinical efficacy. Finasteride has been tested in clinical trials with alfuzosin, terazosin,
doxazosin or terazosin, and dutasteride with tamsulosin.
Efficacy: Several studies have investigated the efficacy of combination therapy against an α1-blocker,
5-ARI or placebo alone. Initial studies with follow-up periods of six to twelve months demonstrated that the
α1-blocker was superior to finasteride in symptom reduction, whereas combination therapy of both agents
was not superior to α1-blocker monotherapy [162, 163, 258]. In studies with a placebo arm, the α1-blocker
was consistently more effective than placebo, but finasteride was not. Data at one year in the MTOPS study
showed similar results [65].
Long-term data (four years) from the MTOPS and CombAT studies showed that combination
treatment is superior to monotherapy for symptoms and Qmax, and superior to α1-blocker alone in reducing the
risk of AUR or need for surgery [65, 147, 148].
The CombAT study demonstrated that combination treatment is superior to either monotherapy
regarding symptoms and flow rate starting from month nine, and superior to α1-blocker for AUR and the
need for surgery after eight months [148]. Thus, the differences in MTOPS may reflect different inclusion and
exclusion criteria and baseline patient characteristics.
Discontinuation of the α1-blocker after six to nine months of combination therapy was investigated
by an RCT and an open-label multicentre trial [259, 260]. The first trial evaluated the combination of tamsulosin
with dutasteride and the impact of tamsulosin discontinuation after six months [259], with almost three quarters
of patients reporting no worsening of symptoms. However, patients with severe symptoms (IPSS > 20) at
baseline may benefit from longer combination therapy.
A more recent trial evaluated the symptomatic outcome of finasteride monotherapy at three and
nine months after discontinuation of nine-month combination therapy [260]. Lower urinary tract symptom
improvement after combination therapy was sustained at three months (IPSS difference 1.24) and nine months
(IPSS difference 0.4). The limitations of the studies include the short duration of the studies and the short
follow-up period after discontinuation.
In both the MTOPS and CombAT studies, combination therapy was superior to monotherapy in preventing
clinical progression as defined by an IPSS increase of at least four points, AUR, UTI, incontinence, or an
increase in creatinine > 50%. The MTOPS study found that the risk of long-term clinical progression (primarily
due to increasing IPSS) was reduced by 66% with combined therapy vs. placebo and to a greater extent than
with either finasteride or doxazosin monotherapy (34% and 39%, respectively) [65]. In addition, finasteride
(alone or in combination), but not doxazosin alone, significantly reduced both the risks of AUR and the need
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
25
for BPO-related surgery over the four-year study. In the CombAT study, combination therapy reduced the
relative risks of AUR by 68%, BPO-related surgery by 71%, and symptom deterioration by 41% compared with
tamsulosin, after four years [261]. To prevent one case of urinary retention and/or surgical treatment thirteen
patients need to be treated for four years with dutasteride and tamsulosin combination therapy compared to
tamsulosin monotherapy while the absolute risk reduction (risk difference) was 7.7%.
The CONDUCT study compared efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin
to a WW approach with the potential initiation of tamsulosin (step-up approach) in a two year RCT with a total
of 742 patients. In both arms detailed lifestyle advice was given. This fixed-dose combination resulted in a
rapid and sustained improvement in men with moderate LUTS at risk of disease progression, the difference
in IPSS at 24 months was 5.4 in the active arm and 3.6 in the placebo arm (p < 0.001) [262]. Furthermore,
tamsulosin plus dutasteride significantly reduced the relative risk of clinical progression (mainly characterised
as a worsening in symptoms) by 43.1% when compared with WW, with an absolute risk reduction of 11.3%
(number needed to treat [NNT] = 9).
The influence of baseline variables on changes in IPSS after combination therapy with dutasteride
plus tamsulosin or either monotherapy was tested based on the four year results of the CombAT study.
Combination therapy provided consistent improvement of LUTS over tamsulosin across all analysed baseline
variables at 48 months [263].
More recently, a combination of the 5-ARI finasteride and tadalafil 5 mg was tested in a large scale
RCT against finasteride monotherapy. This study supports the concept of this novel combination therapy and is
described in more detail in the chapter on PDE5Is [241].
Tolerability and safety: Adverse events for both drug classes have been reported with combination treatment
[65, 147, 148]. The adverse events observed during combination treatment were typical of α1-blockers and
5-ARIs. The frequency of adverse events was significantly higher for combination therapy. The MTOPS study
demonstrated that the incidence of treatment related adverse events is higher during the first year of combined
treatment between doxazosin and finasteride [264]. A meta-analysis measuring the impact of medical
treatments for LUTS/BPH on ejaculatory function, reported that combination therapy with α1-blockers and
5-ARIs resulted in a three-fold increased risk of EjD as compared with each of the monotherapies [157].
Practical considerations: Compared with α1-blockers or 5-ARI monotherapy, combination therapy results in
a greater improvement in LUTS and increase in Qmax and is superior in prevention of disease progression.
However, combination therapy is also associated with a higher rate of adverse events. Combination therapy
should therefore be prescribed primarily in men who have moderate-to-severe LUTS and are at risk of disease
progression (higher prostate volume, higher PSA concentration, advanced age, higher PVR, lower Qmax, etc.).
Combination therapy should only be used when long-term treatment (more than twelve months) is intended
and patients should be informed about this. Discontinuation of the α1-blocker after six months might be
considered in men with moderate LUTS.
Summary of evidence
Long-term data (four years) from the MTOPS and CombAT studies showed that combination treatment
is superior to monotherapy for symptoms and Qmax, and superior to α1-blocker alone in reducing the
risk of AUR or need for surgery.
The MTOPS study found that the risk of long-term clinical progression (primarily due to increasing
IPSS) was reduced by 66% with combined therapy vs. placebo and to a greater extent than with either
finasteride or doxazosin monotherapy.
The CombAT study found that combination therapy reduced the relative risks of AUR by 68%, BPHrelated surgery by 71%, and symptom deterioration by 41% compared with tamsulosin, after four years.
Adverse events of both drug classes are seen with combined treatment using α1-blockers and 5-ARIs.
Recommendation
Offer combination treatment with an α1-blocker and a 5α-reductase inhibitor to men with
moderate-to-severe LUTS and an increased risk of disease progression (e.g. prostate
volume > 40 mL).
LE
1b
1b
1b
1b
Strength rating
Strong
5.2.7.2
α1-blockers + muscarinic receptor antagonists
Mechanism of action: Combination treatment consists of an α1-blocker together with an antimuscarinic aiming
to antagonise both α1-adrenoceptors and muscarinic receptors. The possible combinations have not all been
tested in clinical trials yet.
26
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Efficacy: Several RCTs and prospective studies investigated combination therapy, lasting four to twelve weeks,
either as an initial treatment in men with OAB and presumed BPO or as a sequential treatment for storage
symptoms persisting while on an α1-blocker [197, 261, 265-271]. One trial used the α1-blocker naftopidil (not
registered in most European countries) with and without antimuscarinics [272]. A high proportion of men with
voiding and storage LUTS need to add anticholinergics after α1-blocker monotherapy, particularly those with
longer duration of symptoms at presentation, and men with storage symptoms and a small prostate volume
[273].
Combination treatment is more efficacious in reducing urgency, UUI, voiding frequency, nocturia,
or IPSS compared with α1-blockers or placebo alone, and improves QoL [197, 274]. Symptom improvement
is higher regardless of PSA concentration with combination therapy, whereas tolterodine alone improved
symptoms mainly in men with a serum PSA of < 1.3 ng/mL [200].
Persistent LUTS during α1-blocker treatment can be reduced by the additional use of an
antimuscarinic, [261, 265, 271, 275, 276]. Two SRs of the efficacy and safety of antimuscarinics in men
suggested that combination treatment provides significant benefit [277, 278]. In a meta-analysis of sixteen
studies with 3,548 patients with BPH/OAB, initial combination treatment of an α1-blocker with anticholinergic
medication improvement storage symptoms and QoL compared to α1-blocker monotherapy without causing
significant deterioration of voiding function [279]. There was no difference in total IPSS and Qmax between the
two groups.
Effectiveness of therapy is evident primarily in those men with moderate-to-severe storage LUTS
[280]. Long term use of combination therapy has been reported in patients receiving treatment for up to one
year, showing symptomatic response is maintained, with a low incidence of AUR [281]. In men with moderateto-severe storage symptoms, voiding symptoms and PVR < 150 mL, the reduction in symptoms using
combination therapy is associated with patient-relevant improvements in health related quality of life compared
with placebo and α1-blocker monotherapy [282].
Tolerability and safety: Adverse events of both drug classes are seen with combined treatment using
α1-blockers and antimuscarinics. The most common side-effect is dry mouth. Some side-effects (e.g. dry
mouth or ejaculation failure) may show increased incidence which cannot simply be explained by summing
the incidence with the drugs used separately. Increased PVR may be seen, but is usually not clinically
significant, and risk of AUR is low up to one year of treatment [277, 283]. Antimuscarinics do not cause evident
deterioration in maximum flow rate used in conjunction with an α1-blocker in men with OAB symptoms [274,
284].
A recent RCT investigated safety in terms of maximum detrusor pressure and Qmax for solifenacin
(6 mg or 9 mg) with tamsulosin in men with LUTS and BOO compared with placebo [285]. The combination
therapy was not inferior to placebo for the primary urodynamic variables; Qmax was increased vs. placebo [285].
Practical considerations: Class effects are likely to underlie efficacy and QoL using an α1-blocker and
antimuscarinic. Trials used mainly storage symptom endpoints, were of short duration, and included only men
with low PVR volumes at baseline. Therefore, measuring PVR is recommended during combination treatment.
Summary of evidence
Combination treatment with α1-blockers and antimuscarinics is effective for improving LUTS-related
QoL impairment.
Combination treatment with α1-blockers and antimuscarinics is more effective for reducing urgency,
UUI, voiding frequency, nocturia, or IPSS compared with α1-blockers or placebo alone.
Adverse events of both drug classes are seen with combined treatment using α1-blockers and
antimuscarinics.
There is a low risk of AUR using α1-blockers and antimuscarinics in men known to have a PVR urine
volume of < 150 mL.
LE
2
2
1
2
Recommendations
Strength rating
Strong
Use combination treatment of a α1-blocker with a muscarinic receptor antagonist in
patients with moderate-to-severe LUTS if relief of storage symptoms has been insufficient
with monotherapy with either drug.
Do not prescribe combination treatment in men with a post-void residual volume > 150 mL. Weak
Note: A
ll patients should be counselled about pharmacological treatment related adverse events in
order to select the most appropriate treatment for each individual patient.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
27
5.3
Surgical treatment
Surgical treatment is one of the cornerstones of LUTS/BPO management. Based on its ubiquitous availability,
as well as its efficacy, M-TURP has long been considered as the reference technique for the surgical
management of LUTS/BPO. However, in recent years various techniques have been developed with the aim
of providing a safe and effective alternative to M-TURP. Previously, the surgical section of the Guidelines was
based on technology rather than surgical approach; additionally, most of the studies are restricted by prostate
size, which is also reflected in the present Guidelines. Notably, only a small fraction of RCTs are performed
in patients with a prostate volume > 80 mL; therefore, high-level evidence for larger prostates is limited. As
the clinical reality is primarily reflected by surgical approach and not necessarily by a specific technology, the
chapter on surgical management has been restructured. It is now divided into the following five sections:
1.
2.
3.
4.
5.
Resection;
Enucleation;
Vaporisation;
Alternative ablative techniques; and
Non-ablative techniques.
Based on Panel consensus, timeframes defining short-, mid- and long-term follow-up of patients submitted to
surgical treatments are 12, 36 and over 36 months, respectively. The durability of a technique is reflected by the
re-operation rate during follow-up, the failure to wean patients off medication as well as the initiation of novel
LUTS medication after surgery. However, for the majority of techniques only the re-operation rate is reported
and clinicians should inform patients that long-term surgical RCTs are often lacking. Some patients value
sexual function and perceived higher safety than maximum efficacy; therefore, it is not surprising that some
patients consciously choose an alternative ablative or non-ablative technique despite the knowledge that it
might not be their definitive treatment. In contrast, many urologists are critical about these ‘lesser’ procedures
due to their inferior relief of BOO.
Recommendations on new devices or interventions will only be included in the Guidelines once
supported by a minimum level of evidence. To clarify this the Panel have published their position on certainty
of evidence (CoE) [286]. In summary, a device or technology is only included once supported by RCTs looking
at both efficacy and safety, with adequate follow-up, and secondary studies to confirm the reproducibility
and generalisability of the first pivotal studies [286]. Otherwise, there is a danger that a single pivotal study
can be overexploited by device manufacturers. Studies that are needed include (1) proof of concept, (2) RCTs
on efficacy and safety, as well as (3) cohort studies with a broad range of inclusion and exclusion criteria
to confirm both reproducibility and generalisability of the benefits and harms [286]. The panel assesses the
quality of all RCTs and if they do not meet the standard required the intervention will continue to have no
recommendation i.e. a RCT does not guarantee inclusion in the Guidelines.
In addition, the Guidelines continues to include techniques under investigation. These are devices
or technologies that have shown promising results in initial studies; however, they do not meet the
aforementioned criteria yet to provide a CoE which allows the Panel to regard these devices or technologies
as recommended alternatives. To account for evolving evidence, recommendations for some techniques under
investigation have been made; however, these techniques remain under investigation until further studies
provide the recommended CoE.
5.3.1
Resection of the prostate
5.3.1.1
Monopolar and bipolar transurethral resection of the prostate
Mechanism of action: Transurethral resection of the prostate (TURP) is performed using two techniques:
monopolar TURP (M-TURP) and bipolar TURP (B-TURP). Monopolar transurethral resection of the prostate
removes tissue from the transition zone of the gland. Bipolar TURP addresses a major limitation of M-TURP by
allowing performance in normal saline. Prostatic tissue removal is identical to M-TURP. Contrary to M-TURP,
in B-TURP systems, the energy does not travel through the body to reach a skin pad. Bipolar circuitry is
completed locally; energy is confined between an active (resection loop) and a passive pole situated on the
resectoscope tip (“true” bipolar systems) or the sheath (“quasi” bipolar systems). The various bipolar devices
available differ in the way in which current flow is delivered [287, 288].
Efficacy: In a meta-analysis of 20 RCTs with a maximum follow-up of five years, M-TURP resulted in a
substantial mean Qmax improvement (+162%), a significant reduction in IPSS (-70%), QoL score (-69%),
and PVR (-77%) [289]. Monopolar-TURP delivers durable outcomes as shown by studies with a follow-up of
8-22 years. There are no similar data on durability for any other surgical treatment for BPO [290]. One study
with a mean follow-up of thirteen years reported a significant and sustained decrease in most symptoms
and improvement in urodynamic parameters. Failures were associated with DUA rather than re-development
28
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
of BPO [102]. A second prostatic operation, usually re-TURP, has been reported at a constant annual rate of
approximately 1-2%. A review analysing 29 RCTs found a retreatment rate of 2.6% after a mean follow-up of
sixteen months [291]. Data from an Austrian nationwide study of two cohorts totalling 41,059 men submitted to
M-TURP showed that the overall retreatment rates (re-TURP, urethrotomy and bladder neck incision) remained
unchanged during the last decade (0.9%, 3.7%, 9.5% and 12.7% at three months, one year, five years, and
eight years, respectively), and that the respective incidence of re-TURP was 0.8%, 2.4%, 6.1% and 8.3%,
respectively [292, 293].
Bipolar TURP is the most widely and thoroughly investigated alternative to M-TURP. Results from 56 RCTs
have been reported [294], of which around half have been pooled in RCT-based meta-analyses [289, 295299]. Early pooled results concluded that no clinically relevant differences exist in short-term efficacy (IPSS,
QoL score and Qmax) [296]. Subsequent meta-analyses supported these conclusions though trial quality was
generally poor [289, 295, 297-299]. Data from RCTs with mid- to long-term follow-up (up to 60 months) showed
no differences in efficacy parameters [300-308].
A meta-analysis was conducted to evaluate the quasi-bipolar transurethral resection in saline
(TURis, Olympus Medical) system vs. M-TURP. Ten unique RCTs (1,870 patients) were included and it was
concluded that TURis was of equivalent efficacy to M-TURP [309].
Tolerability and safety: Peri-operative mortality and morbidity of M-TURP have decreased over time, but
morbidity remains considerable (0.1% and 11.1%, respectively) [310]. Data from an Austrian nationwide study
of two cohorts totalling 41,059 men submitted to M-TURP showed a 20% reduction in mortality rate over time,
to 0.1% at 30 days and 0.5% at 90 days [292, 293].
The risk of TUR-syndrome decreased to < 1.1% [291, 311]. Data from 10,654 M-TURPs reported
bleeding requiring transfusion in 2.9% [310]. Short- to mid-term complications reported in an analysis of RCTs
using M-TURP as a comparator were: bleeding requiring transfusion 2% (0-9%), TUR-syndrome 0.8% (0-5%),
AUR 4.5% (0-13.3%), clot retention 4.9% (0-39%), and UTI 4.1% (0-22%) [289]. Long-term complications of
M-TURP comprise urinary incontinence, urinary retention and UTIs, bladder neck contracture (BNC), urethral
stricture, retrograde ejaculation and ED [291].
Early pooled results concluded that no differences exist in short-term urethral stricture/BNC rates, but B-TURP
is preferable to M-TURP due to a more favourable peri-operative safety profile (elimination of TUR-syndrome;
lower clot retention/blood transfusion rates; shorter irrigation, catheterisation, and possibly hospitalisation
times) [296]. Subsequent meta-analyses supported these conclusions [289, 295, 297-299]; however, trial
quality was relatively poor and limited follow-up might cause under-reporting of late complications, such as
urethral stricture/BNC [296]. An RCT based meta-analysis has shown that TURis reduces the risk of TURsyndrome and the need for blood transfusion compared to M-TURP [299]. It was concluded that TURis is
associated with improved peri-operative safety, eliminating the risk of TUR syndrome, reducing the risk of blood
transfusion/clot retention and hospital stay. No significant difference was detected in urethral stricture rates.
Data from the vast majority of individual RCTs with mid- to long-term follow-up (up to 60 months),
showed no differences between M-TURP and B-TURP in urethral stricture/BNC rates [300-308], in accordance
with all published meta-analyses. However, two individual RCTs have shown opposing results [307, 312]. A
significantly higher stricture (urethral stricture + BNC) rate was detected in the B-TURP arm performed with
a “quasi” bipolar system (TURis, Olympus Medical) in patients with a prostate volume > 70 mL at 36 months
follow-up [307]. In addition, a significantly higher BNC, but not urethral stricture, rate was detected in the
B-TURP arm performed with a “true” bipolar system (Gyrus PK SuperPulse, Olympus Medical) in 137 patients
followed up to twelve months [312].
Randomised controlled trials using the erectile function domain of the IIEF (IIEF-ED) and the
ejaculatory domain of the male sexual-health questionnaire (Ej-MSHQ) showed that M-TURP and B-TURP
have a similar effect on erectile and ejaculatory function [313, 314]. Comparative evaluations of the effects on
overall sexual function, quantified with IIEF-15, showed no differences between B-TURP and M-TURP at twelve
months follow-up (erection, orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction) [314,
315].
Practical considerations: Monopolar-TURP is an effective treatment for moderate-to-severe LUTS secondary to
BPO. The choice should be based primarily on prostate volume (30-80 mL suitable for M-TURP). No studies on
the optimal cut-off value exist, but the complication rates increase with prostate size [310]. The upper limit for
M-TURP is suggested as 80 mL (based on Panel expert opinion, under the assumption that this limit depends
on the surgeon’s experience, choice of resectoscope size and resection speed), as surgical duration increases,
there is a significant increase in the rate of complications and the procedure is safest when performed in under
90 minutes [316].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
29
Bipolar TURP in patients with moderate-to-severe LUTS secondary to BPO, has similar efficacy to
M-TURP, but lower peri-operative morbidity. The duration of improvements with B-TURP were documented in
a number of RCTs with mid-term follow-up. Long-term results (up to five years) for B-TURP showed that safety
and efficacy are comparable to M-TURP [300-308]. The choice of B-TURP should be based on equipment
availability, surgeon’s experience, and patient’s preference.
Summary of evidence
Bipolar- or monopolar-TURP is the current standard surgical procedure for men with prostate sizes of
30-80 mL and bothersome moderate-to-severe LUTS secondary of BPO.
Bipolar-TURP achieves short-, mid- and long-term results comparable with M-TURP, but B-TURP has
a more favourable peri-operative safety profile.
Recommendation
Offer bipolar- or monopolar-transurethral resection of the prostate to surgically treat
moderate-to-severe LUTS in men with prostate size of 30-80 mL.
LE
1a
1a
Strength rating
Strong
5.3.1.2
Holmium laser resection of the prostate
With the advent of holmium laser enucleation of the prostate (section 5.3.2.3) and the fact that no relevant
publications on holmium laser resection of the prostate (HoLRP) have been published since 2004, HoLRP of
the prostate does not play a role in contemporary treatment algorithms.
5.3.1.3
Thulium:yttrium-aluminium-garnet laser (Tm:YAG) vaporesection of the prostate
Mechanism of action: In the thulium lasers, a wavelength between 1,940 nm (thulium fiber laser) and 2,013 nm
(Tm:YAG) is emitted in continuous wave mode. The laser is primarily used in front-fire applications [317].
Different applications such as vaporesection (ThuVARP) have been published [318].
Efficacy: Several meta-analyses with pooled data from both RCTs (generally low quality), and non-RCTs have
evaluated ThuVARP vs. M-TURP [319-321], and B-TURP [322-324]. The largest meta-analyses included nine
RCTs and seven non-RCTs and reported no clinically relevant differences in efficacy (IPSS, QoL score and
Qmax) between ThuVARP and M-TURP or B-TURP at twelve months [323]. Data from one RCT with long-term
follow-up showed no difference in efficacy and re-operation rates between ThuVARP and M-TURP (2.1%
vs. 4.1%, respectively) [325]. A prospective multicentre study on ThuVARP, including 2,216 patients, showed
durable post-operative improvement in IPSS, QoL, Qmax, and PVR for the entire eight years of follow-up [326].
Tolerability and safety: In a number of meta-analyses longer operation times, shorter catheterisation/
hospitalisation times and less blood loss without significant differences in transfusion rates or in any other
short-term complication rates have been reported for ThuVARP compared to TURP [319-324]. A significantly
higher transfusion rate was reported after M-TURP in two meta-analyses [321, 323]. However, overall RCT
quality was relatively low with limited follow-up potentially accounting for under-reporting of late complications,
such as urethral stricture/BNC [323]. Data from three RCTs with mid- to long-term follow-up (18 to 48 months)
showed no differences in late complication rates between ThuVARP and TURP (BNC: 0.0%-2.1% vs. 0.0%4.1%; stricture: 0.0%-2.2% vs. 0.0%-2.2%, respectively) [325, 327, 328].
Haemoglobin drop was significantly higher in the bridging group in a retrospectively analysed case
series of 103 patients who underwent ThuVARP and received either low molecular weight heparin bridging or
continued antiplatelet/anticoagulant therapy [329].
Practical considerations: As a limited number of RCTs with mid- to long-term follow-up support the efficacy of
ThuVARP, there is a need for ongoing investigation of the technique.
Summary of evidence
Laser vaporesection of the prostate using Tm:YAG laser (ThuVARP) has longer operation times and
shorter catheterisation/hospitalisation times compared to TURP with no clinically relevant differences
in short-term efficacy and safety. Mid- to long-term results on efficacy and safety compared to TURP
are very limited.
Recommendation
Offer laser resection of the prostate using Tm:YAG laser (ThuVARP) as an alternative to
TURP.
30
LE
1a
Strength rating
Weak
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
5.3.1.4
Transurethral incision of the prostate
Mechanism of action: Transurethral incision of the prostate (TUIP) involves incising the bladder outlet without
tissue removal. Transurethral incision of the prostate is conventionally performed with Collins knife using
monopolar electrocautery; however, alternative energy sources such as holmium laser may be used [330]. This
technique may replace M-TURP in selected cases, especially in prostate sizes < 30 mL without a middle lobe.
Efficacy: An RCT comparing conventional TUIP vs. TUIP using holmium laser in prostates ≤ 30 mL with a
follow-up of twelve months, found both procedures to be equally effective in relieving BOO with similarly
low re-operation rates [330]. A meta-analysis of ten RCTs found similar LUTS improvements and lower but
significant improvements in Qmax for TUIP [331]. In this meta-analysis, an upper limit of prostate size was
reported as an entry criterion for eight studies with five < 30 mL and three < 60 mL. A meta-analysis of six trials
showed that re-operation was more common after TUIP (18.4%) than after M-TURP (7.2%) [331].
Tolerability and safety: An RCT comparing conventional TUIP vs. TUIP using holmium laser reported both
procedures to be safe with low complication rates; however, the operation time and retrograde ejaculation rate
was significantly lower in the conventional TUIP arm [330]. No cases of TUR-syndrome have been recorded
after TUIP. The risk of bleeding after TUIP is small [331].
Practical considerations: Transurethral incision of the prostate is an effective treatment for moderate-to-severe
LUTS secondary to BPO. The choice between M-TURP and TUIP should be based primarily on prostate
volume (30 mL TUIP) [331].
Summary of evidence
Transurethral incision of the prostate shows similar efficacy and safety to M-TURP for treating
moderate-to-severe LUTS secondary to BPO in men with prostates < 30 mL.
No case of TUR-syndrome has been recorded, the risk of bleeding requiring transfusion is negligible
and retrograde ejaculation rate is significantly lower after TUIP, but the re-operation rate is higher
compared to M-TURP.
The choice between TUIP and TURP should be based primarily on prostate volume (< 30 mL and
30-80 mL suitable for TUIP and TURP, respectively).
Recommendation
Offer transurethral incision of the prostate to surgically treat moderate-to-severe LUTS in
men with prostate size < 30 mL, without a middle lobe.
LE
1a
1a
4
Strength rating
Strong
5.3.2
Enucleation of the prostate
5.3.2.1
Open prostatectomy
Mechanism of action: Open prostatectomy is the oldest surgical treatment for moderate-to-severe LUTS
secondary to BPO. Obstructive adenomas are enucleated using the index finger, approaching from within
the bladder (Freyer procedure) or through the anterior prostatic capsule (Millin procedure). It is used for
substantially enlarged glands (> 80-100 mL).
Efficacy: Open prostatectomy reduces LUTS by 63-86% (12.5-23.3 IPSS points), improves QoL score by
60-87%, increases mean Qmax by up to 375% (+16.5-20.2 mL/s), and reduces PVR by 86-98%. Efficacy is
maintained for up to six years [332-337]. Data from an Austrian nationwide study of 1,286 men submitted to
OP showed that the endourological re-intervention rates after primary OP were 0.9%, 3.0%, 6.0%, and 8.8%,
at three months, one year, five years, and eight years, respectively. The respective incidence of re-TURP was
0.5%, 1.8%, 3.7% and 4.3%, respectively [9].
Two meta-analyses [338, 339] evaluated the overall efficacy of OP performed via a transvesical
approach vs. two transurethral enucleation techniques for treating patients with large glands, namely bipolar
transurethral enucleation of the prostate (B-TUEP) and holmium laser enucleation of the prostate (HoLEP).
The larger study included nine RCTs involving 758 patients [339]. Five RCTs compared OP with B-TUEP [337,
340-343] and four RCTs compared OP with HoLEP [332, 333, 344, 345]. At three, six, twelve and 24-months
follow-up there were no significant differences in Qmax [339]. Post-void residual, PSA, IPSS and QoL score
showed no significant differences at one, three, six and twelve months follow-up [339]. Randomised controlled
trials indicate that OP is as effective as HoLEP for improving micturition in large prostates [332, 333], with
similar improvement regarding Qmax, IPSS score and re-operation rates after five years [332].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
31
Tolerability and safety: Open prostatectomy mortality has decreased significantly during the past two decades
(< 0.25%) [336]. Data from an Austrian nationwide study totalling 1,286 men submitted to OP showed mortality
rates of 0.2% at 30 days and 0.4% at 90 days [293]. The estimated transfusion rate is about 7-14% [332,
335, 336, 338]. Long-term complications include transient urinary incontinence (up to 10%), BNC and urethral
stricture (about 6%) [332-334, 338, 346].
Two meta-analyses evaluated the overall safety of OP performed via a transvesical approach vs.
B-TUEP and HoLEP [338, 339]. Operation time did not differ significantly between OP and B-TUEP, but was
significantly shorter for OP compared to HoLEP. Catheterisation and hospitalisation time were significantly
longer for OP, which was also associated with more blood transfusions. There were no significant differences
regarding other complications. There was no significant difference in IIEF-5 at three, six, twelve and 24-months
follow-up.
Practical considerations: Open prostatectomy is the most invasive surgical method, but it is an effective
and durable procedure for the treatment of LUTS/BPO. In the absence of an endourological armamentarium
including a holmium laser or a bipolar system and with appropriate patient consent, OP is a reasonable surgical
treatment of choice for men with prostates > 80 mL.
Summary of evidence
Open prostatectomy is an effective and durable procedure for the treatment of LUTS/BPO, but it is the
most invasive surgical method.
Open prostatectomy shows similar short- and mid-term efficacy to B-TUEP and HoLEP for treating
moderate-to-severe LUTS secondary to BPO in patients with large prostates.
Open prostatectomy has a less favourable peri-operative safety profile compared to B-TUEP and
HoLEP.
The long-term functional results of OP are comparable to HoLEP.
LE
1b
1a
1a
1b
Recommendation
Strength rating
Offer open prostatectomy in the absence of bipolar transurethral enucleation of the prostate Strong
and holmium laser enucleation of the prostate to treat moderate-to-severe LUTS in men
with prostate size > 80 mL.
5.3.2.2
Bipolar transurethral enucleation of the prostate (B-TUEP)
Mechanism of action: Following the principles of bipolar technology (section 5.3.1.1), the obstructive adenoma
is enucleated endoscopically by the transurethral approach. Bipolar transurethral enucleation evolved from
plasmakinetic (PK) B-TURP and was introduced by Gyrus ACMI. The technique, also referred to as PK
enucleation of the prostate (PKEP), utilises a bipolar high-frequency generator and a variety of detaching
instruments, for this true bipolar system, including a point source in the form of a axipolar cystoscope
electrode suitable for enucleation [347] or a resectoscope tip/resection loop [348, 349]. More recently, a novel
form of B-TUEP has been described, bipolar plasma enucleation of the prostate (BPEP), stemming from
B-TURP (TURis, Olympus Medical), that utilises a bipolar high frequency generator and a variety of detaching
instruments including a mushroom- or button-like vapo-electrode [343, 350] and a Plasmasect enucleation
electrode [351] for this quasi-bipolar system. Bipolar transurethral enucleation of the prostate is followed by
either morcellation [343, 347] or resection [348-350, 352-354] of the enucleated adenoma.
Efficacy: One RCT evaluating PKEP vs. M-TURP in 204 patients with mean prostate volume < 80 mL reported
a significant improvement in IPSS, QoL, and Qmax, with urodynamically proven de-obstruction favouring PKEP
at 36 months follow-up [349]. The RCT concluded that the mid-term clinical efficacy of PKEP was comparable
to M-TURP [349]. A meta-analysis evaluating data from five RCTs including 666 patients submitted to B-TUEP
(PKEP or BPEP) vs. B-TURP, reported similar efficacy at twelve months in terms of IPSS, QoL and Qmax
[355]. Two RCTs evaluated the mid-term efficacy of PKEP vs. B-TURP at 36 months [348, 353] and one RCT
evaluated long-term efficacy at 60 months [354]. Efficacy was significantly better for PKEP in patients with large
prostates at 36, 48 and 60 months [348, 354]. Comparative data on efficacy for B-TUEP vs. OP and the various
forms of laser enucleation are presented in section 5.3.2.1 to 5.3.2.5, respectively.
Tolerability and safety: An RCT evaluating PKEP vs. M-TURP in patients with mean prostate volume < 80 mL
and 36 month follow-up reported that PKEP is superior to M-TURP in terms of haemoglobin drop, irrigation,
catheterisation and hospitalisation time [349]. No significant differences between the arms were reported in
operation time, blood transfusion rates, sexual function or any other reported complications (TUR-syndrome,
clot retention, incontinence, retrograde ejaculation, urethral structures/BNC) [349]. A meta-analysis including
32
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
five RCTs evaluating B-TUEP vs. B-TURP reported: similar operation, catheterisation and hospitalisation
times; lower acute urine retention rates; significantly reduced haemoglobin drop and blood transfusion rates;
no difference in erectile function; and no difference in all other reported complication rates including urethral
stricture/BNC rates for B-TUEP at 24 months follow-up [355]. No difference in urethral stricture/BNC rates was
reported at 60 months follow-up [354]. Comparative data on efficacy for B-TUEP vs. OP and the various forms
of laser enucleation are presented in section 5.3.2.1 to 5.3.2.5, respectively.
Summary of evidence
Bipolar transurethral (plasmakinetic) enucleation of the prostate shows favourable mid- to long-term
efficacy compared to TURP.
Bipolar transurethral (plasmakinetic) enucleation of the prostate has a favourable peri-operative safety
profile and demonstrates similar mid- to long-term safety compared to TURP.
Recommendation
Offer bipolar transurethral (plasmakinetic) enucleation of the prostate to men with
moderate-to-severe LUTS as an alternative to transurethral resection of the prostate.
LE
1b
1b
Strength rating
Weak
5.3.2.3
Holmium laser enucleation of the prostate
Mechanism of action: The holmium:yttrium-aluminium garnet (Ho:YAG) laser (wavelength 2,140 nm) is a pulsed
solid-state laser that is absorbed by water and water-containing tissues. Tissue coagulation and necrosis are
limited to 3-4 mm, which is enough to obtain adequate haemostasis [356].
Efficacy: An initial meta-analysis reported no significant differences in short-term efficacy (Qmax) and
re-intervention rates (4.3% vs. 8.8%) between HoLEP and M-TURP [357]; however, subsequent meta-analyses
reported favourable short-term efficacy (Qmax and IPSS) for HoLEP [289, 320, 355, 358]. Two meta-analyses
evaluating HoLEP vs. B-TURP showed no significant differences in short-term efficacy (IPSS, QoL score and
Qmax) [355, 359]. One RCT comparing HoLEP with M-TURP in a small number of patients with mean prostate
volume < 80 mL and a seven year follow-up found that the functional long term results were comparable
[360]. Another RCT comparing HoLEP with B-TURP in patients with prostate volume < 80 mL reported no
significant difference in IPSS, QoL score and Qmax at 24 months [361]. Long-term (72 months) improvement in
IPSS and Qmax was better for HoLEP, but there were no clinically relevant differences between the arms [362].
Comparative efficacy data for HoLEP vs. OP is presented in section 5.3.2.1. One small RCT evaluating HoLEP
vs. PKEP in patients with mean prostate volume < 80 mL reported similar improvements in IPSS and Qmax as
well as similar re-operation rates at twelve months follow-up [347].
Tolerability and safety: Meta-analyses found that HoLEP has longer operation times, shorter catheterisation and
hospitalisation times, reduced blood loss, fewer blood transfusions and no significant differences in urethral
strictures (2.6% vs. 4.4%) and stress urinary incontinence (1.5% vs. 1.5%) rates compared to M-TURP [320,
355, 357, 358, 363]. Two meta-analyses evaluated HoLEP vs. B-TURP [355, 359]. Zhang et al., reported longer
operation times for HoLEP, but no significant differences in hospitalisation time or complication rates whilst
Qian et al., reported no significant differences in operation and catheterisation times or short-term complication
rates [355, 359]. A RCT comparing HoLEP with B-TURP in patients with prostate volume < 80 mL reported
longer operation time, shorter catheterisation and hospitalisation times and a lower risk for haemorrhage for
HoLEP with no significant differences in blood transfusion rates or other complication rates at 24 months
[361]. Comparative data on safety of HoLEP vs. OP are presented in section 5.3.2.1. One small RCT evaluating
HoLEP vs. PKEP in patients with mean prostate volume < 80 mL reported significantly shorter operation
times for HoLEP, but similar catheterisation and hospitalisation times and complication rates at twelve months
follow-up [347].
Holmium laser enucleation of the prostate has been safely performed in patients using anticoagulant
and/or antiplatelet medications [364, 365]. However, current limitations include: a lack of RCTs; limited data
on short- and mid-term complications and bridging therapy; data presentation does not allow for separate
interpretation of either of the two substantially different topics of antiplatelet and anticoagulant therapy.
The impact on erectile function and retrograde ejaculation is comparable between HoLEP and TURP
[366, 367]. Erectile function did not decrease from baseline in either group; three quarters of sexually active
patients had retrograde ejaculation after HoLEP. Data have shown that ejaculation and orgasm perception are
the two most impacted domains after HoLEP [368]. Attempts to maintain ejaculatory function with HoLEP have
been reported to be successful in up to 46.2% of patients [369].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
33
Practical considerations: Holmium laser enucleation of the prostate requires experience and relevant
endoscopic skills. The experience of the surgeon is the most important factor affecting the overall occurrence
of complications [370, 371]. Mentorship programmes are advised to improve surgical performance from both
an institutional and personal learning curve perspective [372-374].
Summary of evidence
Laser enucleation of the prostate using Ho:YAG laser (HoLEP) demonstrates similar mid- to long-term
efficacy when compared to TURP.
Laser enucleation of the prostate using Ho:YAG laser (HoLEP) demonstrates similar short-term safety
when compared to TURP.
Laser enucleation of the prostate using Ho:YAG laser (HoLEP) demonstrates longer operation times,
but a more favourable peri-operative profile when compared to TURP.
Recommendation
Offer laser enucleation of the prostate using Ho:YAG laser (HoLEP) to men with moderateto-severe LUTS as an alternative to transurethral resection of the prostate or open
prostatectomy.
LE
1b
1a
1a
Strength rating
Strong
5.3.2.4
Thulium:yttrium-aluminium-garnet laser (Tm:YAG) enucleation of the prostate
Mechanism of action: The Tm:YAG laser has been described in section 5.3.1.3. Enucleation using the Tm:YAG
laser includes ThuVEP (vapoenucleation i.e. excising technique) and ThuLEP (blunt enucleation).
Efficacy: A meta-analysis evaluating ThuLEP vs. M-TURP and B-TURP reported no clinically relevant
differences in Qmax, IPSS and QoL score [355]. An RCT with five years follow-up comparing ThuLEP with
B-TURP found no difference between the two procedures for Qmax, IPSS, PVR, and QoL [375]. A meta-analysis
[376] evaluating ThuLEP vs. HoLEP showed no clinically relevant differences in IPSS, QoL score and Qmax at
twelve months in accordance with one RCT showing similar results at eighteen months [377]. Furthermore,
ThuLEP and PKEP were compared in one RCT with twelve months follow-up the outcome of which showed no
difference with regard to efficacy [378].
There are mainly prospective case studies on ThuVEP showing a significant improvement in IPSS,
Qmax, and PVR after treatment [379-382].
Tolerability and safety: A meta-analysis evaluating ThuLEP vs. M-TURP and B-TURP reported a longer
operation time and a shorter hospitalisation time for ThuLEP compared to M-TURP and B-TURP, respectively
with no difference in complication rates [355]. A meta-analysis [376] evaluating ThuLEP vs. HoLEP showed
a significant difference is enucleation time favouring ThuLEP, but no significant differences in operation,
catheterisation and hospitalisation times short-term complication rates, in accordance with one RCT showing
similar results, including no urethral and bladder neck strictures, at eighteen months [377]. ThuLEP and PKEP
were compared in one RCT with twelve months follow-up [378]. No significant difference in complication rates
was detected, but haemoglobin level decrease and catheterisation time was significantly lower for ThuLEP.
In comparative studies ThuVEP show high intra-operative safety [383], as well as in case series in
patients with large prostates [379] and anticoagulation or bleeding disorders [380, 384]. A study focusing on
post-operative complications after ThuVEP reported adverse events in 31% of cases, with 6.6% complications
greater then Clavien grade 2 [385]. One case control study on ThuVEP with 48-month follow-up reported longterm durability of voiding improvements and overall re-operation rates of 2.4% [384]. Two studies addressed
the impact of ThuVEP on sexual function, demonstrating no effect on erectile function with increased
prevalence of retrograde ejaculation post-operatively [386, 387].
Practical considerations: ThuLEP seems to offer similar efficacy and safety when compared to TURP, bipolar
enucleation and HoLEP; whereas, ThuVEP is not supported by RCTs. Based on the limited number of RCTs
and lack of long-term follow-up data there is a need for ongoing investigation of these techniques.
Summary of evidence
LE
1b
Enucleation of the prostate using the Tm:YAG laser demonstrates similar efficacy when compared to
M-TURP/bipolar transurethral (plasmakinetic) enucleation, HoLEP and B-TURP in the short-, mid-, and
long-term, respectively.
1b
Enucleation of the prostate using the Tm:YAG laser (ThuLEP) demonstrates similar safety compared
to TURP/bipolar transurethral (plasmakinetic) enucleation, and HoLEP in the short- and mid-term,
respectively.
34
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Vapoenucleation of the prostate using a Tm:YAG laser (ThuVEP) seems to be safe in patients with
large prostates and those receiving anticoagulant or antiplatelet therapy.
Recommendations
Offer enucleation of the prostate using the Tm:YAG laser (ThuLEP, ThuVEP) to men with
moderate-to-severe LUTS as an alternative to transurethral resection of the prostate,
holmium laser enucleation or bipolar transurethral (plasmakinetic) enucleation.
Offer Tm:YAG laser enucleation of the prostate to patients receiving anticoagulant or
antiplatelet therapy.
2b
Strength rating
Weak
Weak
5.3.2.5
Diode laser enucleation of the prostate
Mechanism of action: For prostate surgery, diode lasers with a wavelength of 940, 980, 1,318, and 1,470 nm
(depending on the semiconductor used) are marketed for vaporisation and enucleation. Only a few have been
evaluated in clinical trials [385].
Efficacy: One small RCT comparing 1,318 nm diode laser enucleation of the prostate (DiLEP) with B-TURP in
patients with mean prostate volume < 80 mL reported no significant differences in IPSS, QoL score, Qmax and
PVR at six months follow-up [388]. Another RCT comparing 1,470 nm DiLEP with B-TURP in 157 patients with
mean prostate volume < 80 mL also reported no significant differences in IPSS, QoL score, Qmax and PVR at
twelve months follow-up [389]. In addition, three RCTs comparing 980 nm DiLEP with PKEP in patients with
mean prostate volume < 80 mL [390, 391] and > 80 mL [392] reported no significant differences in IPSS, QoL
score, Qmax and PVR at twelve months follow-up.
Tolerability and safety: One small RCT comparing 1,318 nm DiLEP with B-TURP in patients with mean prostate
volume < 80 mL and six months follow-up reported a significantly longer operation time for DiLEP, but shorter
catheterisation and hospitalisation times, as well as less blood loss (without differences in blood transfusion
rates) [388]. No differences in complication rates were reported between the two arms [388]. Another RCT
comparing 1,470 nm DiLEP with B-TURP in 157 patients with mean prostate volume < 80 mL and twelve
months follow-up reported significantly shorter operation, catheterisation and hospitalisation times with less
blood loss (without differences in blood transfusion rates) for DiLEP, with no differences in complication rates
between the two arms [389]. Three RCTs comparing 980 nm DiLEP with PKEP in patients with mean prostate
volume < 80 mL [390, 391] and > 80 mL [392] and twelve months follow-up reported conflicting peri-operative
outcomes: operation time (no difference between arms [390], significanly shorter for DiLEP [391] or sgnificanly
longer for DiLEP [392]); catheterisation time (no difference between the two arms [390], significanly shorter for
DiLEP [391, 392]); hospitalisation time (no difference between arms [390, 391], significanly shorter for DiLEP
[392]); blood loss (no difference in haemoglobin drop between arms [390], significantly lower haemoglobin drop
for DiLEP [391, 392]). All trials reported no differences in blood transfusion rates and complication rates [390392].
Practical considerations: Diode laser enucleation seems to offer similar efficacy and safety when compared
to either B-TURP or bipolar transurethral (plasmakinetic) enucleation. Based on the limited number, mainly
low-quality RCTs, and controversial data on the retreatment rate, results for diode laser enucleation should be
evaluated in further higher quality RCTs.
Summary of evidence
Laser enucleation of the prostate using the 1,318 nm or 1,470 laser showed comparable short-term
efficacy and safety to B-TURP. Peri-operative parameters like blood loss, catheterisation time and
hospital stay are in favour of diode enucleation.
Laser enucleation of the prostate using the 980 nm laser showed comparable short-term efficacy and
safety to bipolar transurethral (plasmakinetic) enucleation.
Recommendation
Offer 120-W 980 nm, 1,318 nm or 1,470 nm diode laser enucleation of the prostate to
men with moderate-to-severe LUTS as a comparable alternative to bipolar transurethral
(plasmakinetic) enucleation or bipolar transurethral resection of the prostate.
LE
1b
1b
Strength rating
Weak
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
35
5.3.2.6
Enucleation techniques under investigation
5.3.2.6.1 Minimal invasive simple prostatectomy
Mechanism of action: The term minimal invasive simple prostatectomy (MISP) includes laparoscopic simple
prostatectomy (LSP) and robot-assisted simple prostatectomy (RASP). The technique for LSP was first
described in 2002 [393], while the first RASP was reported in 2008 [394]. Both LSP and RASP are performed
using different personalised techniques, based on the transcapsular (Millin) or transvesical (Freyer) techniques
of OP. An extraperitoneal approach is mostly used for LSP, while a transperitoneal approach is mostly used for
RASP.
Efficacy: A SR and meta-analysis showed that in 27 observational studies including 764 patients, the mean
increase in Qmax was 14.3 mL/s, and the mean improvement in IPSS was 17.2 [395]. Mean duration of
operation was 141 minutes and the mean intra-operative blood loss was 284 mL. One hundred and four
patients (13.6%) developed a surgical complication. In comparative studies to OP, length of hospital stay,
length of catheter use and estimated blood loss were significantly lower in the MISP group, while the duration
of operation was longer than in OP. There were no differences in improvements in Qmax, IPSS and perioperative complications between both procedures.
Two recent retrospective series on RASP were not included in the meta-analysis which confirm
these findings [396, 397]. The largest retrospective series reports 1,330 consecutive cases including 487
robotic (36.6%) and 843 laparoscopic (63.4%) simple prostatectomy cases. The authors confirm that both
techniques can be safely and effectively done in selected centres [396].
Tolerability and safety: In the largest series, the post-operative complication rate was 10.6% (7.1% for LSP and
16.6% for RASP), most of the complications being of low grade. The most common complications in the RASP
series were haematuria requiring irrigation, UTI and AUR; in the LSP series, the most common complications
were UTI, ileus and AUR. In the most recent, largest comparative analysis of robotic vs. OP for large-volume
prostates, a propensity score-matched analysis was performed with five covariates. Robotic compared with OP
demonstrated a significant shorter average length of hospital stay, but longer mean operative time. The robotic
approach was also associated with a lower estimated blood loss. Improvements in maximal flow rate, IPSS,
QoL, PVR and post-operative PSA levels were similar before and after surgery for both groups. There was no
difference in complications between the groups [398].
Practical considerations: Minimal invasive simple prostatectomy seems comparable to OP in terms of
efficacy and safety, providing similar improvements in Qmax and IPSS [395]. However, most studies are of a
retrospective nature. High-quality studies are needed to compare the efficacy, safety, and hospitalisation times
of MISP and both OP and endoscopic methods. Long-term outcomes, learning curve and cost of MISP should
also be evaluated.
Summary of evidence
LE
Minimal invasive simple prostatectomy is feasible in men with prostate sizes > 80 mL needing surgical 1a
treatment; however, RCTs are needed.
5.3.2.6.2 532 nm (‘Greenlight’) laser enucleation of the prostate
Mechanism of action: The Potassium-Titanyl-Phosphate (KTP) and the lithium triborate (LBO) lasers work at
a wavelength of 532 nm. Laser energy is absorbed by haemoglobin, but not by water. Vaporisation leads to
immediate removal of prostatic tissue. Three “Greenlight” lasers exist, which differ not only in maximum power
output, but more significantly in fibre design and the associated energy tissue interaction of each. The standard
Greenlight device today is the 180-W XPS laser, but the majority of evidence is published with the former 80-W
KTP or 120-W HPS (LBO) laser systems.
Two approaches for KTP/LBO laser based enucleation technique exist [399]. GreenLEP is an
anatomical enucleation technique following the principle of blunt dissection of the adenoma with the sheath
and laser energy for incision as described for ThuLEP [400]. En bloc GreenLEP preparation has been
popularised with the same approach. A variation of the most commonly applied GreenLEP technique, with
tissue morcellation, is the in situ vaporisation of apically enucleated tissue, also referred to as anatomic
vaporisation-incision technique [400, 401]. Lithium triborate/Greenlight vapoenucleation on the other hand uses
vapoincising laser energy to cut out the tissue [402]. To date no RCTs evaluating enucleation using the KTP/
LBO laser exist [403].
36
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
5.3.3
Vaporisation of the prostate
5.3.3.1
Bipolar transurethral vaporisation of the prostate
Mechanism of action: Bipolar transurethral vaporisation of the prostate (B-TUVP) was introduced in the late
1990s (“PK” B-TUVP). The technique was derived from PK B-TURP and utilised a bipolar electrode and a highfrequency generator to create a plasma effect able to vaporise prostatic tissue [404]. With minimal direct tissue
contact (near-contact; hovering technique) and heat production the bipolar electrode produces a constant
plasma field (thin layer of highly ionized particles; plasma corona), allowing it to glide over the tissue and
vaporise a limited layer of prostate cells without affecting the underlying tissue whilst achieving haemostasis,
leaving behind a TURP-like cavity [405]. A distinct difference between B-TUVP and its ancestor (monopolar
TUVP), is that B-TUVP displays thinner (< 2 mm) coagulation zones [406], compared to the disproportionate
extent of those created by the former (up to 10 mm) [407], that potentially lead to mostly irritative side-effects
and stress urinary incontinence [406, 408, 409].
Efficacy: Bipolar-TUVP has been evaluated as a TURP alternative for treating moderate-to-severe LUTS in
thirteen RCTs to date, including a total of 1,244 men with a prostate size of < 80 mL [303, 410-421]. Early
RCTs evaluated the PK B-TUVP system [410-414]; however, during the last decade, only the “plasma” B-TUVP
system with the “mushroom- or button-like” electrode (Olympus, Medical) has been evaluated [303, 415-421].
Results have been pooled in three RCT-based meta-analyses [289, 422, 423], and a narrative synthesis has
been produced in two SRs [289, 424]. The follow-up in most RCTs is twelve months [410-413, 415-417, 419,
421]. The longest follow-up is 36 months in a small RCT (n = 40) and eighteen months in a subsequent RCT
n = 340); evaluating PK [414] and plasma B-TUVP [303], respectively.
Early pooled results concluded that no significant differences exist in short-term efficacy (IPSS,
QoL score, Qmax and PVR) between PK B-TUVP and TURP [289]. However, the promising initial efficacy profile
of the former may be compromised by inferior clinical outcomes (IPSS, Qmax) at mid-term. Larger RCTs with
longer follow-up are necessary to draw definite conclusions [289, 414]. A SR of seven RCTs comparing PK
and plasma B-TUVP with TURP concluded that functional outcomes of B-TUVP and TURP do not differ [424].
The poor quality of the included RCTs and the fact that most data was derived from a single institution was
highlighted [424]. A similar SR of eight RCTs comparing both B-TUVP techniques with TURP concluded that
not enough consistent data suitable for a meta-analysis exists; that main functional results are contradictory;
and that heterogeneity of RCTs, non-standardised techniques and methodological limitations do not permit firm
conclusions [289]. A meta-analysis of six RCTs specifically evaluating plasma B-TUVP vs. TURP, concluded
that both techniques result in a similar improvement of LUTS [423].
Tolerability and safety: Early pooled results concluded that no statistically significant differences exist
collectively for intra-operative and short-term complications between PK B-TUVP and TURP, but peri-operative
complications are significantly fewer after B-TUVP [289]. However, the results of a statistical analysis comparing
pooled specific complication rates were not directly reported in this meta-analysis [289]. Mid-term safety results
(urethral stricture, ED, and retrograde ejaculation) have also been reported to be similar [414], but larger RCTs
with longer follow-up are necessary to draw definite conclusions [289, 414]. A SR of seven RCTs comparing
PK and plasma B-TUVP with TURP concluded that most RCTs suggest a better haemostatic efficiency for
B-TUVP, resulting in shorter catheterisation (42.5 vs. 77.5 hours) and hospitalisation times (3.1 vs. 4.4 days)
[424]. A similar SR of eight RCTs comparing both B-TUVP techniques with TURP concluded that not enough
consistent data suitable for a meta-analysis exists and that heterogeneity of RCTs, non-standardised techniques
and methodological limitations do not permit firm conclusions [289]. A meta-analysis of six RCTs specifically
evaluating plasma B-TUVP vs. TURP, concluded that no significant differences exist between the techniques
in overall complication and transfusion rates [423]. However, a statistically significant difference was detected
collectively in major complication rates (Clavien 3, 4; including urethral stricture, severe bleeding necessitating
re-operation and urinary incontinence) and in the duration of catheterisation favouring plasma B-TUVP.
Practical considerations: Bipolar-TUVP and TURP have similar short-term efficacy. Plasmakinetic B-TUVP has a
favourable peri-operative profile, similar mid-term safety, but inferior mid-term efficacy compared to TURP. Plasma
B-TUVP has a lower short-term major morbidity compared to TURP. Randomised controlled trials of higher quality,
multicentre RCTs, and longer follow-up periods are needed to evaluate B-TUVP in comparison to TURP.
Summary of evidence
Bipolar-TUVP and TURP have similar short-term efficacy.
Plasmakinetic B-TUVP has a favourable peri-operative profile, similar mid-term safety, but inferior
mid-term efficacy compared to TURP.
Plasma B-TUVP has a lower short-term major morbidity rate compared to TURP.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
LE
1a
1a
1a
37
Recommendation
Offer bipolar transurethral vaporisation of the prostate as an alternative to monopolar
transurethral resection of the prostate to surgically treat moderate-to-severe LUTS in men
with a prostate volume of 30-80 mL.
Strength rating
Weak
5.3.3.2
532 nm (‘Greenlight’) laser vaporisation of the prostate
Mechanism of action: The Potassium-Titanyl-Phosphate (KTP) and the lithium triborate (LBO) lasers have been
described in section 5.3.2.6.2.
Efficacy: A meta-analysis of the nine available RCTs comparing photoselective vaporisation of the prostate
(PVP) using the 80-W and 120-W lasers with TURP was performed in 2012 [425]. No differences were found in
Qmax and IPSS between 80-W PVP and TURP, but only three RCTs provided sufficient twelve month data to be
included in the meta-analysis [426-428]. Another meta-analysis from 2016, of four RCTs including 559 patients,
on the 120-W laser, demonstrated no significant difference in functional and symptomatic parameters at 6-,
12-, and 24-month follow-up when compared to TURP [429].
The only available RCT for the 180-W laser reported non-inferiority to TURP in terms of IPSS, Qmax,
PVR volume, prostate volume reduction, PSA decrease and QoL questionnaires. Efficacy outcomes were
similar to TURP with stable results at 24 months follow-up [430].
The longest RCT comparing the 120-W HPS laser with TURP had a follow-up of 36 months and
showed a comparable improvement in IPSS, Qmax, and PVR [431]. Comparable improvements in IPSS, QoL,
Qmax, or urodynamic parameters were reported from two RCTs with a maximum follow-up of 24 months [427,
432]. A SR and meta-analysis of eleven RCTs comparing M-TURP with the 80-W KTP or 120-W HPS system
found no significant difference with respect to IPSS and Qmax improvement [433].
One RCT comparing HoLEP to PVP, in patients with prostates > 60 mL, showed comparable
symptom improvement, but significantly higher flow rates and lower PVR volume after HoLEP at short-term
follow-up; in addition, PVP showed a 22% conversion rate to TURP [434].
Tolerability and safety: A meta-analysis of RCTs comparing the 80-W and 120-W lasers with TURP showed a
significantly longer operating time, but shorter catheterisation time and length of hospital stay after PVP [289].
Blood transfusions and clot retention were less with PVP. No difference was noted in post-operative urinary
retention, infection, meatal stenosis, urethral stricture, or bladder neck stenosis [289]. In a meta-analysis
including trials with the 120-W laser, patients in the PVP group demonstrated significantly lower transfusion
rates, shorter catheterisation time and shorter duration of hospital stay compared to TURP. Re-operation rates
and operation time were in favour of TURP. No significant differences were demonstrated for treatment for
urethral stricture, BNC, incidence of incontinence and infection [429]. A SR and meta-analysis of eleven RCTs
comparing M-TURP with the 80-W KTP or 120-W HPS system found that PVP was superior to M-TURP with
regard to transfusion rate, clot retention, catheterisation and hospitalisation time [433].
180-W Greenlight laser prostatectomy is non-inferior to TURP in terms of peri-operative
complications. Re-operation free survival during 24 months follow-up was comparable between the TURP-arm
and the 180-W XPS laser-arm [430]. In an RCT comparing the 120-W HPS laser with TURP, with a follow-up of
36 months, the re-operation rate was significantly higher after PVP (11% vs. 1.8%; p = 0.04) [431].
Based mostly on case series the 80-,120- and 180-W Greenlight laser appears to be safe in
high-risk patients undergoing anticoagulation treatment [435-438]; however, patients under anticoagulation
therapy were either excluded from or represented a very small sample in currently available RCTs. In one
study, anticoagulant patients had significantly higher rates of bladder irrigation (17.2%) compared with
those not taking anticoagulants (5.4%) [438]. In contrast, another retrospective study focusing on the 180-W
LBO laser did not find any significant differences between patients receiving or not receiving anticoagulants
[439]. A retrospective study of a mixed cohort of patients, treated with 80-W KTP PVP and 120-W LBO HPS,
revealed that delayed gross haematuria was common in patients (33.8%) during an average follow-up of 33
months [440]. A retrospective review of a database of patients undergoing 180-W PVP, without interruption of
anticoagulation therapy, had a 30.5% rate of peri-operative adverse events with a significant occurrence of
high grade Clavien Dindo events [441].
Safety in patients with urinary retention, impaired detrusor contractility, elderly patients or prostates
> 80 mL was shown in various prospective short-term non-randomised trials. No RCT including prostates
> 100 mL has been reported; therefore, comparison of retreatment rates between prostate volumes of different
sizes is not possible [442-444].
An RCT with twelve months follow-up reported a retrograde ejaculation rate of 49.9% following PVP
with an 80-W laser vs. 56.7% for TURP, there was no impact on erectile function in either arm of the trial [445].
Additional studies have also reported no difference between OP/TURP and Greenlight PVP for erectile function
[446, 447]. However, IIEF-5 scores were significantly decreased at 6-, 12-, and 24- months in patients with preoperative IIEF-5 greater than 19 [448].
38
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Practical considerations: The 180-W XPS represents the current standard of generators for PVP; however, the
number and quality of supporting publications are low, especially for large glands (> 100 mL), with no long-term
follow up.
Summary of evidence
Laser vaporisation of the prostate using the 80-W KTP and the 120-W LBO laser (PVP) demonstrated
higher intra-operative safety with regard to haemostatic properties when compared to TURP. Perioperative parameters such as catheterisation time and hospital stay are in favour of PVP, whereas
operation time and risk of re-operation are in favour of TURP. Short-term results for the 80-W KTP
laser and mid-term results for the 120-W LBO laser were comparable to TURP.
Laser vaporisation of the prostate using the 180-W LBO laser (PVP) demonstrated higher intraoperative safety with regard to haemostatic properties when compared to TURP. Peri-operative
parameters such as catheterisation time and hospital stay were in favour of PVP, whereas operation
time was in favour of TURP. Short- to mid-term results are comparable to TURP.
Laser vaporisation of the prostate using the 80-W KTP and 120-W LBO lasers seems to be safe for the
treatment of patients receiving antiplatelet or anticoagulant therapy.
Laser vaporisation of the prostate using the 180-W LBO laser seems to be safe for the treatment of
patients receiving antiplatelet or anticoagulant therapy; however, the level of available evidence is low.
Recommendations
Offer 80-W 532-nm Potassium-Titanyl-Phosphate (KTP) laser vaporisation of the prostate
to men with moderate-to-severe LUTS with a prostate volume of 30-80 mL as an alternative
to transurethral resection of the prostate (TURP).
Offer 120-W 532-nm Lithium Borat (LBO) laser vaporisation of the prostate to men with
moderate-to-severe LUTS with a prostate volume of 30-80 mL as an alternative to TURP.
Offer 180-W 532-nm LBO laser vaporisation of the prostate to men with moderate-tosevere LUTS with a prostate volume of 30-80 mL as an alternative to TURP.
Offer laser vaporisation of the prostate using 80-W KTP, 120- or 180-W LBO lasers for the
treatment of patients receiving antiplatelet or anticoagulant therapy with a prostate volume
< 80 mL.
LE
1a
1b
2
3
Strength rating
Strong
Strong
Strong
Weak
5.3.3.3
Vaporisation techniques under investigation
5.3.3.3.1 Diode laser vaporisation of the prostate
Mechanism of action: For prostate surgery, diode lasers with a wavelength of 980 nm are marketed for
vaporisation; however, only a few have been evaluated in clinical trials [317].
Efficacy: Two RCTs for 120-W 980 nm diode laser vaporisation vs. M-TURP are available [449, 450]. The first
RCT with 24 month follow-up reported equal symptomatic and clinical parameters at one and six months.
However, at 12- and 24-months the results were significantly in favour of TURP, repeat TURP was more
frequent in the diode laser group [449]. The second RCT reported equivocal results for both interventions at
3-month follow-up [450].
Tolerability and safety: Published studies on 980 nm diode laser vaporisation indicate high haemostatic
potential, although anticoagulants or platelet aggregation inhibitors were taken in 24% and 52% of patients,
respectively [451, 452]. In a number of studies, a high rate of post-operative dysuria was reported [449, 451453]. In an RCT reflecting on peri-operative and post-operative complications no significant differences were
demonstrated for clot retention, re-catheterisation, UUI and UTI [449]. Moreover, for late complications no
significant differences could be demonstrated for re-operation rate, urethral stricture, bladder neck sclerosis,
de novo sexual dysfunction and mean time of dysuria [449].
Fibre modifications can potentially reduce surgical time [454]. Early publications on diode
vaporisation reported high re-operation rates (8-33%) and persisting stress urinary incontinence (9.1%) [449,
451-453].
Practical considerations: Diode laser vaporisation leads to similar improvements in clinical and symptomatic
parameters during short-term follow-up and provides good haemostatic properties. Based on the limited
number, mainly low quality RCTs, and controversial data on the retreatment rate, results for diode laser
vaporisation should be evaluated in further higher quality RCTs.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
39
Summary of evidence
Laser vaporisation of the prostate using the 120-W 980 nm diode laser demonstrated high intraoperative safety with regard to haemostatic properties when compared to TURP. Peri-operative
parameters like catheterisation time and hospital stay were in favour of diode lasers. Evidence is
limited by the number and quality of the available studies.
In a number of studies severe post-operative complications such as severe storage symptoms and
persisting incontinence occurred with laser vaporisation of the prostate using the 120-W 980 nm diode
laser.
Laser vaporisation using the 120-W 980 nm diode laser seems to be safe with regard to haemostasis
in patients receiving anticoagulant therapy.
LE
1b
3
3
5.3.4
Alternative ablative techniques
5.3.4.1
Aquablation – image guided robotic waterjet ablation: AquaBeam
Mechanism of action: AquaBeam uses the principle of hydro-dissection to ablate prostatic parenchyma while
sparing collagenous structures like blood vessels and the surgical capsule. A targeted high velocity saline
stream ablates prostatic tissue without the generation of thermal energy under real-time transrectal ultrasound
guidance; therefore, it is truly a robotic operation. After completion of ablation haemostasis is performed with a
Foley balloon catheter on light traction or diathermy or low-powered laser, if necessary [455].
Efficacy: In a double-blind, multicentre, prospective RCT 181 patients were randomised to TURP or
Aquablation [456, 457]. Mean total operative time was similar for Aquablation and TURP (33 vs. 36 minutes),
but resection time was significantly lower for Aquablation (4 vs. 27 minutes). At six months patients treated with
Aquablation and TURP experienced large IPSS improvements (-16.9 and -15.1, respectively). The study noninferiority hypothesis was satisfied. Larger prostates (50-80 mL) demonstrated a more pronounced benefit. At
one year follow-up, mean IPSS reduction was 15.1 in the Aquablation group and 15.1 in the TURP group with a
mean percent reduction in IPSS score of 67% in both groups. Ninety three percent and 86.7% of patients had
improvements of at least five points from baseline, respectively. No significant difference in improvement of
IPSS, QoL, Qmax and reduction of PVR was reported between the groups. One TURP subject (1.5%) and three
Aquablation subjects (2.6%) underwent re-TURP within one year of the study procedure [458]. In the American
cohort of this study (90 patients) one year data showed less anejaculation in patients treated with aquablation
(9%) compared with TURP (45%) in sexually active subjects [457].
A subgroup analysis of the WATER study [456] reported that in men with larger more complex
prostates Aquablation was associated with both superior symptom improvement and a better safety profile
with less post-operative anejaculation [459].
In a cohort study of 101 men with a prostate volume between 80-150 mL mean IPSS improved
from 23.2 at baseline to 5.9 at six months. Improvement in IPSS, QoL, Qmax and reduction of PVR were also
significant at six months. No secondary procedures for tissue removal occurred as of the six months [460].
Another RCT comparing Aquablation with TURP performed urodynamic studies on 66 patients at six
months follow-up and reported significant changes in pdetQmax (reductions of 35 and 34 cm H20, respectively)
and large improvements in BOO Index in both groups [461].
Tolerability and safety: An RCT has shown that fewer men in the Aquablation group had a persistent ClavienDindo grade 1 or 2 or higher adverse event compared to TURP (26% vs. 42%) at three months following
treatment. Among sexually active men the rate of anejaculation was lower in those treated with Aquablation
compared to TURP (10% vs. 36%, respectively). There were no procedure-related adverse events after six
months [458]. In patients with a prostate volume between 80-150 mL, bleeding related events were observed
in fourteen patients (13.9%) of which eight (7.9%) occurred prior to discharge and six (5.9%) occurred within
one month of discharge. Blood transfusions were required in eight (7.9%) patients, return to the theatre for
fulguration in three (3.0%) patients, and both transfusion and fulguration in two patients (2.0%). Ejaculatory
dysfunction occurred in 19% of sexually active men [460].
Practical considerations: During short-term follow-up, Aquablation provides non-inferior functional outcomes
compared to TURP in patients with LUTS and a prostate volume between 30-80 mL. Longer term follow-up is
necessary to assess the clinical value of Aquablation.
Summary of evidence
Aquablation appears to be as effective as TURP both subjectively and objectively; however, there are
still some concerns about the best methods of achieving post-treatment haemostasis.
40
LE
1b
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Recommendations
Offer Aquablation* to patients with moderate-to-severe LUTS and a prostate volume of
30-80 mL as an alternative to TURP.
Inform patients about the risk of bleeding and the lack of long-term follow-up data.
Strength rating
Weak
Strong
*Approach remains under investigation
5.3.4.2
Prostatic artery embolisation
Mechanism of action: Prostatic artery embolisation (PAE) can be performed as a day case procedure under
local anaesthesia with access through the femoral or radial arteries. Digital subtraction angiography displays
arterial anatomy and the appropriate prostatic arterial supply is selectively embolised to effect stasis in treated
prostatic vessels. Different techniques have been used for PAE. Atherosclerosis, excessive tortuosity of the
arterial supply and the presence of adverse collaterals are anatomical obstacles for the technical approach.
Cone beam computed tomography and contrast enhanced MR angiography can help identify prostatic arteries
and prevent off-target embolisation particularly in patients with challenging anatomical configurations [462, 463].
Efficacy: Two RCTs were conducted for direct comparison of PAE with TURP [464, 465]. Both studies observed
significant treatment outcomes for both procedures as compared to baseline values, but TURP was superior
when considering urodynamic parameters such as Qmax and PVR. Improvement of LUTS as determined by
IPSS and QoL was slightly more pronounced after TURP and reduction of prostate volume was significantly
more efficient after TURP than PAE.
Another RCT comparing PAE with TURP in 99 patients showed a mean reduction in IPSS from
baseline to twelve weeks of −9.23 points after PAE and −10.77 points after TURP. At twelve weeks, PAE
was less effective than TURP regarding improvements in Qmax (5.19 mL/s vs. 15.34 mL/s), PVR (−86.36 mL
vs. −199.98 mL), prostate volume (−12.17 mL vs. −30.27 mL), and significant de-obstructive effectiveness
according to pressure flow studies (56% vs. 93% shift towards less obstructive category). For secondary
outcomes, compared with PAE, procedural time was shorter for TURP, but in PAE patients, bladder catheter
indwelling time, and duration of hospital stay were significantly shorter [462].
Another SR and meta-analysis including the three above mentioned RCTs and two non-randomised
comparative studies (n = 708 patients), showed that TURP achieved a significantly higher mean postoperative difference for IPSS and IPSS-QoL, 3.80 and 0.73 points, respectively compared to PAE [466]. All of
the functional outcomes assessed were significantly superior after TURP: 3.62 mL/s for Qmax, 11.51 mL for
prostate volume, 11.86 mL for PVR, and 1.02 ng/mL for PSA [466].
Tolerability and safety: In a SR of comparative studies PAE resulted in significantly more adverse events than
TURP/OP (41.6% vs. 30.4%). The frequency of AUR after the procedures was significantly higher in the PAE
group (9.4% vs. 2.0%) [467].
Another RCT however, reported fewer adverse events occurred after PAE than after TURP (36 vs.
70 events; p = 0.003). For secondary outcomes, PAE showed favourable results in terms of blood loss [462]. A
SR and meta-analysis of four studies (506 patients) comparing PAE and TURP found no significant difference in
the post-operative complication rate between TURP and PAE [468]. A SR of 708 patients whilst confirming that
PAE was not as effective as TURP, it did report fewer side effects than established surgical procedures [466].
Post-operative erectile function measured by IIEF-5 was in favour of PAE with mean difference in change of
2.56 points. Concerns still exist about non-target embolisation, reported in earlier studies [469]; however, more
recent studies report less incidents [466, 470].
Practical considerations: A multidisciplinary team approach of urologists and radiologists is mandatory and
patient selection should be done by urologists and interventional radiologists together. The investigation of
patients with LUTS to indicate suitability for invasive techniques should be performed by urologists only. This
technically demanding procedure should only be done by an interventional radiologist with specific mentored
training and expertise in PAE [471]. Patients with larger prostates (> 80 mL) may have the most to gain from
PAE. The selection of LUTS patients who will benefit from PAE still needs to be better defined [466]. Further
data with medium- and long-term follow-up are still required and comparison with other minimally invasive
techniques would be valuable. However, current evidence of safety and efficacy of PAE appears adequate
to support the use of this procedure for men with moderate-to-severe LUTS provided proper arrangements
for consent and audit are in place; therefore, a recommendation has been given, but PAE remains under
investigation.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
41
Summary of evidence
Prostatic artery embolisation is less effective than TURP at improving symptoms and urodynamic
parameters such as flow rate.
Procedural time is longer for PAE compared to TURP, but blood loss, catheterisation and
hospitalisation time are in favour of PAE.
Recommendations
Offer prostatic artery embolisation (PAE)* to men with moderate-to-severe LUTS who
wish to consider minimally invasive treatment options and accept less optimal outcomes
compared with transurethral resection of the prostate.
Perform PAE only in units where the work up and follow-up is performed by urologists
working collaboratively with trained interventional radiologists for the identification of PAE
suitable patients.
*Approach remains under investigation
LE
1a
1b
Strength rating
Weak
Strong
5.3.4.3
Alternative ablative techniques under investigation
5.3.4.3.1 Convective water vapour energy (WAVE) ablation: The Rezum system
Mechanism of action: The Rezum system uses radiofrequency power to create thermal energy in the form of
water vapour, which in turn deposits the stored thermal energy when the steam phase shifts to liquid upon cell
contact. The steam disperses through the tissue interstices and releases stored thermal energy onto prostatic
tissue effecting cell necrosis. The procedure can be performed in an office based setting. Usually, one to three
injections are needed for each lateral lobe and one to two injections may be delivered into the median lobe.
Efficacy: In a multicentre, randomised, controlled study 197 men were enrolled and randomised in a 2:1 ratio
to treatment with water vapour energy ablation or sham treatment [472]. At three months relief of symptoms,
measured by a change in IPSS and Qmax were significantly improved and maintained compared to the sham
arm, although only the active treatment arm was followed up to twelve months. No relevant impact was
observed on PVR. Quality of life outcome was significantly improved with a meaningful treatment response
of 52% at twelve months. Further validated objective outcome measures such as BPH impact index (BPHII),
Overactive Bladder Questionnaire Short Form for OAB bother, and impact on QoL and International Continence
Society Male Item Short Form Survey for male incontinence demonstrated significant amelioration of
symptoms at three months follow-up with sustained efficacy throughout the study period of twelve months.
The reported two year results in the Rezum cohort arm of the same study and the recently reported four year
results confirmed durability of the positive clinical outcome after convective water vapour energy ablation [473,
474]. Surgical retreatment rate was 4.4% over four years [474].
Tolerability and safety: Safety profile was favourable with adverse events documented to be mild-to-moderate
and resolving rapidly. Preservation of erectile and ejaculatory function after convective water vapour thermal
therapy was demonstrated utilising validated outcome instruments such as IIEF and Male Sexual Health
Questionnaire-Ejaculation Disorder Questionnaire [472].
Practical considerations: Randomised controlled trials against a reference technique are needed to confirm the
first promising clinical results and to evaluate mid- and long-term efficacy and safety of water vapour energy
treatment.
5.3.5
Non-ablative techniques
5.3.5.1
Prostatic urethral lift
Mechanism of action: The prostatic urethral lift (PUL) represents a novel minimally invasive approach under
local or general anaesthesia. Encroaching lateral lobes are compressed by small permanent suture-based
implants delivered under cystoscopic guidance (Urolift®) resulting in an opening of the prostatic urethra leaving a
continuous anterior channel through the prostatic fossa extending from the bladder neck to the verumontanum.
Efficacy: In general, PUL achieves a significant improvement in IPSS (-39% to -52%), Qmax (+32% to +59%)
and QoL (-48% to -53%) [475-480]. Prostatic urethral lift was initially evaluated vs. sham in a multicentre
study with one [477] three [481] and five [482] years follow-up. The primary endpoint was met at three months
with a 50% reduction in IPSS. In addition, Qmax increased significantly from 8.1 to 12.4 mL/s compared to
baseline at three months and this result was confirmed at twelve months. The difference in clinical response
for Qmax between both groups was of statistical significance. A relevant benefit with regard to PVR was
not demonstrated compared to baseline or sham. At three years, average improvements from baseline
were significant for total IPSS, QoL, Qmax and individual IPSS symptoms. There was no de novo, sustained
42
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
ejaculatory or erectile dysfunction events and all sexual function assessments showed average stability or
improvement after PUL. Improvements in IPSS, QoL, BPHII and Qmax were durable throughout the five years
with improvement rates of 36%, 50%, 52%, and 44%, respectively. The re-treatment rate was 13.6% over five
years. Adverse events were mild to moderate and transient. Sexual function was stable over five years with no
de novo, sustained erectile, or ejaculatory dysfunction.
Another RCT of 80 patients was conducted in three European countries, comparing PUL to
TURP. At twelve months, IPSS improvement was -11.4 for PUL and -15.4 for TURP. There was no retrograde
ejaculation among PUL patients with 40% in the TURP patients. Surgical recovery was measured using a
validated instrument and confirmed that recovery from PUL is more rapid and more extensive in the first three
to six months [483]. However, TURP resulted in much greater improvements in Qmax after twelve months
compared to PUL. At 24 months, significant improvements in IPSS, IPSS QoL, BPHII, and Qmax were observed
in both arms. Change in IPSS and Qmax in the TURP arm were superior to the PUL arm [484]. Improvements in
QoL and BPHII score were not statistically different between the study arms. Prostatic urethral lift resulted in
superior quality of recovery and ejaculatory function preservation. Ejaculatory function and bother scores did
not change significantly in either treatment arm.
In a meta-analysis of retrospective and prospective trials, pooled estimates showed an overall
improvement following PUL, including IPSS, Qmax, and QoL [480]. Sexual function was preserved with a small
improvement estimated at twelve months.
Tolerability and safety: The most common complications reported post-operatively included haematuria
(16-63%), dysuria (25-58%), pelvic pain (5-17.9%), urgency (7.1-10%), transient incontinence (3.6-16%), and
UTI (2.9-11%) [477, 480-482]. Most symptoms were mild-to-moderate in severity and resolved within two to
four weeks after the procedure.
Prostatic urethral lift seems to have no significant impact on sexual function. Evaluation of sexual
function as measured by IIEF-5, Male Sexual Health Questionnaire-Ejaculatory Dysfunction, and Male Sexual
Health Questionnaire-Bother in patients undergoing PUL showed that erectile and ejaculatory function were
preserved [475-479].
Practical considerations: There are only limited data on treating patients with an obstructed/protruding middle
lobe [485]. It appears that they can be effectively treated with a variation in the standard technique, but further
data are needed [485]. The effectiveness in large prostate glands has not been shown yet. Long-term studies
are needed to evaluate the duration of the effect in comparison to other techniques.
Summary of evidence
Prostatic urethral lift improves IPSS, Qmax and QoL; however, these improvements are inferior to TURP
at 24 months.
Prostatic urethral lift has a low incidence of sexual side effects.
Patients should be informed that long-term effects including the risk of retreatment have not been
evaluated.
Recommendation
Offer Prostatic urethral lift (Urolift®) to men with LUTS interested in preserving ejaculatory
function, with prostates < 70 mL and no middle lobe.
LE
1b
1b
4
Strength rating
Strong
5.3.5.2
Intra-prostatic injections
Mechanism of action: Various substances have been injected directly into the prostate in order to improve
LUTS, these include Botulinum toxin-A (BoNT-A), fexapotide triflutate (NX-1207) and PRX302. The primary
mechanism of action of BoNT-A is through the inhibition of neurotransmitter release from cholinergic neurons
[486]. The detailed mechanisms of action for the injectables NX-1207 and PRX302 are not completely
understood, but experimental data associates apoptosis-induced atrophy of the prostate with both drugs [486].
Efficacy: Results from clinical trials have shown only modest clinical benefits, that do not seem to be superior
to placebo, for BoNT-A [487, 488]. A recent SR and meta-analysis showed no differences in efficacy compared
with placebo and concluded that there is no evidence of clinical benefits in medical practice [489]. The positive
results from Phase II-studies have not be confirmed in Phase III-trials for PRX302 [490, 491]. NX-1207 was
evaluated in two multicentre placebo controlled double-blind randomised parallel group trials including a total
of 995 patients with a mean follow-up of 3.6 years, IPSS change from baseline was significantly higher and
AUR rate was significantly reduced in the treatment arm. The authors concluded that NX-1207 is an effective
transrectal injectable for long-term treatment for LUTS and that treated patients have reduced need for further
intervention [492].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
43
Safety: Studies including safety assessments have reported only a few mild and self-limiting adverse events
for all injectable drugs [486]. A recent SR and meta-analysis showed low incident rates of procedure-related
adverse events [489]. Two multicentre placebo controlled double-blind randomised parallel group trials with
long-term follow-up evaluating NX-1207 detected no significant safety differences between the study arms
[492].
Practical considerations: Although experimental evidence for compounds such as BoNT-A and PRX302 were
promising for their transition to clinical use positive results from Phase II-studies have not be confirmed in
Phase III-trials. Randomised controlled trials against a reference technique are needed to confirm the first
promising clinical results of NX-1207.
Summary of evidence
Results from clinical trials have shown no clinical benefits for BoNT-A compared to placebo for the
management of LUTS due to BPO.
Results from clinical trials have shown clinical benefits for NX-1207 compared to placebo for the
management of LUTS due to BPO.
Recommendation
Do not offer intraprostatic Botulinum toxin-A injection treatment to patients with male
LUTS.
LE
1a
1b
Strength rating
Strong
5.3.5.3
Non-ablative techniques under investigation
5.3.5.3.1 (i)TIND
Mechanism of action: The iTIND is a device designed to remodel the bladder neck and the prostatic urethra
and is composed of three elongated struts and an anchoring leaflet, all made of nitinol. Under direct
visualisation the iTIND is deployed inside the prostate in expanded configuration. The intended mode of action
is to compress obstructive tissue by the expanded device, thereby exerting radial force leading to ischaemic
necrosis in defined areas of interest. The iTIND is left in position for five days. The resulting incisions may be
similar to a Turner Warwick incision. In an outpatient setting the device is removed by standard urethroscopy.
Efficacy: A single-arm, prospective study of 32 patients with a follow-up of three years was conducted to
evaluate feasibility and safety of the procedure [493]. The change from baseline in IPSS, QoL score and Qmax
was significant at every follow-up time point [494].
Tolerability and safety: The device has been reported to be well tolerated by all patients. Four early
complications (12.5%) were recorded, including one case of urinary retention (3.1%), one case of transient
incontinence due to device displacement (3.1%), and two cases of infection (6.2%). No further complications
were recorded during the 36-month follow-up period.
Practical considerations: Randomised controlled trials comparing iTIND to a reference technique are ongoing.
5.4
Patient selection
The choice of treatment depends on the assessed findings of patient evaluation, ability of the treatment to
change the findings, treatment preferences of the individual patient, and the expectations to be met in terms of
speed of onset, efficacy, side effects, QoL, and disease progression.
Behavioural modifications, with or without medical treatments, are usually the first choice of therapy.
Figure 3 provides a flow chart illustrating treatment choice according to evidence-based medicine and patient
profiles. Surgical treatment is usually required when patients have experienced recurrent or refractory urinary
retention, overflow incontinence, recurrent UTIs, bladder stones or diverticula, treatment-resistant macroscopic
haematuria due to BPH/BPE, or dilatation of the upper urinary tract due to BPO, with or without renal
insufficiency (absolute operation indications, need for surgery).
Additionally, surgery is usually needed when patients have not obtained adequate relief from
LUTS or PVR using conservative or medical treatments (relative operation indications). The choice of
surgical technique depends on prostate size, comorbidities of the patient, ability to have anaesthesia,
patients’ preferences, willingness to accept surgery-associated specific side-effects, availability of the surgical
armamentarium, and experience of the surgeon with these surgical techniques. An algorithm for surgical
approaches according to evidence-based medicine and the patient’s profile is provided in Figure 4.
44
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Figure 3: Treatment algorithm of male LUTS using medical and/or conservative treatment options.
Treatment decisions depend on results assessed during initial evaluation.
Note that patients’ preferences may result in different treatment decisions.
Male LUTS
(without indications for surgery)
Bothersome
symptoms?
no
yes
Nocturnal
polyuria
predominant
no
no
Prostate
volume
> 40 mL?
no
Education + lifestyle
advice with or without
α1-blocker/PDE5I
no
Storage symptoms
predominant?
yes
yes
yes
Long-term
treatment?
yes
Residual
storage
symptoms
Watchful
waiting
with or without
education +
lifestyle advice
Add muscarinic
receptor
antagonist/beta
-3 agonist
Education +
lifestyle advice
with or without
5α-reductase
inhibitor ± α1blocker/PDE5I
Education +
lifestyle advice
with or without
muscarinic
receptor
antagonist/beta
-3 agonist
Education +
lifestyle advice
with or without
vasopressin
analogue
PDE5I = phosphodiesterase type 5 inhibitors.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
45
Figure 4: Treatment algorithm of bothersome LUTS refractory to conservative/medical treatment or
in cases of absolute operation indications. The flowchart is stratified by the patient’s ability to
have anaesthesia, cardiovascular risk, and prostate size.
Male LUTS
with absolute indicaons for surgery or non-responders to medical treatment or those who do not
want medical treatment but request acve treatment
High-risk
paents?
no
yes
yes
< 30 mL
Prostate
volume
Can stop
ancoagulaon/
anplatelet therapy
yes
Can have
surgery under
anaesthesia?
no
no
> 80 mL
30 – 80 mL
TUIP (1)
TURP
TURP (1)
Laser
enucleaon
Bipolar
enucleaon
Laser
vaporisaon
PU liˆ
Open
prostatectomy (1)
HoLEP (1)
Bipolar
enucleaon (1)
Laser
vaporisaon
Thulium
enucleaon
TURP
Laser
vaporisaon (1)
Laser
enucleaon
PU liˆ
(1) Current standard/first choice. The alternative treatments are presented in alphabetical order.
Laser vaporisation includes GreenLight, thulium, and diode laser vaporisation. Laser enucleation includes
holmium and thulium laser enucleation.
HoLEP = holmium laser enucleation; TUIP = transurethral incision of the prostate; TURP = transurethral
resection of the prostate and PU = prostatic urethral.
46
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
5.5
Management of Nocturia in men with lower urinary tract symptoms
The following section reports a SR of therapy for the management of nocturia in men with LUTS. It also
emphasises the need to consider the wide range of possible causes of nocturia [495].
Nocturia is defined as the complaint of waking at night to void [6]. It reflects the relationship
between the amount of urine produced while asleep, and the ability of the bladder to store the urine received.
Nocturia can occur as part of lower urinary tract dysfunction (LUTD), such as OAB and chronic pelvic pain
syndrome. Nocturia can also occur in association with other forms of LUTD, such as BOO, but here it is
debated whether the link is one of causation or simply the co-existence of two common conditions. Crucially,
nocturia may have behavioural, sleep disturbance (primary or secondary) or systemic causes unrelated to
LUTD (Table 2). Differing causes often co-exist and each has to be considered in all cases. Only where LUTD is
contributory should nocturia be termed a LUTS.
Table 2: Categories of nocturia
CATEGORY
Behavioural
Disproportionate urine production
(at all times, or during sleep)
Inappropriate fluid intake
Systemic
Sleep disorder
Water, salt and metabolite output
Variable water and salt output
LUTD
Low volume of each void
(at all times, or overnight)
“Bladder awareness” due to
secondary sleep disturbance
“Bladder awareness” due to
primary sleep disturbance
Impaired storage function and
increased filling sensation
5.5.1
Diagnostic assessment
Evaluation is outlined in Figure 5;
1.Evaluate for LUTD according to the relevant guidelines. The severity and bother of individual LUTS
should be identified with a symptom score, supplemented by directed questioning if needed. A validated
bladder diary is mandatory.
2.
Review whether behavioural factors affecting fluid balance and sleep are contributing.
3.Review of medical history and medications, including directed evaluation for key conditions, such as
renal failure, diabetes mellitus, cardiac failure, and obstructive sleep apnoea. If systemic factors or sleep
disorders are potentially important, consider involving appropriate medical expertise (see Figure 6). This
is appropriate where a known condition is suboptimally managed, or symptoms and signs suggest an
undiagnosed condition.
5.5.2
Medical conditions and sleep disorders Shared Care Pathway
Causative categories for nocturia comprise [496]:
1.
bladder storage problems;
2.
24-hour polyuria (> 40 mL/kg urine output over a 24-hour period);
3.nocturnal polyuria (NP; nocturnal output exceeding 20% of 24-hour urine output in the young, or 33% of
urine output in people > 65 [6]);
4.
sleep disorders;
5.
mixed aetiology.
Potentially relevant systemic conditions are those which impair physiological fluid balance, including influences
on: levels of free water, salt, other solutes and plasma oncotic pressure; endocrine regulation e.g. by
antidiuretic hormone; natriuretic peptides; cardiovascular and autonomic control; renal function; neurological
regulation, e.g. circadian regulation of the pineal gland, and renal innervation. As nocturia is commonly referred
to the specialty without full insight into cause, the urologist must review the likely mechanisms underlying
a presentation with nocturia and instigate review by relevant specialties accordingly. Thus, the managing
urologist needs to evaluate nocturia patients in a context where additional medical expertise is available (Table
3). They should not proceed along any LUTD management pathway unless a causative link with LUTD is
justifiably suspected, and systemic or sleep abnormalities have been considered.
In patients with non-bothersome nocturia, the medical evaluation (history and physical examination)
should consider the possibility of early stages of systemic disease, and whether there is possibility of earlier
diagnosis or therapy adjustment.
Some important potentially treatable non-urological causes of nocturia include; obstructive sleep
aponea, congestive cardiac failure, poorly controlled diabetes mellitus and medications (e.g. diuretics, or
lithium).
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
47
Figure 5. Evaluation of Nocturia in non-neurogenic Male LUTS.
•
•
•
•
•
History (+ sexual function)
Symptom Score Questionnaire
Physical Examination
Urinalysis
PSA (if diagnosis of PCa will change
the management – discuss with patient)
• Measurement of PVR
Bothersome Nocturia
yes
no
Significant PVR
• US of kidneys +/- renal
function assessment
• Abnormal DRE, high PSA
• Haematuria
• Chronic pelvic pain
Evaluate according to
relevant guidelines or
clinical standard
Treat underlying condition
or sleep disorder
Offer shared care
• US assessment of prostate
• Uroflowmetry
• FVC with predominant storage LUTS
Mixed features
Polyuria/
NP
LUTS
Medical Conditions/Sleep
disorders Care Pathway
Nocturia with LUTS in
benign LUT conditions
Behavioural and drug NP
treatment
Behavioural and drug
LUTS treatment
LUTS Algorithm
Interventional LUTS
treatment
(Indirect MoA for
nocturia)
Assessment must establish whether the patient has polyuria, LUTS, a sleep disorder or a combination. Therapy
may be driven by the bother it causes, but non-bothersome nocturia may warrant assessment with a frequency
volume chart (indicated by the dotted line) depending on history and clinical examination since potential
presence of a serious underlying medical condition must be considered.
FVC = frequency volume chart; DRE = digital rectal examination; NP = nocturnal polyuria; MoA = mechanism of
action; PVR = post-void residual; PSA = prostate-specific antigen; US = ultrasound.
48
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Table 3: Shared care pathway for nocturia, highlighting the need to manage potentially complex patients using
relevant expertise for the causative factors.
UROLOGICAL CONTRIBUTION
Diagnosis of LUTD
• Urological/LUTS evaluation
• Nocturia symptom scores
• Bladder diary
SHARED CARE
Conservative management
Behavioural therapy
• Fluid/sleep habits advice
• Drugs for storage LUTS
• Drugs for voiding LUTS
• ISC/catherisation
• Increased exercise
• Leg elevation
• Weight loss
Conservative
management
• Antidiuretic
• Diuretics
• Drugs to aid
sleep
Interventional therapy
• Therapy of refractory
storage LUTS
• Therapy of refractory
voiding LUTS
MEDICAL CONTRIBUTION
Diagnosis of conditions causing NP
• Evaluate patient’s known
conditions
• Screening for sleep disorders
• Screening for potential causes
of polyuria*
Management
• Initiation of therapy for new
diagnosis
• Optimised therapy of known
conditions
* Potential causes of polyuria
NEPHROLOGICAL DISEASE
•
Tubular dysfunction
•
Global renal dysfunction
CARDIOVASCULAR DISEASE
•
Cardiac disease
•
Vascular disease
ENDOCRINE DISEASE
•
Diabetes insipidus/mellitus
•
Hormones affecting diuresis/natriuresis
NEUROLOGICAL DISEASE
•
Pituitary and renal innervation
•
Autonomic dysfunction
RESPIRATORY DISEASE
•
Obstructive sleep apnoea
BIOCHEMICAL
•
Altered blood oncotic pressure
5.5.3
Treatment for Nocturia
5.5.3.1
Antidiuretic therapy
The antidiuretic hormone arginine vasopressin (AVP) plays a key role in body water homeostasis and control
of urine production by binding to V2 receptors in the renal collecting ducts. Arginine vasopressin increases
water re-absorption and urinary osmolality, so decreasing water excretion and total urine volume. Arginine
vasopressin also has V1 receptor mediated vasoconstrictive/hypertensive effects and a very short serum halflife, which makes the hormone unsuitable for treating nocturia/nocturnal polyuria.
Desmopressin is a synthetic analogue of AVP with high V2 receptor affinity and no relevant
V1 receptor affinity. It has been investigated for treating nocturia [497], with specific doses, titrated
dosing, differing formulations, and options for route of administration. Most studies have short follow-up.
Global interpretation of existing studies is difficult due to the limitations, imprecision, heterogeneity and
inconsistencies of the studies.
A SR of randomised or quasi-randomised trials in men with nocturia found that desmopressin may decrease
the number of nocturnal voids by -0.46 compared to placebo over short-term follow-up (up to three months);
over intermediate-term follow-up (three to twelve months) there was a change of -0.85 in nocturnal voids in a
substantial number of participants without increase in major adverse events [498].
Another SR of comparative trials of men with nocturia as the primary presentation and LUTS
including nocturia or nocturnal polyuria found that antidiuretic therapy using dose titration was more effective
than placebo in relation to nocturnal voiding frequency and duration of undisturbed sleep [495]. Adverse events
include headache, hyponatremia, insomnia, dry mouth, hypertension, abdominal pain, peripheral edema, and
nausea. Three studies evaluating titrated-dose desmopressin in which men were included, reported seven
serious adverse events in 530 patients (1.3%), with one death. There were seventeen cases of hyponatraemia
(3.2%) and seven of hypertension (1.3%). Headache was reported in 53 (10%) and nausea in fifteen (2.8%)
[495]. Hyponatremia is the most important concern, especially in patients > 65 years of age, with potential life
threatening consequences. Baseline values of sodium over 130 mmol/L have been used as inclusion criteria
in some research protocols. Assessment of sodium levels must be undertaken at baseline, after initiation of
treatment or dose titration and during treatment. Desmopressin is not recommended in high-risk groups [495].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
49
Desmopressin oral disintegrating tablets (ODT) have been studied separately in the sex-specific pivotal trials
CS41 and CS40 in patients with nocturia [499, 500]. Almost 87% of included patients had nocturnal polyuria
and approximately 48% of the patients were > 65 years. The co-primary endpoints in both trials were change
in number of nocturia episodes per night from baseline and at least a 33% decrease in the mean number
of nocturnal voids from baseline during three months of treatment. The mean change in nocturia episodes
from baseline was greater with desmopressin ODT compared to placebo (difference: women = -0.3 [95% CI:
-0.5, -0.1]; men = -0.4 [95% CI: -0.6, -0.2]). The 33% responder rate was also greater with desmopressin ODT
compared to placebo (women: 78% vs. 62%; men: 67% vs. 50%).
Analysis of three published placebo-controlled trials of desmopressin ODT for nocturia showed
that clinically significant hyponatraemia was more frequent in patients aged ≥ 65 years than in those aged
< 65 years in all dosage groups, including those receiving the minimum effective dose for desmopressin (11%
of men aged ≥ 65 years vs. 0% of men aged < 65 years receiving 50 mcg; 4% of women ≥ 65 aged years vs.
2% of women aged < 65 years receiving 25 mcg). Severe hyponatraemia, defined as ≤ 125 mmol/L serum
sodium, was rare, affecting 22/1,431 (2%) patients overall [501].
Low dose desmopressin (ODT) has been approved in Europe, Canada and Australia for the
treatment of nocturia with ≥ 2 episodes in gender-specific low doses 50 mcg for men and 25 mcg for women;
however, it initially failed to receive FDA approval, with the FDA citing uncertain benefit relative to risks as the
reason. Following resubmission to the FDA in June 2018 desmopressin acetate sublingual tablet, 50 mcg for
men and 25 mcg for women, was approved for the treatment of nocturia due to nocturnal polyuria in adults
who awaken at least two times per night to void with a boxed warning for hyponatremia.
Desmopressin acetate nasal spray is a new low-dose formulation of desmopressin and differs from other types
of desmopressin formulation due to its bioavailability and route of administration. Desmopressin acetate nasal
spray has been investigated in two RCTs including men and women with nocturia (over two episodes per night)
and a mean age of 66 years. The average benefit of treatment relative to placebo was statistically significant
but low, -0.3 and -0.2 for the 1.5 mcg and 0.75 mcg doses of desmopressin acetate, respectively. The number
of patients with a reduction of more than 50% of nocturia episodes was 48.5% and 37.9%, respectively
compared with 30% in the placebo group [502]. The reported adverse event rate of the studies was rather
low and the risk of hyponatremia was 1.2% and 0.9% for desmopressin acetate 1.5 mcg and 0.75 mcg,
respectively. Desmopressin acetate nasal spray was approved by the FDA in 2017 for the treatment of nocturia
due to nocturnal polyuria, but it is not available in Europe.
Practical considerations
A complete medical assessment should be made, to exclude potentially non-urological underlying causes,
e.g. sleep apnea, before prescribing desmopressin in men with nocturia due to nocturnal polyuria. The optimal
dose differs between patients, in men < 65 years desmopressin treatment should be initiated at a low dose
(0.1 mg/day) and may be gradually increased up to a dosage of 0.4 mg/day every week until maximum efficacy
is reached. Desmopressin is taken once daily before sleeping. Patients should avoid drinking fluids at least one
hour before and for eight hours after dosing. Low dose desmopressin may be prescribed in patients > 65 years.
In men ≥ 65 years or older, low dose desmopressin should not be used if the serum sodium concentration
is below normal: all patients should be monitored for hyponatremia. Urologists should be cautious when
prescribing low-dose desmopressin in patients under-represented in trials (e.g. patients > 75 years) who may
have an increased risk of hyponatremia.
5.5.3.2
Medications to treat LUTD
Where LUTD is diagnosed and considered causative of nocturia, relevant medications for storage (and
voiding) LUTS may be considered. Applicable medications include; selective α1-adrenergic antagonists
[503], antimuscarinics [504-506], 5-ARIs [507] and PDE5Is [508]. However, effect size of these medications
is generally small, or not significantly different from placebo when used to treat nocturia [495]. Data on OAB
medications (antimuscarinics, beta-3 agonist) generally had a female-predominant population. No studies
specifically addressing the impact of OAB medications on nocturia in men were identified [495]. Benefits with
combination therapies were not consistently observed.
5.5.3.3
Other medications
Agents to promote sleep [509], diuretics [510], non-steroidal anti-inflammatory agents (NSAIDs) [511] and
phytotherapy [512] were reported as being associated with response or QoL improvement [495]. Effect size of
these medications in nocturia is generally small, or not significantly different from placebo. Larger responses
have been reported for some medications, but larger scale confirmatory RCTs are lacking. Agents to promote
sleep do not appear to reduce nocturnal voiding frequency, but may help patients return to sleep.
50
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
Summary of evidence
No clinical trial of pathophysiology-directed primary therapy has been undertaken.
No robust clinical trial of behavioural therapy as primary intervention has been undertaken.
Antidiuretic therapy reduces nocturnal voiding frequency in men with baseline severity of two or more
voids per night.
There is an increased risk of hyponatremia in patients 65 years of age or older under antidiuretic
therapy.
Antidiuretic therapy increases duration of undisturbed sleep.
Alpha 1-blocker use is associated with improvements in undisturbed sleep duration and nocturnal
voiding frequency, which are generally of only marginal clinical significance.
Antimuscarinic medications can reduce night-time urinary urgency severity, but the reduction in overall
nocturia frequency is small or non-significant.
Antimuscarinic medications are associated with higher incidence of dry mouth compared with placebo.
5α-reductase inhibitors reduce nocturia severity in men with baseline nocturia severity of two or more
voids per night.
A trial of timed diuretic therapy may be offered to men with nocturia due to nocturnal polyuria.
Screening for hyponatremia should be undertaken at baseline and during treatment.
LE
4
4
1b
1b
1b
2
2
2
2
1b
Recommendations
Treat underlying causes of nocturia, including behavioural, systemic condition(s), sleep
disorders, lower urinary tract dysfunction, or a combination of factors.
Discuss behavioural changes with the patient to reduce nocturnal urine volume and
episodes of nocturia, and improve sleep quality.
Offer desmopressin to decrease nocturia due to nocturnal polyuria in men < 65 years of age.
Strength rating
Weak
Offer low dose desmopressin for men > 65 years of age with nocturia at least twice per
night due to nocturnal polyuria.
Screen for hyponatremia at baseline, day three and day seven, one month after initiating
therapy and periodically during treatment. Measure serum sodium more frequently in
patients > 65 years of age and in patients at increased risk of hyponatremia.
Discuss with the patient the potential clinical benefit relative to the associated risks from
the use of desmopressin, especially in men > 65 years of age.
Offer α1-adrenergic antagonists for treating nocturia in men who have nocturia associated
with LUTS.
Offer antimuscarinic drugs for treating nocturia in men who have nocturia associated with
overactive bladder.
Offer 5α-reductase inhibitors for treating nocturia in men who have nocturia associated with
LUTS and an enlarged prostate (> 40 mL).
Do not offer phosphodiesterase type 5 inhibitors for the treatment of nocturia.
Weak
6.
FOLLOW-UP
6.1
Watchful waiting (behavioural)
Weak
Weak
Strong
Strong
Weak
Weak
Weak
Weak
Patients who elect to pursue a WW policy should be reviewed at six months and then annually, provided there
is no deterioration of symptoms or development of absolute indications for surgical treatment. The following
are recommended at follow-up visits: history, IPSS, uroflowmetry, and PVR volume.
6.2
Medical treatment
Patients receiving α1-blockers, muscarinic receptor antagonists, beta-3 agonists, PDE5Is or the combination
of α1-blockers and 5-ARIs or muscarinic receptor antagonists should be reviewed four to six weeks after
drug initiation to determine the treatment response. If patients gain symptomatic relief in the absence of
troublesome adverse events, drug therapy may be continued. Patients should be reviewed at six months
and then annually, provided there is no deterioration of symptoms or development of absolute indications
for surgical treatment. The following are recommended at follow-up visits: history, IPSS, uroflowmetry, and
PVR volume. Frequency volume charts or bladder diaries should be used to assess response to treatment for
predominant storage symptoms or nocturnal polyuria.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
51
Patients receiving 5-ARIs should be reviewed after twelve weeks and six months to determine their
response and adverse events. The following are recommended at follow-up visits: history, IPSS, uroflowmetry
and PVR volume. Men taking 5-ARIs should be followed up regularly using serial PSA testing if life expectancy
is greater than ten years and if a diagnosis of PCa could alter management. A new baseline PSA should be
determined at six months, and any confirmed increase in PSA while on 5-ARIs should be evaluated.
In patients receiving desmopressin, serum sodium concentration should be measured at day three
and seven, one month after initiating therapy and periodically during treatment. If serum sodium concentration
has remained normal during periodic screening follow-up screening can be carried out every three months
subsequently. However, serum sodium concentration should be monitored more frequently in patients ≥ 65
years of age and in patients at increased risk of hyponatremia. The following tests are recommended at followup visits: serum-sodium concentration and FVC. The follow-up sequence should be restarted after dose
escalation.
6.3
Surgical treatment
After prostate surgery, patients should be reviewed four to six weeks after catheter removal to evaluate
treatment response and adverse events. If patients have symptomatic relief and are without adverse events,
no further re-assessment is necessary. The following tests are recommended at follow-up visit after four to six
weeks: IPSS, uroflowmetry and PVR volume.
Summary of evidence
LE
Follow-up for all conservative, medical, or operative treatment modalities is based on empirical data or 4
theoretical considerations, but not on evidence-based studies.
Recommendations
Follow-up all patients who receive conservative, medical or surgical management.
Strength rating
Weak
Define follow-up intervals and examinations according to the specific treatment.
Weak
7.
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CONFLICT OF INTEREST
All members of the EAU Non-neurogenic Male LUTS Guidelines Panel have provided disclosure statements
on all relationships that they have that might be perceived to be a potential source of a conflict of interest.
This information is publically accessible through the EAU website: http://www.uroweb.org/guidelines/. These
Guidelines were developed with the financial support of the EAU. No external sources of funding and support
have been involved. The EAU is a non-profit organisation, and funding is limited to administrative assistance
and travel and meeting expenses. No honoraria or other reimbursements have been provided.
9.
CITATION INFORMATION
The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the
citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location,
or an ISBN number may vary.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
81
The compilation of the complete Guidelines should be referenced as:
EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4.
If a publisher and/or location is required, include:
EAU Guidelines Office, Arnhem, the Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/
References to individual guidelines should be structured in the following way:
Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.
82
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021
EAU Guidelines on
Muscle-invasive
and Metastatic
Bladder Cancer
J.A. Witjes (Chair), H.M. Bruins, R. Cathomas, E. Compérat,
N.C. Cowan, J.A. Efstathiou, R. Fietkau, G. Gakis,
V. Hernández, A. Lorch, M.I. Milowsky, M.J. Ribal (Vice-chair),
G.N. Thalmann, A.G. van der Heijden, E. Veskimäe
Guidelines Associates: E. Linares Espinós, M. Rouanne,
Y. Neuzillet
© European Association of Urology 2021
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION
1.1
Aims and scope
1.2
Panel composition
1.3
Available publications
1.4
Publication history and summary of changes
1.4.1
Publication history
1.4.2
Summary of changes
6
6
6
6
6
6
6
2.
METHODS
2.1
Data identification
2.2
Peer-review
2.2.1
Lay review
2.3
Future goals
9
9
10
10
11
3.
EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY
3.1
Epidemiology
3.2
Aetiology
3.2.1
Tobacco smoking
3.2.2
Occupational exposure to chemicals
3.2.3
Radiotherapy
3.2.4
Dietary factors
3.2.5
Metabolic disorders
3.2.6
Bladder schistosomiasis and chronic urinary tract infection
3.2.7
Gender
3.2.8
Genetic factors
3.2.9
Summary of evidence and guidelines for epidemiology and risk factors
3.3
Pathology
3.3.1
Handling of transurethral resection and cystectomy specimens
3.3.2
Pathology of muscle-invasive bladder cancer
3.3.3
Guidelines for the assessment of tumour specimens
3.3.4
EAU-ESMO consensus statements on the management of advanced- and
variant bladder cancer
11
11
11
11
11
11
12
12
12
12
13
13
13
13
14
14
4.
15
15
15
5.
STAGING AND CLASSIFICATION SYSTEMS
4.1
Pathological staging
4.2
Tumour, node, metastasis classification
DIAGNOSTIC EVALUATION
5.1
Primary diagnosis
5.1.1
Symptoms
5.1.2
Physical examination
5.1.3
Bladder imaging
5.1.4
Urinary cytology 5.1.5
Cystoscopy
5.1.6
Transurethral resection of invasive bladder tumours
5.1.7
Concomitant prostate cancer
5.1.8
Summary of evidence and guidelines for the primary assessment of presumably
invasive bladder tumours
5.1.9
EAU-ESMO consensus statements on the management of advanced- and
variant bladder cancer 5.2
Imaging for staging of MIBC
5.2.1
Local staging of MIBC
5.2.1.1
CT imaging for local staging of MIBC
5.2.2
Imaging of lymph nodes in MIBC
5.2.3
Upper urinary tract urothelial carcinoma
5.2.3.1
Computed tomography urography
5.2.3.2
Magnetic resonance urography
5.2.4
Distant metastases at sites other than lymph nodes
2
15
16
16
16
16
16
16
16
17
17
17
18
18
18
19
19
19
19
19
19
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5.2.5
Future developments
5.2.6
Summary of evidence and guidelines for staging in muscle-invasive bladder
cancer
5.3
MIBC and health status
5.3.1
Evaluation of comorbidity, frailty and cognition
5.3.2
Comorbidity scales, anaesthetic risk classification and geriatric assessment
5.3.3
Summary of evidence and guidelines for comorbidity scales
19
20
20
20
22
23
6.
MARKERS
6.1
Introduction
6.2
Prognostic markers
6.2.1
Histopathological and clinical markers
6.2.2
Molecular markers
6.2.2.1
Molecular subtypes based on the Cancer Genome Atlas cohort
6.3
Predictive markers
6.3.1
Clinical and histopathological markers
6.3.2
Molecular markers
6.4
Conclusion
6.5
Summary of evidence and recommendations for urothelial markers
24
24
24
24
24
24
25
25
25
26
26
7.
26
26
26
26
27
28
28
28
29
29
29
30
DISEASE MANAGEMENT
7.1
Neoadjuvant therapy
7.1.1
Introduction
7.1.2
Role of cisplatin-based chemotherapy
7.1.2.1
Summary of available data
7.1.3
The role of imaging and predictive biomarkers
7.1.4
Role of neoadjuvant immunotherapy
7.1.5
Summary of evidence and guidelines for neoadjuvant therapy
7.2
Pre- and post-operative radiotherapy in muscle-invasive bladder cancer
7.2.1
Post-operative radiotherapy
7.2.2
Pre-operative radiotherapy
7.2.3
Summary of evidence and guidelines for pre- and post-operative radiotherapy
7.2.4
EAU-ESMO consensus statements on the management of advanced- and
variant bladder cancer 7.3
Radical surgery and urinary diversion
7.3.1
Removal of the tumour-bearing bladder
7.3.1.1
Introduction
7.3.1.2
Radical cystectomy: timing
7.3.2
Radical cystectomy: indications
7.3.3
Radical cystectomy: technique and extent
7.3.3.1
Radical cystectomy in men
7.3.3.1.1
Summary of evidence and recommendations for sexual
preserving techniques in men
7.3.3.2
Radical cystectomy in women
7.3.3.2.1
Summary of evidence and recommendations for sexual
preserving techniques in women
7.3.4
Lymphadenectomy: role and extent
7.3.5
Laparoscopic/robotic-assisted laparoscopic cystectomy
7.3.5.1
Laparoscopic radical cystectomy versus robot-assisted radical
cystectomy
7.3.5.2
Summary of evidence and guidelines for laparoscopic/robotic
assisted laparoscopic cystectomy
7.3.6
Urinary diversion after radical cystectomy
7.3.6.1
Patient selection and preparations for surgery
7.3.6.2
Different types of urinary diversion
7.3.6.2.1
Uretero-cutaneostomy
7.3.6.2.2
Ileal conduit
7.3.6.2.3
Orthotopic neobladder
7.3.7
Morbidity and mortality
7.3.8
Survival
LIMITED UPDATE MARCH 2021
30
30
30
30
30
31
31
31
32
32
32
33
33
34
35
35
35
36
36
37
37
37
39
3
7.3.9
Impact of hospital and surgeon volume on treatment outcomes
7.3.10
Summary of evidence and guidelines for radical cystectomy and
urinary diversion
7.3.11
EAU-ESMO consensus statements on the management of advanced
and variant bladder cancer
7.4
Unresectable tumours
7.4.1
Palliative cystectomy for muscle-invasive bladder carcinoma
7.4.1.1
Guidelines for unresectable tumours
7.4.1.2
EAU-ESMO consensus statements on the management of advanced
and variant bladder cancer
7.4.2
Supportive care
7.4.2.1
Obstruction of the upper urinary tract
7.4.2.2
Bleeding and pain
7.5
Bladder-sparing treatments for localised disease
7.5.1
Transurethral resection of bladder tumour
7.5.1.1
Guideline for transurethral resection of bladder tumour
7.5.1.2
EAU-ESMO consensus statements on the management of advanced
and variant bladder cancer
7.5.2
External beam radiotherapy 7.5.2.1
Summary of evidence and guideline for external beam radiotherapy
7.5.2.2
EAU-ESMO consensus statements on the management of advanced
and variant bladder cancer
7.5.3
Chemotherapy
7.5.3.1
Summary of evidence and guideline for chemotherapy
7.5.4
Trimodality bladder-preserving treatment
7.5.4.1
Summary of evidence and guidelines for trimodality bladder
preserving treatment
7.5.4.2
EAU-ESMO consensus statements on the management of advanced
and variant bladder cancer
7.6
Adjuvant therapy
7.6.1
Role of adjuvant platinum-based chemotherapy
7.6.2
Role of adjuvant immunotherapy
7.6.3
Guidelines for adjuvant therapy
7.7
Metastatic disease
7.7.1
Introduction
7.7.1.1
Prognostic factors and treatment decisions
7.7.1.2
Comorbidity in metastatic disease
7.7.2
First-line systemic therapy for metastatic disease
7.7.2.1
Definitions: ‘Fit for cisplatin, fit for carboplatin, unfit for any platinum
based chemotherapy’
7.7.2.2
Chemotherapy in patients fit for cisplatin
7.7.2.3
Chemotherapy in patients fit for carboplatin (but unfit for cisplatin)
7.7.2.4
Integration of immunotherapy in the first-line treatment of patients fit
for platinum-based chemotherapy
7.7.2.4.1
Immunotherapy combination approaches
7.7.2.4.2
Use of single-agent immunotherapy
7.7.2.4.3
Switch maintenance with immunotherapy
7.7.2.5
Treatment of patients unfit for any platinum-based chemotherapy
7.7.2.6
Non-platinum combination chemotherapy
7.7.3
Second-line systemic therapy for metastatic disease
7.7.3.1
Second-line chemotherapy
7.7.3.2
Second-line immunotherapy for platinum-pre-treated patients
7.7.3.2.1
Side-effect profile of immunotherapy
7.7.4
Novel agents for second- or later-line therapy
7.7.5
Post-chemotherapy surgery and oligometastatic disease
7.7.6
Treatment of patients with bone metastases
7.7.7
Summary of evidence and guidelines for metastatic disease
7.8
Quality of life
7.8.1
Introduction
7.8.2
Neoadjuvant chemotherapy
4
39
40
41
42
42
42
42
42
42
42
42
42
43
43
43
44
44
44
44
45
46
47
47
47
48
48
48
48
48
49
49
49
49
50
50
50
50
51
51
51
51
51
52
52
52
53
53
54
55
55
55
LIMITED UPDATE MARCH 2021
7.8.3
7.8.4
7.8.5
7.8.6
Radical cystectomy and urinary diversion
Bladder sparing trimodality therapy
Non-curative or metastatic bladder cancer
Summary of evidence and recommendations for health-related quality of life
8.
56
56
56
56
FOLLOW-UP
8.1
Follow-up in muscle invasive bladder cancer
8.2
Site of recurrence
8.2.1
Local recurrence
8.2.2
Distant recurrence
8.2.3
Urothelial recurrences
8.3
Time schedule for surveillance
8.4
Follow-up of functional outcomes and complications
8.5
Summary of evidence and recommendations for specific recurrence sites
8.6
EAU-ESMO consensus statements on the management of advanced- and variant
bladder cancer
57
57
57
57
57
58
58
58
59
9.
REFERENCES 60
10.
CONFLICT OF INTEREST
94
11.
CITATION INFORMATION
94
LIMITED UPDATE MARCH 2021
59
5
1.
INTRODUCTION
1.1
Aims and scope
The European Association of Urology (EAU) Guidelines Panel for Muscle-invasive and Metastatic Bladder
Cancer (MIBC) have prepared these guidelines to help urologists assess the evidence-based management of
MIBC and to incorporate guideline recommendations into their clinical practice.
Separate EAU guidelines documents are available addressing upper urinary tract (UUT) tumours [1],
non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) (NMIBC) [2], and primary urethral carcinomas [3].
It must be emphasised that clinical guidelines present the best evidence available to the experts
but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.
1.2
Panel composition
The EAU Guidelines Panel consists of an international multidisciplinary group of clinicians, including urologists,
oncologists, a pathologist, a radiologist and radiotherapists. Section 5.3 -MIBC and health status, was
developed with the assistance of Dr. S. O’Hanlon, consultant geriatrician, International Society of Geriatric
Oncology (SIOG) representative and member of the EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer
Guidelines Panel. The MIBC Panel is most grateful for his support.
All experts involved in the production of this document have submitted potential conflict
of interest statements which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/
bladdercancermuscle-invasive-and-metastatic/?type=panel.
1.3
Available publications
A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and Android
devices. These are abridged versions which may require consultation together with the full text version.
Several scientific publications are available (the most recent paper dating back to 2020 [4]), as are
a number of translations of all versions of the EAU MIBC Guidelines. All documents are accessible through the
EAU website: http://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.
1.4
Publication history and summary of changes
1.4.1
Publication history
The EAU published its first guidelines on bladder cancer (BC) in 2000. This document covered both NMIBC and
MIBC. Since these conditions require different treatment strategies, it was decided to give each condition its
own guidelines, resulting in the first publication of the MIBC Guidelines in 2004. This 2021 document presents
a limited update of the 2020 version.
1.4.2
Summary of changes
New relevant references have been identified through a structured assessment of the literature and
incorporated in the various chapters of the 2021 EAU MIBC Guidelines resulting in new sections and added
and revised recommendations in:
•
Section 3.3.3 Guidelines for the assessment of tumour specimens
Recommendation
Record the sampling sites, as well as information on tumour size when providing
specimens to the pathologist.
•
Strength rating
Strong
ection 5.1.8 Summary of evidence and guidelines for the primary assessment of presumably invasive
S
bladder tumours
Summary of evidence
LE
In men, prostatic urethral biopsy includes resection from the bladder neck to the verumontanum 2b
(between the 5 and 7 o’clock position) using a resection loop. In case any abnormal-looking
areas in the prostatic urethra are present at this time, these need to be biopsied as well.
6
LIMITED UPDATE MARCH 2021
Recommendations
In men with a negative prostatic urethral biopsy undergoing subsequent orthotopic
neobladder construction, an intra-operative frozen section can be omitted.
In men with a prior positive transurethral prostatic biopsy, subsequent orthotopic
neobladder construction should not be denied a priori, unless an intra-operative
frozen section of the distal urethral stump reveals malignancy at the level of urethral
dissection.
Strength rating
Strong
Strong
•
Section 5.2.1 - Local staging of MIBC; inclusion of data on multiparametric MRI using the Vesical Imaging
Reporting and Data System (VI-RADS) scoring system. No new recommendation has been provided.
•
Section 5.3 - MIBC and health status; this section has been updated, introducing the concept of frailty.
•
Chapter 6 - Markers; this chapter has been significantly revised, presenting two new recommendations.
6.5 Summary of evidence and recommendations for urothelial markers
Summary of evidence
There is insufficient evidence to use TMB, molecular subtypes, immune or other gene
expression signatures for the management of patients with urothelial cancer.
Recommendations
Evaluate PD-L1 expression (by immunohistochemistry) to determine the potential
for use of pembrolizumab or atezolizumab in previously untreated patients with
locally advanced or metastatic urothelial cancer who are unfit for cisplatin-based
chemotherapy.
Evaluate for FGFR2/3 genetic alterations for the potential use of erdafitinib in
LE
-
Strength rating
Weak
Weak
patients with locally advanced or metastatic urothelial carcinoma who have
progressed following platinum-containing chemotherapy (including within 12 months
of neoadjuvant or adjuvant platinum-containing chemotherapy).
•
.2 - Pre- and post-operative radiotherapy in muscle-invasive bladder cancer; this section was revised
7
and new data added, resulting in an additional recommendation.
7.2.3 Summary of evidence and guidelines for pre- and post-operative radiotherapy
Summary of evidence
Addition of adjuvant RT to chemotherapy is associated with an improvement in local relapsefree survival following cystectomy for locally advanced bladder cancer (pT3b─4, or nodepositive).
LE
2a
Recommendation
Strength rating
Consider offering adjuvant radiation in addition to chemotherapy following radical
Weak
cystectomy, based on pathologic risk (pT3b–4, or positive nodes, or positive margins).
7.3.10 Summary of evidence and guidelines for radical cystectomy and urinary diversion
Summary of evidence
Ensuring that patients are well informed about the various urinary diversion options prior to
making a decision may help prevent or reduce decision regret, independent of the method of
diversion selected.
LE
3
•
7.5.4 Trimodality bladder-preserving treatment
•
7.7 Metastatic disease: data from a number of key trials has been included, in particular on
immunotherapy combinations in first- and later-line setting, resulting in a number of new
recommendations and a change to the treatment flowchart (Figure 7.2).
LIMITED UPDATE MARCH 2021
7
7.7.8 Summary of evidence and guidelines for metastatic disease
Summary of evidence
LE
PD-1 inhibitor pembrolizumab has been approved for patients that have progressed during or
after previous platinum-based chemotherapy based on the results of a phase III trial.
PD-L1 inhibitors atezolizumab, nivolumab, durvalumab and avelumab have been FDA approved
for patients that have progressed during or after previous platinum-based chemotherapy based
on the results of a phase II trial.
PD-1 inhibitor pembrolizumab and PD-L1 inhibitor atezolizumab have been approved for
patients with advanced or metastatic UC unfit for cisplatinum-based first-line chemotherapy
and with overexpression of PD-L1 based on the results of single-arm phase II trials.
The combination of chemotherapy plus pembrolizumab or atezolizumab and the combination
of durvalumab and tremelimumab have not demonstrated an OS survival benefit compared to
platinum-based chemotherapy alone.
Switch maintenance with the PD-L1 inhibitor avelumab has demonstrated significant OS benefit
in patients achieving at least stable disease on first-line platinum-based chemotherapy.
Recommendations
First-line treatment for platinum-fit patients
Use cisplatin-containing combination chemotherapy with GC or HD-MVAC.
In patients unfit for cisplatin but fit for carboplatin use the combination of
carboplatin and gemcitabine.
In patients achieving stable disease, or better, after first-line platinum-based
chemotherapy use maintenance treatment with PD-L1 inhibitor avelumab.
First-line treatment in patients unfit for platinum-based chemotherapy
Consider checkpoint inhibitors pembrolizumab or atezolizumab.
Second-line treatment
Offer checkpoint inhibitor pembrolizumab to patients progressing during, or after,
platinum-based combination chemotherapy for metastatic disease. If this is not
possible, offer atezolizumab, nivolumab (EMA, FDA approved); avelumab or
durvalumab (FDA approved).
Further treatment after platinum- and immunotherapy
Offer treatment in clinical trials testing novel antibody drug conjugates (enfortumab
vedotin, sacituzumab govitecan); or in case of patients with FGFR3 alterations,
FGFR tyrosine kinase inhibitors.
Strength rating
Strong
Strong
Strong
Weak
Strong
Strong
GC = gemcitabine plus cisplatin; FGFR = fibroblast growth factor receptor; HD-MVAC = high-dose intensity
methotrexate, vinblastine, adriamycin plus cisplatin.
8
LIMITED UPDATE MARCH 2021
Figure 7.2: Flow chart for the management of metastatic urothelial cancer*
PLATINUM-INELIGIBLE
PLATINUM-ELIGIBLE
cisplatin
PS 2 and GFR < 60 mL/min
PS > 2; GFR < 30 mL/min
carboplatin
PS 0-1 and
GFR > 50-60 mL/min
PS 2 or GFR 30-60
mL/min
cisplatin/gemcitabine
or DD-MVAC 4-6 cycles
carboplatin/gemcitabine
4-6 cycles
PD
PD-L1 +
PD-L1 -
CR/PR/SD
2nd line therapy
PD
Watchful
waiting
Maintenance
• pembrolizumab
(atezolizumab, avelumab,
durvalumab, nivolumab)
• Trials
Switch
maintenance:
avelumab
Immunotherapy
• atezolizumab
• pembrolizumab
Best
supportive
care
LATER-LINE THERAPY
UC patients refractory to platinum-based
chemotherapy and IO
FGFR3 mutation UC progressing on
platinum-based chemotherapy ± prior IO
•
•
•
erdafitinib (FDA) – in trial
chemotherapy:
o paclitaxel
o Docetaxel
o vinflunine
Trials
•
•
•
enfortumab vedotin (FDA) – in trial
chemotherapy:
o paclitaxel
o docetaxel
o vinflunine
Trials
*Treatment within clinical trials is highly encouraged.
BSC = best supportive care; CR = complete response; DD-MVAC = dose dense methotrexate vinblastine
doxorubicin cisplatin; EV = enfortumab vedotin; FDA = US Food and Drug Administration;
FGFR = pan-fibroblast growth factor receptor tyrosine kinase inhibitor; GFR = glomerular filtration rate;
IO = immunotherapy; PR = partial response; PS = performance status; SD = stable disease.
2.
METHODS
2.1
Data identification
For the 2021 MIBC Guidelines, new and relevant evidence has been identified, collated and appraised through a
structured assessment of the literature. A broad and comprehensive literature search, covering all sections of the
MIBC Guideline was performed. The search was limited to English language publications. Databases searched
included Medline, EMBASE and the Cochrane Libraries, covering a time frame between May 10th, 2019 and
May 14th, 2020. A total of 1,837 unique records were identified, retrieved and screened for relevance resulting
in 83 new publications having been included in the 2021 print. A detailed search strategy is available online:
http://uroweb.org/guideline/bladdercancer-muscle-invasive-andmetastatic/?type=appendices-publications.
LIMITED UPDATE MARCH 2021
9
For each recommendation within the guidelines there is an accompanying online strength rating form, the basis
of which is a modified GRADE methodology [5, 6] which addresses a number of key elements namely:
1.
the overall quality of the evidence which exists for the recommendation, references used in
this text are grade according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [7];
2.
the magnitude of the effect (individual or combined effects);
3.
the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
4.
the balance between desirable and undesirable outcomes;
5.
the impact of patient values and preferences on the intervention;
6.
the certainty of those patient values and preferences.
These key elements are the basis which panels use to define the strength rating of each recommendation.
The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [6]. The strength of each
recommendation is determined by the balance between desirable and undesirable consequences of alternative
management strategies, the quality of the evidence (including certainty of estimates), and nature and variability
of patient values and preferences.
Additional information can be found in the general Methodology section of this print, and online at
the EAU website; http://www.uroweb.org/guideline/. A list of Associations endorsing the EAU Guidelines can
also be viewed online at the above address.
The results of a collaborative multi-stakeholder consensus project on the management of advanced and
variant bladder cancer have been incorporated in the 2020 MIBC Guidelines update [8, 9]. Only statements
which reached the a priori defined level of agreement - ≥ 70% agreement and ≤ 15% disagreement - across
all stakeholders involved in this consensus project are listed. The methodology is presented in detail in the
scientific publications. Since the publication of these consensus papers, emerging evidence prompted a
re-evaluation of these findings, resulting in the removal of a number of consensus statements.
2.2
Peer-review
The 2021 print of the MIBC guidelines was peer reviewed prior to publication.
2.2.1
Lay review
Post publication, the 2018 MIBC Guidelines were shared with seven patients treated for MIBC. Their comments
were requested, but not limited to:
•
the overall tone of the guidelines content;
•
any missing information;
•
any information considered incorrect;
•
any information which is not presented in a clear fashion;
•
any text which is considered redundant and should be omitted;
•
any text section that should be more detailed.
Common comments across reviewers:
•
In general, the overall tone of the text was considered informational and instructive, but the language
used obviously targets medical professionals, which make certain parts of the text difficult to understand
for lay persons. The use of many abbreviations is considered an additional hindrance, as are the
methodological elements. In case the EAU are considering producing a lay version of this text, the
language needs to be adapted and clear instructions are to be provided.
•
It is difficult for lay reviewers to comment on what may be omitted since, in their opinion, they lack the
expertise.
•
Some sections, such as ‘Recurrent disease’ and ‘Markers’ denote areas where less evidence is available.
Consequently, the available data is less systematically presented which makes these sections more
difficult to understand.
•
There is an interest whether screening for BC is a consideration.
•
In particular ‘follow-up’, ‘quality of life’ and ‘survivorship aspects’ should be elaborated on; providing
additional information on what may be expected after treatment is considered very helpful for patients
and their families. Also lifestyle elements would be of relevance (healthy living, “what to do to
prevent cancer”). For this section, in particular, involvement of patients in the text development was
considered missing. Transparency about the process of patient involvement in guidelines development
was considered most relevant.
The MIBC Guidelines Panel is most grateful for the unique insights and guidance provided by the lay reviewers.
10
LIMITED UPDATE MARCH 2021
2.3
Future goals
The MIBC Panel will integrate two patient advocates in the course of 2021, to ensure that patient views will be
appropriately represented in the course of the production of these guidelines.
Topics considered for inclusion in the 2022 update of the MIBC Guidelines:
•
development of a diagnostic pathway for the assessment of visible and non-visible haematuria;
•
participation in developing strategies to ensure meaningful participation of patients in the development
and implementation of the MIBC Guidelines.
3.
EPIDEMIOLOGY, AETIOLOGY AND
PATHOLOGY
3.1
Epidemiology
Bladder cancer is the 7th most commonly diagnosed cancer in males, whilst it drops to 10th position when both
genders are considered [10]. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.5
for men and 2.4 for women [10]. In the European Union, the age-standardised incidence rate is 20 for men and
4.6 for women [10]. In Europe, the highest age-standardised incidence rate has been reported in Belgium (31 in
men and 6.2 in women) and the lowest in Finland (18.1 in men and 4.3 in women) [10].
Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) was 3.2 for men
vs. 0.9 for women in 2012 [10]. Bladder cancer incidence and mortality rates vary across countries due to
differences in risk factors, detection and diagnostic practices, and availability of treatments. The variations
are, however, also partly caused by the different methodologies used in the studies and the quality of data
collection [11, 12].
The incidence and mortality of BC has decreased in some registries, possibly reflecting the
decreased impact of causative agents [12, 13].
Approximately 75% of patients with BC present with disease confined to the mucosa (stage Ta,
carcinoma in situ [CIS]) or submucosa (stage T1). In younger patients (< 40 years) this percentage is even
higher [14]. Patients with TaT1 and CIS have a high prevalence due to long-term survival in many cases and
lower risk of cancer-specific mortality (CSM) compared to T2-4 tumours [10, 11].
3.2
Aetiology
3.2.1
Tobacco smoking
Tobacco smoking is the most well-established risk factor for BC, causing 50–65% of male cases and 20–30%
of female cases [15]. A causal relationship has been established between exposure to tobacco and cancer in
studies in which chance, bias and confounding can be discounted with reasonable confidence [16].
The incidence of BC is directly related to the duration of smoking and the number of cigarettes
smoked per day [17]. A meta-analysis looked at 216 observational studies on cigarette smoking and
cancer published between 1961 and 2003, and the pooled risk estimates for BC demonstrated a significant
association for both current and former smokers [18]. Recently, an increase in risk estimates for current
smokers relative to never smokers has been described suggesting this could be due to changes in cigarette
composition [15]. Starting to smoke at a younger age increased the risk of death from BC [19]. An immediate
decrease in the risk of BC was observed in those who stopped smoking. The reduction was about 40% within
one to four years of quitting smoking and 60% after 25 years of cessation [17]. Encouraging people to stop
smoking would result in the incidence of BC decreasing equally in men and women [15].
3.2.2
Occupational exposure to chemicals
Occupational exposure is the second most important risk factor for BC. Work-related cases accounted for
20–25% of all BC cases in several series and it is likely to occur in occupations in which dyes, rubbers, textiles,
paints, leathers, and chemicals are used [20]. The risk of BC due to occupational exposure to carcinogenic
aromatic amines is significantly greater after ten years or more of exposure; the mean latency period usually
exceeds 30 years [21, 22]. Population-based studies established the occupational attribution for BC in men to
be 7.1%, while no such attribution was discernible for women [11, 23].
3.2.3
Radiotherapy
Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy
(EBRT) for gynaecological malignancies, with relative risks (RR) of 2-4 [24]. In a population-based cohort study,
LIMITED UPDATE MARCH 2021
11
the standardised incidence ratios for BC developing after radical prostatectomy (RP), EBRT, brachytherapy,
and EBRT-brachytherapy were 0.99, 1.42, 1.10, and 1.39, respectively, in comparison with the general U.S.
population [25].
It has recently been proposed that patients who have received radiotherapy (RT) for prostate
cancer with modern modalities such as intensity-modulated radiotherapy (IMRT) may have lower rates of
in-field bladder- and rectal secondary malignancies [26]. Nevertheless, since longer follow-up data are not
yet available, and as BC requires a long period to develop, patients treated with radiation and with a long life
expectancy are at a higher risk of developing BC [26].
3.2.4
Dietary factors
Several dietary factors have been related to BC; however, the links remain controversial. The European
Prospective Investigation into Cancer and Nutrition (EPIC) study is an on-going multicentre cohort study designed
to examine the association between diet, lifestyle, environmental factors and cancer. They found no links between
BC and fluid intake, red meat, vegetable and fruit consumption and only recently an inverse association between
dietary intake of flavonoids and lignans and the risk of aggressive BC tumours has been described [27].
3.2.5
Metabolic disorders
In a large prospective study pooling six cohorts from Norway, Sweden, and Austria (The Metabolic syndrome
and Cancer project, Me-Can 2.0), metabolic aberrations, especially elevated blood pressure and triglycerides,
were associated with increased risks of BC among men, whereas high body mass index (BMI) was associated
with decreased BC risk. The associations between BMI, blood pressure and BC risk significantly differed
between men and women [28].
The association of diabetes mellitus (DM) with the risk of BC has been evaluated in numerous meta-analyses
with inconsistent results. When analysing specific subpopulations, DM was associated with BC or CSM risk
especially in men [29]. Thiazolidinediones (pioglitazone and rosiglitazone) are oral hypoglycaemic drugs used
for the management of type 2 DM. Their use and the association with BC is still a matter of debate. In a recent
meta-analysis of observational studies the summary results indicated that pioglitazone use was significantly
associated with an increased risk of BC which appears to be linked to higher dose and longer duration of
treatment [30]. The U.S. Food and Drug Administration (FDA) recommend that healthcare professionals should
not prescribe pioglitazone in patients with active BC. Several countries in Europe have removed this agent from
the market or included warnings for prescription. Moreover, the benefits of glycaemic control vs. unknown risks
for cancer recurrence with pioglitazone should be considered in patients with a prior history of BC.
3.2.6
Bladder schistosomiasis and chronic urinary tract infection
Bladder schistosomiasis (bilharzia) is the second most common parasitic infection after malaria, with about
600 million people exposed to infection in Africa, Asia, South America, and the Caribbean [31]. There is a wellestablished relationship between schistosomiasis and urothelial carcinoma (UC) of the bladder, which can
progress to squamous cell carcinoma (SCC), however, better control of the disease is decreasing the incidence
of SCC of the bladder in endemic zones such as Egypt [32, 33].
Similarly, invasive SCC has been linked to the presence of chronic urinary tract infection (UTI)
distinct from schistosomiasis. A direct association between BC and UTIs has been observed in several casecontrol studies, which have reported a two-fold increased risk of BC in patients with recurrent UTIs in some
series [34]. However, a recent meta-analysis found no statistical association when pooling data from the
most recent and highest quality studies which highlights the need for higher quality data to be able to draw
conclusions [35].
Similarly, urinary calculi and chronic irritation or inflammation of the urothelium have been described
as possible risk factors for BC. A meta-analysis of case-control and cohort studies suggests a positive
association between history of urinary calculi and BC [36].
3.2.7
Gender
Although men are more likely to develop BC than women, women present with more advanced disease and
have worse survival rates. A meta-analysis including nearly 28,000 patients shows that female gender was
associated with a worse survival outcome (hazard ratio [HR]: 1.20, 95% CI: 1.09–1.32) compared to male
gender after radical cystectomy (RC) [37]. This finding had already been presented in a descriptive nationwide analysis based on 27,773 Austrian patients. After their analysis the authors found that cancer-specific
survival (CSS) was identical for pT1-tumours in both sexes, while women had a worse CSS in both age cohorts
(< 70 years and ≥ 70 years) with higher tumour stages [38]. However, treatment patterns are unlikely to explain
the differences in overall survival (OS) [39]. In a population-based study from the Ontario Cancer Registry
analysing all patients with BC treated with cystectomy or radical RT between 1994 and 2008, no differences in
12
LIMITED UPDATE MARCH 2021
OS, mortality and outcomes were found between males and females following radical therapy [40]. The genderspecific difference in survival for patients with BC was also analysed in the Norwegian population. Survival
was inferior for female patients but only within the first 2 years after diagnosis. This discrepancy was partly
attributed to a more severe T-stage in female patients at initial diagnoses [41].
A population-based study from the MarketScan databases suggests that a possible reason for
worse survival in the female population may be that women experienced longer delays in diagnosis than men,
as the differential diagnosis in women includes diseases that are more prevalent than BC [42]. Furthermore,
differences in the gender prevalence of BC may be due to other factors besides tobacco and chemical
exposure. In a large prospective cohort study, post-menopausal status was associated with an increase in
BC risk, even after adjustment for smoking status. This finding suggests that the differences in oestrogen
and androgen levels between men and women may be responsible for some of the difference in the gender
prevalence of BC [43-45]. Moreover, a recent population study assessing impact of hormones on BC suggests
that younger age at menopause (≤ 45 years) is associated with an increased risk of BC [46].
3.2.8
Genetic factors
There is growing evidence that genetic susceptibility factors and family association may influence the
incidence of BC. A recent population-based study of cancer risk in relatives and spouses of UC patients
showed an increased risk for first- and second-degree relatives, and suggests genetic or environmental
roots independent of smoking-related behaviour [47]. Shared environmental exposure was recognised as a
potentially confounding factor [48]. Recent studies detected genetic susceptibility with independent loci, which
are associated with BC risk [49].
Genome-wide association studies (GWAS) of BC identified several susceptibility loci associated
with BC risk [50, 51].
3.2.9
Summary of evidence and guidelines for epidemiology and risk factors
Summary of evidence
Worldwide, bladder cancer is the 10th most commonly diagnosed cancer.
Several risk factors associated with bladder cancer diagnosis have been identified.
Active and passive tobacco smoking continues to be the main risk factor, while exposure-related
incidence is decreasing.
The increased risk of developing bladder cancer in patients undergoing external-beam radiotherapy
(EBRT), brachytherapy, or a combination of EBRT and brachytherapy, must be considered during
patient follow-up. As bladder cancer requires time to develop, patients treated with radiation at a
young age are at the greatest risk and should be followed-up closely.
Recommendations
Council patients to stop active and avoid passive smoking.
Inform workers in potentially hazardous workplaces of the potential carcinogenic effects of
a number of recognised substances, including duration of exposure and latency periods.
Protective measures are recommended.
Do not prescribe pioglitazone to patients with active bladder cancer or a history of bladder
cancer.
3.3
LE
2a
3
2a
3
Strength rating
Strong
Strong
Strong
Pathology
3.3.1
Handling of transurethral resection and cystectomy specimens
During transurethral resection (TUR), a specimen from the tumour and normal looking bladder wall should be
taken, if possible. Specimens should be taken from the superficial and deep areas of the tumour and sent
to the pathology laboratory separately, in case the outcome will impact on treatment decisions. If random
biopsies of the flat mucosa are taken, each biopsy specimen of the flat mucosa should also be submitted
separately [52]. The sampling sites must be recorded by the urologist; the pathologist report should include
location of tumour tissue in the cystectomy specimen. Anatomical tumour location is relevant for staging and
prognosis [53, 54].
In RC, bladder fixation must be carried out as soon as possible. The pathologist must open the
specimen from the urethra to the bladder dome and fix the specimen. In a female cystectomy specimen,
the length of the urethral segment removed en bloc with the specimen should be checked, preferably by the
urological surgeon [55].
LIMITED UPDATE MARCH 2021
13
Specimen handling should follow the general rules as published by a collaborative group of pathologists and
urologists [56, 57]. It must be stressed that it may be very difficult to confirm the presence of a neoplastic lesion
using gross examination of the cystectomy specimen after TUR or chemotherapy, so the entire retracted or
ulcerated area should be included.
It is compulsory to study the urethra, the ureters, the prostate in men and the radial margins [58]. In
urethra-sparing cystectomy; the level of urethral dissection, completeness of the prostate, specifically at the
apex (in men), and the inclusion of the entire bladder neck and amount of adjacent urethra, uterus and vaginal
vault (in women) have to be documented by the pathologist.
All lymph node (LN) specimens should be provided in their totality, in clearly labelled containers. In case of
doubt, or adipose differentiation of the LNs, the entire specimen is to be included. Lymph nodes should be
counted and measured on slides; capsular extension and percentage of LN invasion should be reported as
well as vascular embols [59, 60]. In case of metastatic spread in the perivesical fat without real LN structures
(capsule, subcapsular sinus), this localisation should nevertheless be considered as N+.
Potentially positive soft tissue margins should be inked by the pathologist for evaluation [61]. In rare
cases, fresh frozen sections may be helpful to determine treatment strategy [62].
3.3.2
Pathology of muscle-invasive bladder cancer
All MIBC cases are high-grade UCs. For this reason, no prognostic information can be provided by grading
MIBC [63]. However, identification of morphological subtypes is important for prognostic reasons and treatment
decisions [64-66].
The data presented in these guidelines are based on the 2004/2016 World Health Organization (WHO)
classifications [67, 68].
Currently the following differentiations are used [64, 69]:
1.
urothelial carcinoma (more than 90% of all cases);
2.
urothelial carcinomas with partial squamous and/or glandular or trophoblastic differentiation;
3.
micropapillary urothelial carcinoma;
4.
nested variant (including large nested variant) and microcystic urothelial carcinoma;
5.
plasmacytoid, giant cell, signet ring, diffuse, undifferentiated;
6.
lymphoepithelioma-like;
7.
small-cell carcinomas;
8.
sarcomatoid urothelial carcinomas;
9.
neuroendocrine variant of urothelial carcinoma;
10. some urothelial carcinomas with other rare differentiations.
Outcomes may vary for divergent histologies, which need to be mentioned following international reporting
standards [64, 70].
3.3.3
Guidelines for the assessment of tumour specimens
Recommendations
Strength rating
Record the depth of invasion (categories pT2a and pT2b, pT3a and pT3b or pT4a and pT4b). Strong
Record margins with special attention paid to the radial margin, prostate, ureter, urethra,
peritoneal fat, uterus and vaginal vault.
Record the total number of lymph nodes (LNs), the number of positive LNs and extranodal
spread.
Record lymphatic or blood vessel invasion.
Record the presence of carcinoma in situ.
Record the sampling sites as well as information on tumour size when providing specimens
to the pathologist.
14
LIMITED UPDATE MARCH 2021
3.3.4
EAU-ESMO consensus statements on the management of advanced- and variant bladder
cancer [8, 9]*
Consensus statement
Bladder urothelial carcinoma with small cell neuroendocrine variant should be treated with neoadjuvant
chemotherapy followed by consolidating local therapy.
Muscle-invasive pure squamous cell carcinoma of the bladder should be treated with primary radical
cystectomy and lymphadenectomy.
Muscle-invasive pure adenocarcinoma of the bladder should be treated with primary radical cystectomy and
lymphadenectomy.
Muscle-invasive small cell neuroendocrine variant of bladder urothelial carcinoma should not receive
preventive brain irradiation to avoid brain recurrence.
Differentiating between urachal and non-urachal subtypes of adenocarcinoma is essential when making
treatment decisions.
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
4.
STAGING AND CLASSIFICATION SYSTEMS
4.1
Pathological staging
For staging, the Tumour, Node, Metastasis (TNM) Classification (2017, 8th edition) is recommended [71]. Blood
and lymphatic vessel invasion have an independent prognostic significance [72, 73].
4.2
Tumour, node, metastasis classification
The TNM classification of malignant tumours is the method most widely used to classify the extent of cancer
spread [71] (Table 4.1).
Table 4.1: TNM Classification of urinary bladder cancer [71]
T - Primary Tumour
Tx
Primary tumour cannot be assessed
T0
No evidence of primary tumour
Ta
Non-invasive papillary carcinoma
Tis
Carcinoma in situ: “flat tumour”
T1
Tumour invades subepithelial connective tissue
T2
Tumour invades muscle
T2a
Tumour invades superficial muscle (inner half)
T2b
Tumour invades deep muscle (outer half)
T3
Tumour invades perivesical tissue:
T3a
microscopically
T3b
macroscopically (extravesical mass)
T4
Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall,
abdominal wall
T4a
Tumour invades prostate stroma, seminal vesicles, uterus, or vagina
T4b
Tumour invades pelvic wall or abdominal wall
N - Regional Lymph Nodes
Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral)
N2
Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or
presacral)
N3
Metastasis in a common iliac lymph node(s)
LIMITED UPDATE MARCH 2021
15
M - Distant Metastasis
M0
No distant metastasis
M1a Non-regional lymph nodes
M1b Other distant metastasis
Staging after neo-adjuvant chemotherapy (NAC) and radical cystectomy can be done, but must be mentioned
as ypTNM (International Collaboration on Cancer Reporting) [70]. ypT0N0 after NAC and cystectomy is
associated with good prognosis [74, 75].
5.
DIAGNOSTIC EVALUATION
5.1
Primary diagnosis
5.1.1
Symptoms
Painless visible haematuria is the most common presenting complaint. Other presenting symptoms and clinical
signs include non-visible haematuria, urgency, dysuria, increased frequency, and in more advanced tumours,
pelvic pain and symptoms related to urinary tract obstruction.
5.1.2
Physical examination
Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be
found in patients with locally advanced tumours. In addition, bimanual examination under anaesthesia should
be carried out before and after TUR of the bladder (TURB) to assess whether there is a palpable mass or if the
tumour is fixed to the pelvic wall [76, 77]. However, considering the discrepancy between bimanual examination
and pT stage after cystectomy (11% clinical overstaging and 31% clinical understaging), some caution is
suggested with the interpretation of bimanual examination [78].
5.1.3
Bladder imaging
Patients with a bladder mass identified by any diagnostic imaging technique should undergo cystoscopy,
biopsy and/or resection for histopathological diagnosis and staging.
The high specificity of diagnostic imaging for detecting bladder cancer means that patients
with imaging positive for bladder cancer may avoid diagnostic flexible cystoscopy and go directly to rigid
cystoscopy and transurethral resection [79, 80].
5.1.4
Urinary cytology
Examination of voided urine or bladder washings for exfoliated cancer cells has high sensitivity in high-grade
tumours and is a useful indicator in cases of high-grade malignancy or CIS. However, positive urinary cytology
may originate from a urothelial tumour located anywhere in the urinary tract.
Evaluation of cytology specimens can be hampered by low cellular yield, UTIs, stones or intravesical
instillations, but for experienced readers, specificity exceeds 90% [81, 82]. However, negative cytology does
not exclude a tumour. There is no known urinary marker specific for the diagnosis of invasive BC [83].
A standardised reporting system, the ‘Paris System’ redefining urinary cytology diagnostic categories was
published in 2016 [84]:
•
adequacy of urine specimens (Adequacy);
•
negative for high-grade UC (Negative);
•
atypical urothelial cells (AUC);
•
suspicious for high-grade UC (Suspicious);
•
high-grade UC (HGUC);
•
low-grade urothelial neoplasia (LGUN).
5.1.5
Cystoscopy
Ultimately, the diagnosis of BC is made by cystoscopy and histological evaluation of resected tissue. An
(outpatient) flexible cystoscopy is recommended to obtain a complete image of the bladder. However, in
daily practice, If a bladder tumour has been visualised unequivocally by imaging studies such as computed
tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), diagnostic cystoscopy may be
omitted and the patient can proceed directly to TURB for histological diagnosis and resection. During the
procedure, a thorough investigation of the bladder with rigid cystoscopy under anaesthesia is mandatory in
order not to miss any tumours at the level of the bladder neck.
16
LIMITED UPDATE MARCH 2021
Currently, there is no evidence for the role of photodynamic diagnosis (PDD) in the standard diagnosis of
invasive BC.
A careful description of the cystoscopic findings is necessary. This should include documentation
of the site, size, number, and appearance (papillary or solid) of the tumours, as well as a description of any
mucosal abnormalities [85]. The use of a bladder diagram is recommended.
The use of PDD could be considered if a T1 high-grade tumour is present and to identify associated
CIS. Presence of CIS may lead to a modified treatment plan (see EAU Guidelines on Non-muscle-invasive
Bladder Cancer [2]). Photodynamic diagnosis is highly sensitive for the detection of CIS and in experienced
hands the rate of false-positive results may be similar to that with regular white-light cystoscopy [73, 86].
5.1.6
Transurethral resection of invasive bladder tumours
The goal of TURB is to enable histopathological diagnosis and staging, which requires the inclusion of bladder
muscle in the resection specimen.
In case MIBC is suspected, tumours need to be resected separately in parts, which include the
exophytic part of the tumour, the underlying bladder wall with the detrusor muscle, and the edges of the
resection area. At least the deeper part of the resection specimen must be referred to the pathologist in a
separate labelled container to enable making a correct diagnosis. In cases in which RT is considered and CIS is
to be excluded, PDD can be used [87].
The involvement of the prostatic urethra and ducts in men with bladder tumours has been
reported. The exact risk is not known, but it seems to be higher if the tumour is located on the trigone or
bladder neck, with concomitant bladder CIS, and in the case of multiple tumours [54, 88, 89]. Involvement
of the prostatic urethra can be determined either at the time of primary TURB or by frozen section during the
cystoprostatectomy procedure. A frozen section has a higher negative-predictive value and is more accurate
[90-92].
A negative urethral frozen section can reliably identify patients in whom urethrectomy should be avoided.
However, a positive pre-operative biopsy seems to have limited utility as these findings are not reliably
associated with final margin status [90, 93].
Diagnosis of a urethral tumour before cystectomy will result in a urethrectomy which could be a
contraindication for an orthotopic diversion. However, an orthotopic diversion should not be denied based
on positive pre-operative biopsy findings alone and frozen section should be part of the radical cystectomy
procedure, in particular in male patients [94, 95].
5.1.7
Concomitant prostate cancer
Prostate cancer is found in 21–50% of male patients undergoing RC for BC [96-99]. Incidentally discovered
clinically significant prostatic adenocarcinoma did not alter survival [98, 99]. Pathological reporting of
the specimens should follow the recommendations as presented in the EAU-EANM-ESTRO-ESUR-SIOG
Guidelines on Prostate Cancer [100].
5.1.8
Summary of evidence and guidelines for the primary assessment of presumably invasive
bladder tumours
Summary of evidence
Cystoscopy is necessary for the diagnosis of bladder cancer.
Urinary cytology has high sensitivity in high-grade tumours including carcinoma in situ.
In men, prostatic urethral biopsy includes resection from the bladder neck to the verumontanum
(between the 5 and 7 o’clock position) using a resection loop. In case any abnormal-looking areas in
the prostatic urethra are present at this time, these need to be biopsied as well.
Recommendations
Describe all macroscopic features of the tumour (site, size, number and appearance) and
mucosal abnormalities during cystoscopy. Use a bladder diagram.
Take a biopsy of the prostatic urethra in cases of bladder neck tumour, when bladder
carcinoma in situ is present or suspected, when there is positive cytology without evidence
of tumour in the bladder, or when abnormalities of the prostatic urethra are visible.
In men with a negative prostatic urethral biopsy undergoing subsequent orthotopic
neobladder construction an intra-operative frozen section can be omitted.
LIMITED UPDATE MARCH 2021
LE
1
2b
2b
Strength rating
Strong
Strong
Strong
17
Strong
In men with a prior positive transurethral prostatic biopsy, subsequent orthotopic
neobladder construction should not be denied a priori, unless an intra-operative frozen
section of the distal urethral stump reveals malignancy at the level of urethral dissection.
Strong
In women undergoing subsequent orthotopic neobladder construction, obtain procedural
information (including histological evaluation) of the bladder neck and urethral margin, either
prior to, or at the time of cystectomy.
In the pathology report, specify the grade, depth of tumour invasion, and whether the
Strong
lamina propria and muscle tissue are present in the specimen.
(For general information on the assessment of bladder tumours, see EAU Guidelines on Non-muscle-invasive
Bladder Cancer [2]).
5.1.9
EAU-ESMO consensus statements on the management of advanced- and variant bladder
cancer [8, 9]*
Consensus statement
Differentiating between urachal and non-urachal subtypes of adenocarcinoma is essential when making
treatment decisions.
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
5.2
Imaging for staging of MIBC
In clinical practice, tumour stage and histopathological grade are used to guide treatment and determine
prognosis [69, 101, 102].
Computed tomography and MRI are the imaging techniques most commonly used for tumour
staging. If the correct choice of treatment is to be made, staging must be accurate.
The goal of imaging patients with bladder cancer is to determine:
•
extent of local tumour invasion, ideally differentiating T1 from T2 tumours as the treatment is different;
•
tumour spread to LNs;
•
tumour spread to the upper UT and other distant organs (e.g., liver, lungs, bones, peritoneum, pleura, and
adrenal glands).
5.2.1
Local staging of MIBC
Multiparametric MRI (mpMRI) using the Vesical Imaging Reporting and Data System (VI-RADS) scoring system
may differentiate between muscle- and non-muscle-invasive primary BC with high diagnostic accuracy. A
recent meta-analysis found that the pooled sensitivity and specificity of mpMRI with VI-RADS acquisition
and scoring for predicting MIBC were 0.83 and 0.90, respectively. This diagnostic performance of VI-RADS is
similar to the diagnostic performance of bladder MRI in determining MIBC prior to the introduction of VI-RADS
based on a previous meta-analysis of 24 studies in which the pooled sensitivity and specificity were 0.92
(95% CI: 0.88–0.95) and 0.87 (95% CI: 0.78–0.93), respectively [103]. The Vesical Imaging Reporting and Data
System offers a standardised approach to both acquisition and reporting of mpMRI for BC. How mpMRI is best
used in clinical practice and which cut off levels to use for VI-RADS scoring is still to be determined [103].
Magnetic resonance imaging has superior soft tissue contrast resolution compared with CT. The accuracy of
MRI for primary tumour staging varies from 73% to 96% (mean 85%). A meta-analysis of 17 studies showed
a 91% sensitivity and 96% specificity for 3.0-T device MRI combined with diffusion-weighted imaging (DWI) to
differentiate ≤ T1 tumours from ≥ T2 tumours before surgery [104].
Both CT and MRI may be used for assessment of local invasion by T3b disease, or higher, but they
are unable to accurately diagnose microscopic invasion of perivesical fat (T2 vs. T3a) [105].
Magnetic resonance imaging may evaluate post-biopsy reaction because enhancement of the tumour occurs
earlier than that of the normal bladder wall due to neovascularisation [106, 107].
In 2006, a link was established between the use of gadolinium-based contrast agents and nephrogenic
systemic fibrosis (NSF), which may result in fatal or severely debilitating systemic fibrosis. Patients with
impaired renal function are at risk of developing NSF and non-ionic linear gadolinium-based contrast agents
should be avoided (gadodiamide, gadopentetate dimeglumine and gadoversetamide). A stable macrocyclic
contrast agent should be used (gadobutrol, gadoterate meglumine or gadoteridol). Contrast-enhanced CT
using iodinated contrast media can be considered as an alternative [108].
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LIMITED UPDATE MARCH 2021
5.2.1.1
CT imaging for local staging of MIBC
The advantages of CT include high spatial resolution, shorter acquisition time, wider coverage in a single breath
hold, and lower susceptibility to variable patient factors. Computed tomography is unable to differentiate
between stages Ta to T3a tumours, but it is useful for detecting invasion into the perivesical fat (T3b) and
adjacent organs. The accuracy of CT in determining extravesical tumour extension varies from 55% to 92%
[109] and increases with more advanced disease [110].
5.2.2
Imaging of lymph nodes in MIBC
Assessment of LN metastases based solely on size is limited by the inability of both CT and MRI to identify
metastases in normal-sized or minimally-enlarged nodes. The sensitivity for detection of LN metastases is low
(48–87%). Specificity is also low because nodal enlargement may be due to benign disease. Overall, CT and
MRI show similar results in the detection of LN metastases in a variety of primary pelvic tumours [111-115].
Pelvic nodes > 8 mm and abdominal nodes > 10 mm in maximum short-axis diameter, detected by CT or MRI,
should be regarded as pathologically enlarged [116, 117].
Positron emission tomography (PET) combined with CT is increasingly being used in clinical
practice and its exact role continues to be evaluated [118].
5.2.3
Upper urinary tract urothelial carcinoma
5.2.3.1
Computed tomography urography
Computed tomography urography has the highest diagnostic accuracy of the available imaging techniques
[119]. The sensitivity of CT urography for UTUC is 0.67–1.0 and specificity is 0.93–0.99 [120].
Rapid acquisition of thin sections allows high-resolution isotropic images that can be viewed in
multiple planes to assist with diagnosis without loss of resolution. Epithelial “flat lesions” without mass effect or
urothelial thickening are generally not visible with CT.
The secondary sign of hydronephrosis is associated with advanced disease and poor oncological
outcome [121, 122]. The presence of enlarged LNs is highly predictive of metastases in UTUC [123].
5.2.3.2
Magnetic resonance urography
Magnetic resonance urography is indicated in patients who cannot undergo CT urography, usually when
radiation or iodinated contrast media are contraindicated [124]. The sensitivity of MR urography is 0.75 after
contrast injection for tumours < 2 cm [124]. The use of MR urography with gadolinium-based contrast media
should be limited in patients with severe renal impairment (< 30 mL/min creatinine clearance), due to the risk
of NSF. Computed tomography urography is generally preferred to MR urography for diagnosing and staging
UTUC.
5.2.4
Distant metastases at sites other than lymph nodes
Prior to any curative treatment, it is essential to evaluate the presence of distant metastases. Computed
tomography and MRI are the diagnostic techniques of choice to detect lung [125] and liver metastases [126],
respectively. Bone and brain metastases are rare at the time of presentation of invasive BC. A bone scan and
additional brain imaging are therefore not routinely indicated unless the patient has specific symptoms or signs
to suggest bone or brain metastases [127, 128]. Magnetic resonance imaging is more sensitive and specific for
diagnosing bone metastases than bone scintigraphy [129, 130].
5.2.5
Future developments
Evidence is accruing in the literature suggesting that 18F-fluorodeoxyglucose (FDG)-positron emission
tomography (PET)/CT might have potential clinical use for staging metastatic BC [131, 132], but there is no
consensus as yet. The results of further trials are awaited before a recommendation can be made. Recently,
the first study was published showing the superior feasibility of DWI over T2-weighted and dynamic contrastenhanced (DCE)-MRI in assessing the therapeutic response to induction chemotherapy against MIBC [133].
The high specificity of DWI indicates that it is useful for accurate prediction of a complete histopathological
response, allowing better patient selection for bladder-sparing protocols. Results from prospective studies are
awaited.
LIMITED UPDATE MARCH 2021
19
5.2.6
Summary of evidence and guidelines for staging in muscle-invasive bladder cancer
Summary of evidence
LE
Imaging as part of staging in muscle-invasive bladder cancer (MIBC) provides information about
2b
prognosis and assists in selection of the most appropriate treatment.
There are currently insufficient data on the use of diffusion-weighted imaging (DWI) and
18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in MIBC
to allow for a recommendation to be made.
The diagnosis of upper tract urothelial carcinoma depends on CT urography and ureteroscopy.
2
Recommendations
In patients with confirmed muscle-invasive bladder cancer, use computed tomography (CT)
of the chest, abdomen and pelvis for staging, including some form of CT urography with
designated phases for optimal urothelial evaluation.
Use magnetic resonance urography when CT urography is contraindicated for reasons
related to contrast administration or radiation dose.
Use CT or magnetic resonance imaging (MRI) for staging locally advanced or metastatic
disease in patients in whom radical treatment is considered.
Use CT to diagnose pulmonary metastases. Computed tomography and MRI are generally
equivalent for diagnosing local disease and distant metastases in the abdomen.
5.3
Strength rating
Strong
Strong
Strong
Strong
MIBC and health status
Complications from RC may be directly related to pre-existing comorbidity as well as the surgical procedure,
bowel anastomosis, or urinary diversion. A significant body of literature has evaluated the usefulness of age
as a prognostic factor for RC, although chronological age is less important than frailty [134-136]. Frailty is a
syndrome of reduced ability to respond to stressors. Patients with frailty have a higher risk of mortality and
negative side effects of cancer treatment [137]. Controversy remains regarding age, RC and the type of urinary
diversion. Radical cystectomy is associated with the greatest risk reduction in disease-related and nondisease-related death in patients aged < 80 years [138].
The largest retrospective study on RC in septuagenarians and octogenarians based on data from
the National Surgical Quality Improvement Program database (n = 1,710) showed no significant difference
for wound, cardiac, or pulmonary complications. However, the risk of mortality in octogenarians compared
to septuagenarians is higher (4.3% vs. 2.3%) [139]. Although some octogenarians successfully underwent a
neobladder procedure, most patients were treated with an ileal conduit diversion. It is important to evaluate
functioning and quality of life (QoL) of older patients using a standardised geriatric assessment, as well as
carrying out a standard medical evaluation [140].
Sarcopenia has been shown to be an independent predictor for OS and CSS in a large multicentre study
with patients undergoing RC for BC [141]. In order to predict CSM after RC in patients receiving neoadjuvant
chemotherapy (NAC), sarcopenia should be assessed after completing the chemotherapy [142]. Other
risk factors for morbidity include prior abdominal surgery, extravesical disease, and prior RT [143]. Female
gender, an increased BMI and lower pre-operative albumin levels are associated with a higher rate of
parastomal hernias [144]. Low pre-operative serum albumin is also associated with impaired wound healing,
gastrointestinal (GI) complications and a decrease of recurrence-free and OS after RC [145, 146]. Therefore, it
could be used as a prognostic biomarker for patients undergoing RC.
5.3.1
Evaluation of comorbidity, frailty and cognition
Rochon et al. have shown that evaluation of comorbidity provides a better indicator of life expectancy in MIBC
than patient age [147]. Evaluation of comorbidity helps to identify factors likely to interfere with, or have an
impact on, treatment and the evolution and prognosis of MIBC [148].
The value of assessing overall health before recommending and proceeding with surgery was
emphasised by Zietman et al., who have demonstrated an association between comorbidity and adverse
pathological and survival outcomes following RC [149]. Similar results were found for the impact of comorbidity
on cancer-specific and other-cause mortality in a population-based competing risk analysis of > 11,260
patients from the Surveillance, Epidemiology, and End Results (SEER) registries. Age carried the highest risk for
other-cause mortality but not for increased cancer-specific death, while the stage of locally advanced tumour
was the strongest predictor for decreased CSS [150].
Stratifying older patients according to frailty using a multidisciplinary approach will help select
20
LIMITED UPDATE MARCH 2021
patients most likely to benefit from radical surgery and to optimise treatment outcomes [151]. There are many
different screening tools available for frailty and local approaches can be used. Examples include the G8 and
the Clinical Frailty Scale (See Table 5.1 and Figure 5.1 below).
Cognitive impairment can be screened for using a tool such as the mini-COG (https://mini-cog.
com/), which consists of three-word recall and a clock-drawing test, and can be completed within 5 minutes.
A score of ≤ 3/5 indicates the need to refer the patient for full cognitive assessment. Patients with any form of
cognitive impairment (e.g., Alzheimer’s or vascular dementia) may need a capacity assessment of their ability
to make an informed decision, which is an important factor in health status assessment. Cognitive impairment
also predicts risk of delirium, which is important for patients undergoing surgery [152].
Table 5.1: G8 screening tool (adapted from [153])
A
B
C
D
E
F
G
H
Items
Has food intake declined over the past 3 months
due to loss of appetite, digestive problems,
chewing, or swallowing difficulties?
Possible responses (score)
0 = severe decrease in food intake
1 = moderate decrease in food intake
2 = no decrease in food intake
Weight loss during the last 3 months?
0 = weight loss > 3 kg
1 = does not know
2 = weight loss between 1 and 3 kg
3 = no weight loss
Mobility?
0 = bed or chair bound
1 = able to get out of bed/chair but does not go out
2 = goes out
Neuropsychological problems?
0 = severe dementia or depression
1 = mild dementia
2 = no psychological problems
0 = BMI < 19
BMI? (weight in kg)/(height in m2)
1 = BMI 19 to < 21
2 = BMI 21 to < 23
3 = BMI ≥ 23
Takes more than three prescription drugs per day? 0 = yes
1 = no
0.0 = not as good
In comparison with other people of the same
age, how does the patient consider his/her health 0.5 = does not know
status?
1.0 = as good
2.0 = better
Age
0 = ≥ 85
1 = 80–85
2 = < 80
Total score
0–17
LIMITED UPDATE MARCH 2021
21
Figure 5.1: Clinical Frailty Scale©, Version 2.0* [154]
CLINICAL FRAILTY SCALE
1
2
LIVING
WITH
MODERATE
FRAILTY
People who need help with all outside
activities and with keeping house.
Inside, they often have problems with
stairs and need help with bathing and
might need minimal assistance (cuing,
standby) with dressing.
7
LIVING
WITH
SEVERE
FRAILTY
Completely dependent for personal
care, from whatever cause (physical or
cognitive). Even so, they seem stable
and not at high risk of dying (within ~6
months).
8
LIVING
WITH VERY
SEVERE
FRAILTY
VERY People who are robust, active, energetic
FIT and motivated. They tend to exercise
regularly and are among the fittest for
their age.
FIT People who have no active disease
symptoms but are less fit than category
1. Often, they exercise or are very active
occasionally, e.g., seasonally.
3
MANAGING People whose medical problems are
WELL well controlled, even if occasionally
4
LIVING
WITH
VERY MILD
FRAILTY
5
6
symptomatic, but often are not
regularly active beyond routine walking.
LIVING
WITH
MILD
FRAILTY
Previously “vulnerable,” this category
marks early transition from complete
independence. While not dependent on
others for daily help, often symptoms
limit activities. A common complaint
is being “slowed up” and/or being tired
during the day.
People who often have more evident
slowing, and need help with high
order instrumental activities of daily
living (finances, transportation, heavy
housework). Typically, mild frailty
progressively impairs shopping and
walking outside alone, meal preparation,
medications and begins to restrict light
housework.
9
Completely dependent for personal care
and approaching end of life. Typically,
they could not recover even from a
minor illness.
TERMINALLY Approaching the end of life. This
ILL category applies to people with a life
expectancy <6 months, who are not
otherwise living with severe frailty.
(Many terminally ill people can still
exercise until very close to death.)
SCORING FRAILTY IN PEOPLE WITH DEMENTIA
The degree of frailty generally
corresponds to the degree of
dementia. Common symptoms in
mild dementia include forgetting
the details of a recent event, though
still remembering the event itself,
repeating the same question/story
and social withdrawal.
www.geriatricmedicineresearch.ca
In moderate dementia, recent memory is
very impaired, even though they seemingly
can remember their past life events well.
They can do personal care with prompting.
In severe dementia, they cannot do
personal care without help.
In very severe dementia they are often
bedfast. Many are virtually mute.
Clinical Frailty Scale ©2005–2020 Rockwood,
Version 2.0 (EN). All rights reserved. For permission:
www.geriatricmedicineresearch.ca
Rockwood K et al. A global clinical measure of fitness
and frailty in elderly people. CMAJ 2005;173:489–495.
*Permission to reproduce the Clinical Frailty Scale© has been granted by the copyright holder.
5.3.2
Comorbidity scales, anaesthetic risk classification and geriatric assessment
A range of comorbidity scales has been developed [155], seven of which have been validated [156-162]. The
Charlson Comorbidity Index (CCI) ranges from 0 to 30 according to the importance of comorbidity described
at four levels and is calculated by healthcare practitioners based on patients’ medical records. The score has
been widely studied in patients with BC and found to be an independent prognostic factor for peri-operative
mortality [163, 164], overall mortality [165], and CSM [138, 166-168]. Only the age-adjusted version of the CCI
was correlated with both cancer-specific and other-cause mortality [169]. The age-adjusted CCI (Table 5.2) is
the most widely used comorbidity index in cancer for estimating long-term survival and is easily calculated
[170].
Health assessment of oncology patients must be supplemented by measuring their activity level. Extermann
et al. have shown that there is no correlation between morbidity and competitive activity level [171]. The
Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores and Karnofsky index have been
validated to measure patient activity [172]. Performance score is correlated with patient OS after RC [167] and
palliative chemotherapy [173-175].
Patients who have screened positive for frailty or cognitive impairment benefit from an assessment by
a geriatrician. This allows identification of geriatric syndromes and any scope for optimisation. The most
complete protocol is the Comprehensive Geriatric Assessment (CGA) [176] which is useful in the care of cancer
patients [177]. In BC, the CGA has been used to adapt gemcitabine chemotherapy in previously untreated older
patients with advanced BC [178].
22
LIMITED UPDATE MARCH 2021
Table 5.2: Calculation of the Charlson Comorbidity Index
Number of points
1
2
3
4
5
6
Conditions
50–60 years
Myocardial infarction
Heart failure
Peripheral vascular insufficiency
Cerebrovascular disease
Dementia
Chronic lung disease
Connective tissue disease
Ulcer disease
Mild liver disease
Diabetes
61–70 years
Hemiplegia
Moderate to severe kidney disease
Diabetes with organ damage
Tumours of all origins
71–80 years
Moderate to severe liver disease
81–z years
> 90 years
Metastatic solid tumours
AIDS
Interpretation:
1. Calculate Charlson Comorbidity Score or Index = i
a.
Add comorbidity score to age score
b.
Total denoted as ‘i’ in the Charlson Probability calculation (see below).
i = sum of comorbidity score to age score
2. Calculate Charlson Probability (10-year mortality = Y)
a.
Calculate Y = 10(i x 0.9)
b.
Calculate Z = 0.983Y (where Z is the 10-year survival)
5.3.3
Summary of evidence and guidelines for comorbidity scales
Summary of evidence
Chronological age is of limited relevance.
It is important to screen for frailty and cognitive impairment and provide a Comprehensive Geriatric
Assessment (CGA) where optimisation is needed.
Recommendations
Base the decision on bladder-sparing treatment or radical cystectomy in older/frail patients
with invasive bladder cancer on tumour stage and frailty.
Assess comorbidity by a validated score, such as the Charlson Comorbidity Index.
The American Society of Anesthesiologists score should not be used in this setting (see
Section 5.3.2).
LIMITED UPDATE MARCH 2021
LE
3
3
Strength rating
Strong
Strong
23
6.
MARKERS
6.1
Introduction
Both patient and tumour characteristics guide treatment decisions and prognosis of patients with MIBC.
6.2
Prognostic markers
6.2.1
Histopathological and clinical markers
The most important histopathological prognostic variables after RC and LN dissection are tumour stage and
LN status [179]. In addition, other histopathological parameters of the RC specimen have been associated with
prognosis.
The value of lymphovascular invasion was reported in a systematic review and meta-analysis
including 78,000 patients from 65 studies treated with RC for BC [180]. Lymphovascular invasion was present
in 35% of the patients and correlated with a 1.5-fold higher risk of recurrence and CSM, independent of
pathological stage and peri-operative chemotherapy. This correlation was even stronger in those patients with
node-negative disease [181].
In a systematic review and meta-analysis including 23 studies and over 20,000 patients, the presence
of concomitant CIS in the RC specimen was associated with a higher odds ratio (OR) of ureteral involvement
(pooled OR: 4.51, 2.59–7.84). Concomitant CIS was not independently associated with OS, recurrence-free
survival (RFS) and DSS in all patients, but in patients with organ-confined disease concomitant CIS was
associated with worse RFS (pooled HR: 1.57, 1.12–2.21) and CSM (pooled HR: 1.51, 1.001–2.280) [181].
Tumour location has been associated with prognosis. Tumours located at the bladder neck or trigone of the
bladder appear to have an increased likelihood of nodal metastasis (OR: 1.83, 95% CI: 1.11–2.99) and have
been associated with decreased survival [179, 182-184].
Prostatic urethral involvement at the time of RC was also found to be associated with worse survival
outcomes. In a series of 995 patients, prostatic involvement was recorded in 31% of patients. The 5-year CSS
in patients with CIS of the prostatic urethra was 40%, whilst the prognosis of patients with UC invading the
prostatic stroma was worse with a 5-year CSS of only 12% [185].
Neutrophil-to-lymphocyte ratio (NLR) has emerged as a prognostic factor in UUT tumours [1] and
other non-urological malignancies. In a pooled analysis of 21 studies analysing the prognostic role of NLR in
BC, the authors correlated elevated pre-treatment NLR with OS, RFS and disease-free survival (DFS) in both
localised and metastatic disease [186]. In contrast, a secondary analysis of the Southwest Oncology Group
(SWOG) 8710 trial, a randomised phase III trial assessing cystectomy ± NAC in patients with MIBC, suggests
that NLR is neither a prognostic nor a predictive biomarker for OS in MIBCs [187].
In patients with LN-positive disease, the American Joint Committee on Cancer (AJCC)-TNM staging system
provides 3 subcategories. In addition, several other prognostic LN-related parameters have been reported.
These include, but are not limited to, the number of positive LNs, the number of LNs removed, LN density
(the ratio of positive LNs to the number of LNs removed) and extranodal extension. In a systematic review
and meta-analysis, it was reported that LN density was independently associated with OS (HR: 1.45, 95%,
CI: 1.11–1.90) [188]. It has been suggested that LN density outperforms the AJCC-TNM staging system for
LN-positive disease in terms of prognostic value [189]. However, in spite of these studies supporting the
use of LN density, LN density relies on the number of LNs removed which, in turn, is subject to surgical and
pathological factors. This makes the concept of LN density difficult to apply uniformly [190].
Two studies investigated whether any of the reported LN-related parameters may be superior to the
routinely used AJCC-TNM staging system [190, 191]. Whilst the conclusion was that the AJCC-TNM staging
system for LN status did not perform well, none of the other tested variables outperformed the AJCC system.
6.2.2
Molecular markers
6.2.2.1
Molecular subtypes based on the Cancer Genome Atlas cohort
The updated Cancer Genome Atlas (TCGA) reported on 412 MIBCs and identified two main groups; luminal
and basal-squamous - consisting of five mRNA expression-based molecular subtypes including luminalpapillary, luminal-infiltrated, luminal; basal-squamous; and neuronal, a subtype associated with poor survival in
which the majority of tumours do not have small cell or neuroendocrine histology. Each subtype is associated
with distinct mutational profiles, histopathological features and prognostic and treatment implications [192].
The basal-squamous subtype is characterised by expression of basal keratin markers, immune
infiltrates and is felt to be chemo sensitive. The different luminal subtypes are characterised by fibroblast
growth factor receptor 3 (FGFR3) alterations (luminal-papillary), epithelial-mesenchymal transition (EMT)
markers (luminal-infiltrated) and may be associated with chemotherapy resistance [65, 66, 192, 193].
24
LIMITED UPDATE MARCH 2021
In 2019, a consensus on molecular subtype classification was reported [194]. The authors analysed 1,750
MIBC transcriptomic profiles from 18 datasets and identified six MIBC molecular classes that reconcile
all previously published classification schemes. The molecular subgroup classes include luminal papillary
(LumP), luminal non-specified (LumNS), luminal unstable (LumU), stroma-rich, basal/squamous (Ba/Sq), and
neuroendocrine-like (NE-like). Each class has distinct differentiation patterns, oncogenic mechanisms, tumour
micro-environments and histological and clinical associations. However, the authors stressed that consensus
was reached for biological rather than clinical classes. Therefore, at this time, the classification should be
considered as a research tool for retrospective and prospective studies until future studies establish how these
molecular subgroups can be used best in a clinical setting.
Molecular classification of MIBC is still evolving and treatment tailored to molecular subtype is
not a standard yet. A novel 12-gene signature derived from patients in the TCGA utilising published gene
signatures has been developed and externally validated to predict OS in MIBC [195]. Interestingly, a recently
published analysis of molecular subtyping in MIBC demonstrated that although molecular subtypes reflect the
heterogeneity of bladder tumours and are associated with tumour grade, clinical parameters outperformed
subtypes for predicting outcome [196]. In the coming years, new insights into BC carcinogenesis may change
our management of the disease and our ability to better predict outcomes.
6.3
Predictive markers
6.3.1
Clinical and histopathological markers
Based on retrospective data only, patients with secondary MIBC have a worse response to NAC compared
to patients with primary MIBC [197]. Pietzak et al. retrospectively analysed clinico-pathologic outcomes
comparing 245 patients with clinical T2–4a N0M0 primary MIBC and 43 patients with secondary MIBC
treated with NAC and RC. They found that patients with secondary MIBC had lower pathologic response
rates following NAC than those with primary MIBC (univariable 26% vs. 45%, multivariable OR: 0.4 [95% CI:
0.18–0.84, p = 0.02]). They also found that MIBC patients progressing after NAC had worse CSS as compared
to patients treated with cystectomy alone (p = 0.002).
Variant histologies and non-UC have also been linked to worse outcomes after NAC, but there is, as
yet, insufficient data to conclude that they can be considered as predictive markers [198].
6.3.2
Molecular markers
Several predictive biomarkers have been investigated such as serum vascular endothelial growth factor [199],
circulating tumour cells as well as defects in DNA damage repair (DDR) genes including ERCC2, ATM, RB1 and
FANCC that may predict response to cisplatin-based NAC [200, 201]. More recently, alterations in FGFR3 including
both mutations and gene fusions have been shown to be associated with response to FGFR inhibitors [202, 203].
More recent efforts have focused on markers for predicting response to immune checkpoint inhibition.
Programmed death-ligand 1 (PD-L1) expression by immunohistochemistry has been evaluated in several studies
with mixed results which may in part be related to the use of different antibodies and various scoring systems
evaluating different compartments i.e., tumour cells, immune cells, or both. The major limitation of PD-L1
staining relates to the significant proportion of PD-L1-negative patients that respond to immune checkpoint
blockade. For example, in the IMvigor 210 phase II study of atezolizumab in patients with advanced/metastatic
UC who progressed after platinum-based chemotherapy, responses were seen in 18% of patients with low/
no PD-L1 expression [204]. At present, the only indication for PD-L1 testing relates to the use of immune
checkpoint inhibitors as monotherapy in patients with locally advanced or metastatic UC unfit for cisplatincontaining chemotherapy who have not received prior therapy. In this setting, pembrolizumab or atezolizumab
should only be used in patients unfit for cisplatin-containing chemotherapy whose tumours overexpress PD-L1
(i.e., Combined Positive Score [CPS] ≥ 10 using the 22C3 assay for pembrolizumab and tumour-infiltrating
immune cells [IC] covering ≥ 5% of the tumour area using the SP142 assay for atezolizumab) [205].
Urothelial cancer is associated with a high tumour mutational burden (TMB) [206]. Both predicted neoantigen
burden and tumour mutational burden have been associated with response to immune checkpoint blockade
in several malignancies. High TMB has been associated with response to immune checkpoint inhibitors
in metastatic BC [204, 207]. Conflicting results have been seen in studies evaluating immune checkpoint
inhibitors in the neoadjuvant setting with the Pembrolizumab as Neoadjuvant Therapy Before Radical
Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE)-01 study utilising
pembrolizumab demonstrating an association of high TMB with response while there was no association with
atezolizumab in the Phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in MIBC
(ABACUS) [208, 209].
LIMITED UPDATE MARCH 2021
25
Other markers that have been evaluated in predicting response to immune checkpoint inhibitors include
molecular subtypes as discussed earlier, CD8 expression by immunohistochemistry and other immune gene
cell signatures. Recent work has focused on the importance of stroma including the role of TGFß in predicting
response to immune checkpoint blockade [210, 211]. Although promising, there are currently no validated
predictive molecular markers that are routinely used in clinical practice. Further validation studies are awaited.
6.4
Conclusion
The updated Cancer Genome Atlas and other efforts have refined our understanding of the molecular
underpinnings of bladder cancer biology. Molecular subtypes, immune gene signatures as well as stromal
signatures may ultimately have an important role in predicting response to immunotherapy. Although PD-L1
expression by immunohistochemistry and TMB have demonstrated predictive value in certain settings,
additional studies are needed. Prospectively validated prognostic and predictive molecular biomarkers will
present valuable adjuncts to clinical and pathological data, but large phase III randomised controlled trials
(RCTs) with long-term follow-up will be needed to clarify the many questions remaining.
6.5
Summary of evidence and recommendations for urothelial markers
Summary of evidence
There is insufficient evidence to use TMB, molecular subtypes, immune or other gene expression
signatures for the management of patients with urothelial cancer.
Recommendations
Evaluate PD-L1 expression (by immunohistochemistry) to determine the potential for use of
pembrolizumab or atezolizumab in previously untreated patients with locally advanced or
metastatic urothelial cancer who are unfit for cisplatin-based chemotherapy.
Evaluate for FGFR2/3 genetic alterations for the potential use of erdafitinib in patients
with locally advanced or metastatic urothelial carcinoma who have progressed following
platinum-containing chemotherapy (including within 12 months of neoadjuvant or adjuvant
platinum-containing chemotherapy).
7.
DISEASE MANAGEMENT
7.1
Neoadjuvant therapy
LE
-
Strength rating
Weak
Weak
7.1.1
Introduction
The standard treatment for patients with urothelial MIBC and MIBC with variant histologies is RC. However,
RC only provides 5-year survival in about 50% of patients [212-216]. To improve these results in patients with
cN0M0 disease, cisplatin-based NAC has been used since the 1980s [212-218].
7.1.2
Role of cisplatin-based chemotherapy
There are theoretical advantages and disadvantages of administering chemotherapy before planned definitive
surgery to patients with resectable muscle-invasive UC of the bladder and cN0M0 disease:
•
Chemotherapy is delivered at the earliest time-point, when the burden of micrometastatic disease is
expected to be low.
•
Potential reflection of in-vivo chemosensitivity.
•
Tolerability of chemotherapy and patient compliance are expected to be better pre-cystectomy.
•
Patients may respond to NAC and have a favourable pathological response as determined mainly by
achieving ypT0, ≤ ypT1, ypN0 and negative surgical margins.
•
Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy [219221]. However, there are no prospective trials indicating that delayed surgery due to NAC has a negative
impact on survival. In the recently reported French Genito-Urinary Group and the French Association of
Urology (GETUG/AFU) V05 Randomized Phase III VESPER trial, comparing gemcitabine/cisplatin (GC) vs.
high-dose-intensity methotrexate, vinblastine, doxorubicine and cisplatin (HD-MVAC) in the peri-operative
setting, approximately 90% of patients proceeded to surgery after neoadjuvant dose-dense MVAC
(ddMVAC) or GC (median delay of surgery was 48 days for GC and 51 days for ddMVAC) [222].
26
LIMITED UPDATE MARCH 2021
•
•
•
•
Neoadjuvant chemotherapy does not seem to affect the outcome of surgical morbidity. In one
randomised trial the same distribution of grade 3–4 post-operative complications was seen in both
treatment arms [223]. In the combined Nordic trials (n = 620), NAC did not have a major adverse effect
on the percentage of performable cystectomies. The cystectomy frequency was 86% in the experimental
arm and 87% in the control arm with 71% of patients receiving all three chemotherapy cycles [224].
Clinical staging using bimanual palpation, CT or MRI may result in over- and understaging and have a
staging accuracy of only 70% [78]. Overtreatment is a possible negative consequence.
Gender may have an impact on chemotherapeutic response and oncologic outcomes [225, 226].
Neoadjuvant chemotherapy should only be used in patients eligible for cisplatin-combination
chemotherapy; other combinations (or monotherapies) are inferior in metastatic BC and have not been
fully tested in a neoadjuvant setting [223, 227-235].
7.1.2.1
Summary of available data
Several randomised phase III trials addressed the potential survival benefit of NAC administration [223, 227232, 236-240]. The main differences in trial designs were the type of chemotherapy (i.e., single-agent cisplatin
or combination chemotherapy) and the number of cycles provided. Patients had to be fit for cisplatin. Since
these studies differed considerably for patient numbers, patient characteristics (e.g., clinical T-stages included)
and the type of definitive treatment offered (cystectomy and/or RT), pooling of results was not possible.
Three meta-analyses were undertaken to establish if NAC prolongs survival [233-235]. In a
meta-analysis, published in 2005 [235] with updated patient data from 11 randomised trials (n = 3,005),
a significant survival benefit was shown in favour of NAC. The most recent meta-analysis included four
additional randomised trials, and used the updated results from the Nordic I, Nordic II, and BA06 30894 trials
including data from 427 new patients and updated information from 1,596 patients. The results of this analysis
confirmed the previously published data and showed an 8% absolute improvement in survival at five years
with a number needed-to-treat of 12.5 [241]. Only cisplatin-combination chemotherapy with at least one
additional chemotherapeutic agent resulted in a meaningful therapeutic benefit [233, 235]; the regimens tested
were methotrexate, vinblastine, adriamycin (epirubicin) plus cisplatin (MVA(E)C), cisplatin, methotrexate plus
vinblastine (CMV), cisplatin plus methotrexate (CM), cisplatin plus adriamycin and cisplatin plus 5-fluorouracil
(5-FU) [242].
The updated analysis of a large phase III RCT [227] with a median follow-up of eight years
confirmed previous results and provided additional findings:
•
16% reduction in mortality risk;
•
improvement in 10-year survival from 30% to 36% with neoadjuvant CMV;
•
benefit with regard to distant metastases;
•
the addition of neoadjuvant CMV provided no benefit for locoregional control and locoregional DFS,
independent of the definitive treatment.
More modern chemotherapeutic regimens such as GC have shown similar pT0/pT1 rates as methotrexate,
vinblastine, adriamycin plus cisplatin in retrospective series and pooled data analyses [242-245]. Modified
ddMVAC was tested in two small single-arm phase II studies demonstrating high rates of pathologic complete
remission [246, 247]. Moreover, a large cross-sectional analysis showed higher rates of down-staging and
pathological complete response for ddMVAC [248]. The recently reported results from the GETUG/AFU V05
VESPER randomised trial of ddMVAC vs. gemcitabine and cisplatin as peri-operative chemotherapy in patients
with MIBC demonstrated similar pathologic response rates (ypT0N0) in patients treated with neoadjuvant
ddMVAC or GC of 42% and 36%, respectively (p = 0.2). An organ-confined status (< ypT3pN0) was obtained
in 154 (77%) and 124 (63%) patients, respectively (p = 0.001). Dose-dense MVAC was associated with more
severe asthenia and gastrointestinal side effects than GC. Although a higher local control rate (complete
pathological response, tumour down-staging, or organ confined) was observed in the ddMVAC arm (p = 0.021),
the primary endpoint of PFS at three years is not yet mature [222]. Another dose-dense regimen using cisplatin/
gemcitabine was reported in two small phase II trials [249, 250]. While pathological response rates (< pT2)
in the range of 45%–57% were achieved, one trial had to be closed prematurely due to high rates of severe
vascular events [249]. This approach is therefore not recommended outside of clinical trials.
As an alternative to the standard dose of cisplatin-based NAC with 70 mg/m2 on day 1, split-dose
modifications regimens are often used with 35 mg/m2 on days 1+8 or days 1+2. In a retrospective analysis
the standard schedule was compared to a split-dose schedule in terms of complete and partial pathological
response. A lower number of complete and partial response rates was seen in the split-dose group, but these
results were not statistically significant [251].
LIMITED UPDATE MARCH 2021
27
There seem to be differences in the outcomes of patients treated with NAC for primary or secondary MIBC.
However, in the absence of prospective data, patients with secondary MIBC should be treated similarly to
those presenting with primary MIBC [197].
It is unclear, if patients with non-UC histology will also benefit from NAC. A retrospective analysis demonstrated
that patients with neuroendocrine tumours had improved OS and lower rates of non-organ-confined disease
when receiving NAC. In case of micropapillary differentiation, sarcomatoid differentiation and adenocarcinoma,
lower rates of non-organ confined disease were found, but no statistically significant impact on OS. Patients
with SCC did not benefit from NAC [252].
A retrospective analysis assessed the use of NAC in MIBC based on data from the U.S. National Cancer
Database [253]. Only 19% of all patients received NAC before RC (1,619 of 8,732 patients) and no clear
survival advantage for NAC following propensity score adjustment was found despite efforts to include patients
based on SWOG 8710 study criteria [223]. These results have to be interpreted with caution, especially
since no information was available for the type of NAC applied. Such analyses emphasise the importance of
pragmatically designed studies that reflect real-life practice.
7.1.3
The role of imaging and predictive biomarkers
Data from small imaging studies aiming to identify responders in patients treated with NAC suggest that
response after two cycles of treatment is predictive of outcome. Although mpMRI has the advantage of better
resolution of the bladder wall tissue planes as compared to CT, it is not ready yet for standard patient care.
However, bladder mpMRI may be useful to inform on tumour stage after TURB and response to NAC [254]. So
far PET/CT, MRI or DCE-MRI cannot accurately assess treatment response [255-258]. To identify progression
during NAC imaging is being used in many centres notwithstanding the lack of supporting evidence.
For responders to NAC, especially in those with a complete response (pT0 N0), treatment has a
major positive impact on OS [259, 260]. Therefore, reliable predictive markers to identify patients most likely
to benefit from chemotherapy are needed. Molecular tumour profiling might guide the use of NAC in the future
but, as yet, this is not applicable in routine practice [261-263] (see Chapter 6 - Markers).
7.1.4
Role of neoadjuvant immunotherapy
Inhibition of programmed death receptor-1 (PD-1)/PD-L1 checkpoint has demonstrated significant benefit in
patients with unresectable and metastatic BC in the second-line setting and in platinum-ineligible PD-L1+
patients as first-line treatment using different agents. Checkpoint inhibitors are increasingly tested also in
the neoadjuvant setting; either as monotherapy or in combination with chemotherapy or CTLA-4 checkpoint
inhibition. Data from two phase II trials have been presented with encouraging results [208, 209]. The results
of the phase II trial using the PD-1 inhibitor pembrolizumab reported a complete pathological remission (pT0)
in 42% and pathological response (< pT2) in 54% of patients, whereas in the single-arm phase II trial with
atezolizumab a pathologic complete response rate of 31% was reported. However, immunotherapy is not yet
approved in the neoadjuvant setting.
7.1.5
Summary of evidence and guidelines for neoadjuvant therapy
Summary of evidence
Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival (OS) (5–8% at
five years).
Neoadjuvant treatment has a major impact on OS in patients who achieve ypT0 or at least ypT2.
Currently immunotherapy with checkpoint inhibitors as monotherapy, or in different combinations, is
being tested in phase II and III trials. Initial results are promising.
There are still no tools available to select patients who have a higher probability of benefitting from
NAC. In the future, genetic markers in a personalised medicine setting might facilitate the selection of
patients for NAC and differentiate responders from non-responders.
Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of
surgical techniques and current chemotherapy combinations.
28
LE
1a
2
-
3
LIMITED UPDATE MARCH 2021
Recommendations
Offer neoadjuvant chemotherapy (NAC) for T2–T4a, cN0 M0 bladder cancer. In this case,
always use cisplatin-based combination therapy.
Do not offer NAC to patients who are ineligible for cisplatin-based combination
chemotherapy.
Only offer neoadjuvant immunotherapy to patients within a clinical trial setting.
7.2
Strength rating
Strong
Strong
Strong
Pre- and post-operative radiotherapy in muscle-invasive bladder cancer
7.2.1
Post-operative radiotherapy
Given the high rates of local-regional failure after RC in patients with locally advanced (pT3–4) BC, estimated
at~30%, as well as the high risk of distant failure and poor survival for these patients, there is an interest
in adjuvant therapies that address both the risk of local and distant disease. Data on adjuvant RT after RC
are limited and further prospective studies are needed, but a more recent phase II trial compared adjuvant
sequential chemotherapy and radiation vs. adjuvant chemotherapy alone in 120 patients with locally advanced
disease and negative margins after RC (with one or more risk factors: ≥ pT3b, grade 3, or node-positive), in a
study population with 53% UC and 47% SCC. Addition of adjuvant RT to chemotherapy alone was associated
with a statistically significant improvement in local relapse-free survival (at 2 years 96% vs. 69% favouring the
addition of RT). Disease-free survival and OS also favoured the addition of RT, but those differences were not
statistically significant and the study was not powered for those endpoints. Late-grade ≥ 3 gastrointestinal
toxicity in the chemoradiation arm was low (7% of patients) [264].
A 2019 systematic review evaluating the efficacy of adjuvant radiation for BC or UTUC found no clear benefit of
adjuvant radiation following radical surgery (e.g., cystectomy), although the combination of adjuvant radiation
with chemotherapy may be beneficial in locally advanced disease [265].
While there are no conclusive data demonstrating improvements in OS it is reasonable to consider adjuvant
radiation in patients with pT3/pT4 pN0–2 urothelial BC following RC, although this approach has been
evaluated in only a limited number of studies. Radiation fields should encompass areas at risk for harbouring
residual microscopic disease based on pathologic findings at surgery and may include cystectomy bed and
pelvic LNs. Doses in the range of 45 to 50.4 Gy may be considered. For patients who have not had prior NAC,
it may be reasonable to sandwich adjuvant radiation between cycles of adjuvant chemotherapy. The safety and
efficacy of concurrent radiosensitising chemotherapy in the adjuvant setting needs further study.
7.2.2
Pre-operative radiotherapy
To date, six RCTs have been published investigating pre-operative RT, although all are from several decades
ago. In the largest trial, pre-operative RT at a dose of 45 Gy was used in patients with muscle-invasive
tumours resulting in a significant increase in pathological complete response (9% to 34%) in favour of preoperative RT, which was also a prognostic factor for survival [266]. The OS data were difficult to interpret since
chemotherapy was used in a subset of patients only and more than 50% of patients (241/475) did not receive
the planned treatment and were excluded from the final analyses. Two smaller studies using a dose of 20 Gy
showed only a small survival advantage in ≥ T3 tumours [267, 268]. Two other small trials confirmed downstaging after pre-operative RT [269, 270].
A meta-analysis of five RCTs showed a difference in 5-year survival (OR: 0.71, 95% CI: 0.48–1.06)
in favour of pre-operative RT [271]. However, the meta-analysis was potentially biased by data from the largest
trial in which patients were not given the planned treatment. When the largest trial was excluded from the
analysis, the OR became 0.94 (95% CI: 0.57–1.55), which was not significant.
A more recent RCT, comparing pre-operative vs. post-operative RT and RC (n = 100), showed
comparable OS, DFS and complication rates [272]. Approximately half of these patients had UC, while the
other half had SCC.
In general, such older data is limited in being able to provide a robust evidence base for modern guideline
recommendations.
LIMITED UPDATE MARCH 2021
29
7.2.3
Summary of evidence and guidelines for pre- and post-operative radiotherapy
Summary of evidence
No contemporary data exists to support that pre-operative RT for operable MIBC increases survival.
Pre-operative RT for operable MIBC, using a dose of 45–50 Gy in fractions of 1.8–2 Gy, results in
down-staging after 4 to 6 weeks.
Limited high-quality evidence supports the use of pre-operative RT to decrease local recurrence of
MIBC after radical cystectomy.
Addition of adjuvant RT to chemotherapy is associated with an improvement in local relapse-free
survival following cystectomy for locally-advanced bladder cancer (pT3b–4, or node-positive).
Recommendations
Do not offer pre-operative radiotherapy (RT) for operable muscle-invasive bladder cancer
since it will only result in down-staging, but will not improve survival.
Do not offer pre-operative RT when subsequent radical cystectomy (RC) with urinary
diversion is planned.
Consider offering adjuvant radiation in addition to chemotherapy following RC, based on
pathologic risk (pT3b–4 or positive nodes or positive margins).
7.2.4
LE
2a
2
3
2a
Strength rating
Strong
Strong
Weak
EAU-ESMO consensus statements on the management of advanced- and variant bladder
cancer [8, 9]*
Consensus statement
Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed
by at least an oncologist, a urologist and a neutral HCP such as a specialist nurse.
When assessing patient eligibility for bladder preservation, the likelihood of successful debulking surgery
should be taken into consideration (optimal debulking).
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
HCP = healthcare professional.
7.3
Radical surgery and urinary diversion
7.3.1
Removal of the tumour-bearing bladder
7.3.1.1
Introduction
Radical cystectomy is the standard treatment for localised MIBC in most Western countries [212, 273].
Increased recognition of the central patient role as a healthcare consumer and a greater focus on patients’
QoL contributed to an increasing trend of utilising bladder-preserving treatment modalities, such as radioand/or chemotherapy (see Section 7.5). Performance status and life expectancy influence the choice of
primary management as well as the type of urinary diversion with RC being reserved for patients with a longer
life expectancy without concomitant disease and a better PS. The value of assessing overall health before
proceeding with surgery was emphasised in a multivariate analysis [138]. The analysis found an association
between comorbidity and adverse pathological- and survival outcomes following RC [138].
Performance status and comorbidity have a different impact on treatment outcomes and must be
evaluated independently [171].
7.3.1.2
Radical cystectomy: timing
A population-based study utilising the U.S. SEER database analysed patients who underwent a RC between
1992 and 2001 and the authors concluded that a delay of > 12 weeks has a negative impact on outcome
and should be avoided [274]. Moreover, the SEER analysis did not show any significant utilisation and timing
differences between men and women. A 2020 meta-analysis including 19 studies confirmed these findings,
showing that a longer delay of RC after diagnosis (> 3 months) was found to have a detrimental effect on OS
(HR: 134, 95% CI: 1.18–1.53). The authors highlight the lack of standardisation how delays were defined in
the included studies which prohibited defining a clear cut-off time, although most studies used a cut-off of
< 3 months [275]. Overall conclusion was that BC patients scheduled for RC should be treated without delays
to maximise survival.
30
LIMITED UPDATE MARCH 2021
7.3.2
Radical cystectomy: indications
Traditionally, RC was recommended in patients with T2–T4a, N0–Nx, M0 disease [273]. Other indications
include recurrent high-risk non-muscle-invasive tumours, BCG-refractory, BCG-relapsing and BCGunresponsive NMIBC (see EAU Guidelines on Non-muscle-invasive Bladder Cancer [2]), as well as extensive
papillary disease that cannot be controlled with TURB and intravesical therapy alone.
Salvage cystectomy is indicated in non-responders to conservative therapy, recurrence after
bladder-sparing treatment, and non-UC. It is also used as a purely palliative intervention, including for fistula
formation, pain and recurrent visible haematuria (see Section 7.4.1 - Palliative cystectomy).
7.3.3
Radical cystectomy: technique and extent
Different approaches have been described to improve voiding and sexual function in patients undergoing RC
for BC. No consensus exists regarding which approach preserves function best. Concern remains regarding
the impact of “sparing-techniques” on oncological outcomes.
To determine the effect of sexual function-preserving cystectomy (SPC) on functional and
oncological outcomes the Panel undertook two systematic reviews addressing sparing techniques in men and
women [276, 277].
In men, standard RC includes removal of the bladder, prostate, seminal vesicles, distal ureters, and regional
LNs. In women, standard RC includes removal of the bladder, the entire urethra and adjacent vagina, uterus,
distal ureters, and regional LNs [278].
7.3.3.1
Radical cystectomy in men
Four main types of sexual-preserving techniques have been described:
1.
Prostate sparing cystectomy: part of or the whole prostate is preserved including seminal vesicles, vas
deferens and neurovascular bundles.
2.
Capsule sparing cystectomy: the capsule or peripheral part of the prostate is preserved with adenoma
(including prostatic urethra) removed by TURP or en bloc with the bladder. Seminal vesicles, vas deferens
and neurovascular bundles are also preserved.
3.
Seminal sparing cystectomy: seminal vesicles, vas deferens and neurovascular bundles are preserved.
4.
Nerve-sparing cystectomy: the neurovascular bundles are the only tissue left in place.
Twelve studies recruiting a total of 1,098 patients were identified, including nine comparative studies [279-289]
and three single-arm case series [290-292]. In the majority of cases, an open surgical approach was used and
the urinary diversion of choice was an orthotopic neobladder. Median follow-up was longer than three years in
nine studies, with three studies presenting results with a median follow-up longer than five years.
The majority of the studies included patients who were potent pre-operatively with organ-confined disease
without tumour in the bladder neck and/or prostatic urethra. Prostate cancer was ruled out in all of the SPC
techniques, except in nerve-sparing cystectomy.
Oncological outcomes did not differ between groups in any of the comparative studies that
measured local recurrence, metastatic recurrence, DSS and OS, at a median follow-up of three to five years.
Local recurrence after SPC was commonly defined as any UC recurrence below the iliac bifurcation within the
pelvic soft tissue and ranged from 1.2–61.1% vs. 16–55% in the control group. Metastatic recurrence ranged
from 0–33.3%.
For techniques preserving prostatic tissue (prostate- or capsule-sparing), rates of incidental prostate
cancer in the intervention group ranged from 0–15%. In no case was incidental prostate cancer with ISUP
grade ≥ 4 reported.
Post-operative potency was significantly better in patients who underwent any type of sexualpreserving technique compared to conventional RC (p < 0.05), ranging from 80–90%, 50–100% and 29–78%
for prostate-, capsule- or nerve-sparing techniques, respectively. Data did not show superiority of any sexualpreserving technique.
Urinary continence, defined as the use of “no pads” in the majority of studies, ranged from
88–100% (day-time continence) and from 31–96% (night-time continence) in the prostate-sparing cystectomy
patients. No major impact was shown with regard to continence rates for any of the three approaches.
The evidence base suggests that these procedures may yield better sexual outcomes than standard RC
without compromising oncological outcomes. However, the overall quality of the evidence was moderate, and
hence if a sexual-preserving technique is offered, patients must be carefully selected, counselled and closely
monitored.
LIMITED UPDATE MARCH 2021
31
7.3.3.1.1
Summary of evidence and recommendations for sexual-preserving techniques in men
Summary of evidence
LE
The majority of patients motivated to preserve their sexual function will benefit from sexual-preserving 2a
techniques.
None of the sexual-preserving techniques (prostate/capsule/seminal/nerve-sparing) have shown to be 3
superior, and no particular technique can be recommended.
Recommendations
Do not offer sexual-preserving radical cystectomy to men as standard therapy for muscleinvasive bladder cancer.
Offer sexual-preserving techniques to men motivated to preserve their sexual function since
the majority will benefit.
Select patients based on:
• organ-confined disease;
• absence of any kind of tumour at the level of the prostate, prostatic urethra or bladder
neck.
Strength rating
Strong
Strong
Strong
7.3.3.2
Radical cystectomy in women
Pelvic floor disorders, sexual and voiding dysfunction in female patients are prevalent after RC [293]. As part
of the pre-operative evaluation a gynaecological history should be obtained and patients should be counselled
on the potential negative impact of RC on sexual function and/or vaginal prolapse. Most importantly, a history
of cervical cancer screening, abnormal vaginal bleeding and a family history of breast and/or ovarian cancer
should be recorded, as well as ruling out possible pelvic organ prolapse. Equally important is screening for
sexual and urinary function and prolapse post-operatively. Better imaging modalities, increased knowledge of
the function of the pelvic structures and improved surgical techniques have enabled less destructive methods
for treating high-risk BC.
Pelvic organ-preserving techniques involve preserving the neurovascular bundle, vagina, uterus,
ovaries or variations of any of the stated techniques. From an oncological point of view, concomitant
malignancy in gynaecological organs is rare and local recurrences reported after RC are infrequent [294,
295]. In premenopausal women, by preserving ovaries, hormonal homeostasis will be preserved, decreasing
risk of cognitive impairment, cardiovascular diseases and loss of bone density. In case of an increased risk
of hereditary breast or ovarian cancer (i.e., BRCA1/2 mutation carriers or patients with Lynch syndrome),
salpingooophorectomy should be advised after childbearing and to all women over 40 years of age [296]. On
the other hand, preservation of the uterus and vagina will provide the necessary support for the neobladder,
thereby reducing the risk of urinary retention. It also helps to avoid post-operative prolapse as removal of
the uterus predisposes to an anterior or posterior vaginal prolapse. In case of an already existing prolapse
of the uterus, either isolated or combined with a vaginal prolapse, removing the uterus will be beneficial. It
is noteworthy that by resecting the vaginal wall, the vagina shortens which could potentially impair sexual
satisfaction and function.
Based on retrospective low quality data only, a systematic review evaluating the advantages and
disadvantages of sexual-function preserving RC and orthotopic neobladder in female patients concluded that
in well-selected patients, sparing female reproductive organs during RC appears to be oncologically safe and
provides improved functional outcomes [277].
Pelvic organ-preserving RC could be considered also in elderly and fragile patients having
abdominal diversions. By reducing excision range, it might be beneficial from the point of reduced operating
time, estimated blood loss and quicker bowel recovery [297].
7.3.3.2.1
Summary of evidence and recommendations for sexual-preserving techniques in women
Summary of evidence
Data regarding pelvic organ-preserving RC for female patients remain immature.
LE
3
Recommendations
Do not offer pelvic organ-preserving radical cystectomy to women as standard therapy for
muscle-invasive bladder cancer.
32
Strength rating
Strong
LIMITED UPDATE MARCH 2021
Offer sexual organ-preserving techniques to women motivated to preserve their sexual
function since the majority will benefit.
Select patients based on:
• absence of tumour in the area to be preserved to avoid positive soft tissue margins;
• absence of pT4 urothelial carcinoma.
Weak
Strong
7.3.4
Lymphadenectomy: role and extent
Controversies in evaluating the clinical significance of lymphadenectomy (LND) are related to two main aspects
of nodal dissection: therapeutic procedure and/or staging instrument.
Two important autopsy studies have been performed for RC so far. The first study showed that in 215 patients
with MIBC and nodal dissemination, the frequency of metastasis was 92% in regional (perivesical or pelvic),
72% in retroperitoneal, and 35% in abdominal LNs. There was also a significant correlation between nodal
metastases and concomitant distant metastases (p < 0.0001). Approximately 47% of the patients had both
nodal metastases and distant dissemination and only 12% of the patients had nodal dissemination as the sole
metastatic manifestation [298].
The second autopsy study focused on the nodal yield when super-extended pelvic LND was
performed. Substantial inter-individual differences were found with counts ranging from 10 to 53 nodes [299].
These findings demonstrate the limited utility of node count as a surrogate for extent of dissection.
Regional LNs have been shown to consist of all pelvic LNs below the bifurcation of the aorta [300304]. Mapping studies also found that skipping lesions at locations above the bifurcation of the aorta without
more distally located LN metastases is rare [304, 305].
The optimal extent of LND has not been established to date. Standard LND in BC patients involves removal of
nodal tissue cranially up to the common iliac bifurcation, with the ureter being the medial border, and including
the internal iliac, presacral, obturator fossa and external iliac nodes [306]. Extended LND includes all LNs in
the region of the aortic bifurcation, and presacral and common iliac vessels medial to the crossing ureters. The
lateral borders are the genitofemoral nerves, caudally the circumflex iliac vein, the lacunar ligament and the LN
of Cloquet, as well as the area described for standard LND [306-310]. A super-extended LND extends cranially
to the level of the inferior mesenteric artery [311, 312].
In order to assess how and if cancer outcome is influenced by the extent of LND in patients with clinical
N0M0 MIBC, a systematic review of the literature was undertaken [313]. Out of 1,692 abstracts retrieved and
assessed, nineteen studies fulfilled the review criteria [306-310, 312, 314-326]. All five studies comparing LND
vs. no LND reported a better oncological outcome for the LND group. Seven out of twelve studies comparing
(super)extended with limited or standard LND reported a beneficial outcome for (super)extended LND in at
least a subset of patients which is in concordance with the findings of several other meta-analyses [327, 328].
No difference in outcome was reported between extended and super-extended LND in the two high-volumecentre studies identified [312, 324]. The LEA trial, a prospective phase III RCT, including 401 patients with a
median follow-up of 43 months recently reported [329]. Extended LND failed to show a significant advantage
(the trial was designed to show an absolute improvement of 15% in 5-year RFS by extended LND) over limited
LND in RFS, CSS, and OS. Results from another large RCT on the therapeutic impact of the extent of LND are
expected shortly.
It has been suggested that PFS as well as OS might be correlated with the number of LNs removed during
surgery. Although there are no data from RCTs on the minimum number of LNs that should be removed,
survival rates increase with the number of dissected LNs [330]. In retrospective studies removal of at least
ten LNs has been postulated as sufficient for evaluation of LN status, as well as being beneficial for OS [331].
Submitting separate nodal packets instead of en bloc has shown significant increased total LN yield, but did
not result in an increased number of positive LNs, making LN density an inaccurate prognosticator [332]. In
conclusion, extended LND might have a therapeutic benefit compared to less extensive LND, but due to study
bias no firm conclusions can be drawn [145, 313, 333].
7.3.5
Laparoscopic/robotic-assisted laparoscopic cystectomy
A number of recent systematic reviews comparing open RC (ORC) and robot-assisted RC (RARC) reach similar
conclusions; RARC has an approximately one-day shorter length of hospital stay (LOS) and less blood loss, but
a longer operative time. Complication rates seem similar for both approaches but all published reviews suffer
from low quality data.
In minimally-invasive cystectomy, with increasing age, LOS is markedly shorter; up to 2.56 days in
patients over 80 years old [334].
LIMITED UPDATE MARCH 2021
33
Although the low level of evidence of the studies included in these reviews remains a major limitation, a recent
Cochrane review incorporating data from all five published RCTs corroborates most findings [335]. Time to
recurrence, positive surgical margin rates, grade 3–5 complications and QoL were comparable for RARC and
ORC, whilst transfusion rate was likely lower after RARC. For other endpoints outcomes were uncertain due to
study limitations.
The Pasadena Consensus Panel (a group of experts on RC, LND and urinary reconstruction) reached similar
conclusions [336]. Additionally, they reported that RARC was associated with increased costs, although
compared to laparoscopic RC (LRC) there are ergonomic advantages for the surgeon. For both techniques,
surgeons’ experience and institutional volume strongly predicted outcome. According to the literature,
proficiency is reached after 20–250 cases. However, after statistical modelling, the Pasadena Consensus Panel
suggested 30 cases but they also concluded that challenging patients (high BMI, post chemotherapy or RT,
pelvic surgery, T4 or bulky tumours or positive nodes) should be performed by experienced robotic surgeons
only. Safety of RC after RT was confirmed by a small retrospective study (n = 46) [337]. In experienced hands
the percentage of 90-day (major) complications after robotic cystectomy was independent of previous RT. A
recent population-based study addressed benign uretero-enteric strictures, which appeared 5% higher after
robotic - as compared to open surgery (15% vs. 9.5% at 12 months, p = 0.01) [338].
Positive surgical margins, as a surrogate for oncological outcome, are comparable between RARC and ORC,
although with low certainty [335]. Recurrence-free survival, CSS and OS have been documented as similar
in all RCTs including the largest RAZOR (Robot-assisted radical cystectomy versus open radical cystectomy
in patients with bladder cancer) trial (n = 302) [339]. Age over 70, poor PS and major complications were
significant predictors of 36-month PFS whilst stage and positive margins were significant predictors of
recurrence, PFS and OS. The surgical approach was not a significant predictor of any outcome. A larger
(n = 595) single-centre study with a median follow-up of over five years also found comparable recurrence
and survival data, including atypical recurrences (defined as one or a combination of the following: portsite metastasis or peritoneal carcinomatosis) [340]. However, recently, port-site metastases and atypical
recurrences were reviewed by Mantica et al. [341]. Based on 31 studies and 6,720 evaluable patients, 105
patients (1.63%) were identified with an atypical recurrence, of which 63 (60%) were peritoneal carcinomatosis
and 11 (10.5%) port-site metastases. The authors acknowledge, however, that these results may be linked to
publication bias and retrospective study design of the included studies. Wei et al. detected residual cancer
cells in pelvic washing specimens during or after, but not before, RARC in approximately half of the patients
(9/17), which was associated with aggressive variant histology and cancer recurrence. These findings need
confirmation in larger studies [342].
The largest RCT to date, the RAZOR trial, supports all of the above findings showing RARC to be
non-inferior to ORC in terms of 2-year PFS (72.3% vs. 71.6%), adverse events (67% vs. 69%) and QoL [343].
Most reviewed series, including the RAZOR trial, offer extracorporeal reconstruction. Hussein et al.
retrospectively compared extracorporeal reconstruction (n = 1,031) to intracorporeal reconstruction (n = 1,094);
the latter was associated with a shorter operative time and fewer blood transfusions but more high-grade
complications, which, again, decreased over time [344]. A recent retrospective report from a high-volume
centre found less (major) complications after intracorporeal reconstruction (n = 301) as compared to
extracorporeal reconstruction (n = 375) and open RC (n = 272) [345]. It is important to note that, although an
intracorporeal neobladder is a very complex robotic procedure [346], the choice for neobladder or cutaneous
diversion should not depend on the surgical approach.
7.3.5.1
Laparoscopic radical cystectomy versus robot-assisted radical cystectomy
For LRC a review including sixteen studies came to similar conclusions as described for RARC [346]. As
compared to ORC, LRC had a significantly longer operative time, fewer overall complications, less blood
transfusions and analgesic use, less blood loss and a shorter LOS. However, the review was limited by the
inherent limitations of the included studies. Although this review also showed better oncological outcomes,
these appeared comparable to ORC series in a large LRC multicentre study [347].
The CORAL study was a small single-centre RCT comparing open (n = 20) vs. robotic (n = 20)
vs. laparoscopic (n = 19) RC [348, 349]. The 30-day complication rate was significantly higher in the open
arm (70%) compared to the laparoscopic arm (26%). There was no difference between the 90-day Clavien
complication rates in the three study arms. Limitations of this study include the small sample size, three
different although experienced surgeons, and cross over between arms.
34
LIMITED UPDATE MARCH 2021
7.3.5.2
Summary of evidence and guidelines for laparoscopic/robotic-assisted laparoscopic cystectomy
Summary of evidence
Robot-assisted radical cystectomy has longer operative time (1–1.5 hours) and major costs, but
shorter length of hospital stay (1–1.5 days) and less blood loss compared to ORC.
Robotic cystectomy and open cystectomy may result in similar rates of (major) complications.
Most endpoints, if reported, including intermediate-term oncological endpoint and QoL, are not
different between RARC and ORC.
Surgeons experience and institutional volume are considered the key factor for outcome of both
RARC and ORC, not the technique.
Recommendations
Inform the patient of the advantages and disadvantages of open radical cystectomy (ORC)
and robot-assisted radical cystectomy (RARC) to allow selection of the proper procedure.
Select experienced centres, not specific techniques, both for RARC and ORC.
LE
1
2
2
2
Strength rating
Strong
Strong
7.3.6
Urinary diversion after radical cystectomy
From an anatomical standpoint, three alternatives are currently used after cystectomy:
•
abdominal diversion, such as an uretero-cutaneostomy, ileal or colonic conduit, and various forms of a
continent pouch (infrequently used);
•
urethral diversion, which includes various forms of gastrointestinal pouches attached to the urethra as a
continent, orthotopic urinary diversion (neobladder, orthotopic bladder substitution);
•
rectosigmoid diversions, such as uretero-(ileo-)rectostomy (infrequently used).
Different types of segments of the intestinal tract have been used to reconstruct the urinary tract, including the
stomach, ileum, colon and appendix [350].
Several studies have compared certain aspects of health-related quality of life (HRQoL) such as
sexual function, urinary continence and body image in patient cohorts with different types of urinary diversion
[351]. However, further research evaluating the impact of pre-operative tumour stage, functional- and socioeconomic status, and time interval to primary surgery are needed.
7.3.6.1
Patient selection and preparations for surgery
In consultation with the patient, both an orthotopic neobladder and ileal conduit should be considered in case
reconstructive surgery exposes the patient to excessive risk (as determined by comorbidity and age).
Ensuring that patients make a well-informed decision about the type of urinary diversion is
associated with less decision regret post-operatively, independent of the method selected [352].
Diagnosis of an invasive urethral tumour prior to cystectomy leads to urethrectomy which could be a
contraindication for a neobladder reconstruction. If indicated; in males, in case of CIS and extension of tumour
in the prostatic urethra, urethral frozen section has to be performed on the cystoprostatectomy specimen just
under the verumontanum and on the inferior limits of the bladder neck; in females a urethral frozen section has
to be taken just below the bladder neck.
Non-muscle-invasive BC in prostatic urethra or bladder neck biopsies does not necessarily preclude orthotopic
neobladder substitution, provided that patients undergo regular follow-up cystoscopy and urinary cytology [353].
In the presence of positive LNs, orthotopic neobladder can nevertheless be considered in case of
N1 involvement (metastasis in a single node in the true pelvis) but not in N2 or N3 tumours [354].
Oncological results after orthotopic neobladder substitution or conduit diversion are similar in terms
of local or distant metastasis recurrence, but secondary urethral tumours seem less common in patients with a
neobladder compared to those with conduits or continent cutaneous diversions [355].
For cystectomy, general preparations are necessary as for any other major pelvic and abdominal surgery. If the
urinary diversion is constructed from gastrointestinal segments, the length or size of the respective segments
and their pathophysiology when storing urine must be considered [356]. Despite the necessary interruption
and re-anastomosis of the bowel, formal bowel preparation may not be necessary [357]. Bowel recovery
time can be reduced by the use of early mobilisation and early oralisation, gastrointestinal stimulation with
metoclopramide and chewing gum [358]. Patients treated according to the “fast tract”/ERAS (Early Recovery
After Surgery) protocol have shown to score better on the emotional and physical functioning scores and suffer
less from wound healing disorders, fever and thrombosis [359].
LIMITED UPDATE MARCH 2021
35
A cornerstone of the ERAS protocol is post-operative pain management, which involves significantly
reducing the use of opioids; offering opioids mainly as breakthrough pain medication. Instead of patientcontrolled analgesia and epidural opioids, most patients receive high-dose acetaminophen and/or ketorolac,
starting intra-operatively. Patients on ERAS experience more pain as compared to patients on a traditional
protocol (Visual Analogue Scale 3.1 vs. 1.1, p < 0.001), but post-operative ileus decreased from 22% to 7.3%
(p = 0.003) [360].
A multicentre randomised placebo-controlled trial showed that patients receiving alvimopan, a
peripherally acting μ-opioid receptor antagonist, had quicker bowel recovery compared to patients receiving
placebo [361]. However, this drug is, as yet, not approved in Europe.
Venous thromboembolism (VTE) prophylaxis may be implemented as part of an ERAS protocol. A
single-centre non-randomised study showed a significant lower 30-day VTE incidence rate in patients treated for
28 days with enoxaparin compared to patients without prophylaxis [362]. Data from the Ontario Cancer Registry
including 4,205 cystectomy patients of whom 1,084 received NAC showed that VTE rates are higher in patients
treated with NAC as compared to patients treated with cystectomy only (12% vs. 8%, p = 0.002) [363, 364].
Patients undergoing continent urinary diversion must be motivated to learn about their diversion and to be
manually skilful in manipulating their diversion. Contraindications to more complex forms of urinary diversion
include:
•
debilitating neurological and psychiatric illnesses;
•
limited life expectancy;
•
impaired liver or renal function;
•
urothelial carcinoma positive surgical margins.
Relative contraindications specific for an orthotopic neobladder are high-dose pre-operative RT, complex
urethral stricture disease and severe urethral sphincter-related incontinence [365].
7.3.6.2
Different types of urinary diversion
Radical cystectomy and urinary diversion are the two steps of one operation. However, the literature uniformly
reports complications of RC while ignoring the fact that most complications are diversion related [366]. Age
alone is not a criterion for offering continent diversion [365, 367]. Comorbidity, cardiac- and pulmonary function
and cognitive function are all important factors that should be considered, along with the patient’s social
support and preference.
Age > 80 years is often considered to be the threshold after which neobladder reconstruction
is not recommended. However, there is no exact age for a strict contraindication. In most large series from
experienced centres, the rate of orthotopic bladder substitution after cystectomy for bladder tumour is up
to 80% in men and 50% in women [368-371]. Nevertheless, no RCTs comparing conduit diversion with
neobladder or continent cutaneous diversion have been performed.
A retrospective study including 1,383 patients showed that the risk of a decline in estimated
glomerular filtration rate (eGFR) did not significantly differ after ileal conduit vs. neobladder in patients with preoperative chronic kidney disease 2 (eGFR 60–89 mL/min/1.73 m2) or 3a (eGFR 45–59 mL/min/1.73 m2) [372].
Only age and anastomotic strictures were found to be associated with a decline in eGFR.
7.3.6.2.1 Uretero-cutaneostomy
Ureteral diversion to the abdominal wall is the simplest form of cutaneous diversion. Operating time,
complication rate, stay at intensive care and length of hospital stay are lower in patients treated with ureterocutaneostomy as compared to ileal conduit [373]. Therefore, in frail patients and/or in those with a solitary
kidney who need a supravesical diversion, uretero-cutaneostomy is the preferred procedure [374, 375]. Quality
of life, which was assessed using the Bladder Cancer Index (BCI), showed equal urinary bother and function
for patients treated with ileal conduit and uretero-cutaneostomy [373]. However, others have demonstrated
that in carefully selected elderly patients, all other forms of wet and dry urinary diversions, including orthotopic
bladder substitutions, are possible [376].
Technically, in case patients have both kidneys; either one ureter, to which the other shorter one is attached
end-to-side, is connected to the skin (trans-uretero-cutaneostomy) or both ureters are directly anastomosed
to the abdominal wall creating a stoma. Due to the smaller diameter of the ureters, stoma stenosis has been
observed more frequently for this technique as compared to using small or large bowel to create an intestinal
stoma [374].
In a retrospective multicentre study peri-operative morbidity was evaluated for urinary diversion
using bowel as compared to uretero-cutaneostomy. Patients selected for a uretero-cutaneostomy were older
and had a higher ASA score, while their mean Charlson score was lower (4.2 vs. 5.6, p < 0.001) [377].
36
LIMITED UPDATE MARCH 2021
Despite the limited comparative data available, it must be taken into consideration that older
data and clinical experience suggest ureter stenosis at the skin level and ascending UTI are more frequent
complications in uretero-cutaneostomy compared to an ileal conduit diversion. In a retrospective study
comparing various forms of intestinal diversion, ileal conduits had fewer late complications than continent
abdominal pouches or orthotopic neobladders [378].
7.3.6.2.2 Ileal conduit
The ileal conduit is still an established option with well-known/predictable results. However, up to 48% of
patients develop early complications including UTIs, pyelonephritis, ureteroileal leakage and stenosis [378].
The main complications in long-term follow-up studies are stomal complications in up to 24% of patients and
functional and/or morphological changes of the UUT in up to 30% [378-380]. An increase in complications
was seen with longer follow-up in the Berne series of 131 patients who were followed for a minimum of five
years (median follow-up 98 months) [381]; the rate of complications increased from 45% at five years to 94%
in those surviving > 15 years. In the latter group, 50% of patients developed UUT changes and 38% developed
urolithiasis.
7.3.6.2.3 Orthotopic neobladder
An orthotopic bladder substitution to the urethra is now commonly used both in men and women.
Contemporary reports document the safety and long-term reliability of this procedure. In several large centres,
this has become the diversion of choice for most patients undergoing cystectomy [213, 273, 365]. However, in
elderly patients (> 80 years) it is rarely performed even in high-volume expert centres [382, 383].
The terminal ileum is the gastrointestinal segment most often used for bladder substitution.
There is less experience with the ascending colon, including the caecum, and the sigmoid [273]. Emptying
of the reservoir anastomosed to the urethra requires abdominal straining, intestinal peristalsis, and sphincter
relaxation. Early and late morbidity in up to 22% of patients is reported [384, 385]. In two studies of 1,054
and 1,300 patients [365, 386], long-term complications included diurnal (8–10%) and nocturnal (20–30%)
incontinence, uretero-intestinal stenosis (3–18%), metabolic disorders, and vitamin B12 deficiency. A study
comparing cancer control and patterns of disease recurrence in patients with neobladder and ileal conduit
showed no difference in CSS between the two groups when adjusting for pathological stage [387]. Urethral
recurrence in neobladder patients seems rare (1.5–7% in both male and female patients) [365, 388]. These
results indicate that neobladder in male and female patients does not compromise the oncological outcome of
cystectomy. It remains debatable whether patient’s QoL for neobladder is better compared to non-continent
urinary diversion [389, 390].
Continent cutaneous urinary diversion (a low-pressure detubularised ileal reservoir for self-catheterisation)
and uretero-rectosigmoidostomy are rarely used techniques nowadays, due to their high complication rates,
including stomal stenosis, incontinence in the continent cutaneous diversion, UUT infections and stone
formation in case of uretero-rectosigmoidostomy [391].
Various forms of UUT reflux protection, including a simple isoperistaltic tunnel, ileal intussusception, tapered
ileal prolongation implanted subserosally, and direct (sub)mucosal or subserosal ureteral implantation, have
been described [385, 392]. According to the long-term results, the UUT is protected sufficiently by either
method.
A detailed investigation of the bladder neck prior to RC is important for women who are scheduled for an
orthotopic bladder substitute [393]. In women undergoing RC the rate of concomitant urethral malignancy has
been reported to range from 12–16% [394]. Localisation of the primary tumour at the bladder neck correlated
strongly with concomitant urethral malignancy. In addition, tumour involving the bladder neck and urethra
tended to be associated with a higher risk of advanced stage and nodal involvement [395].
Currently, it is not possible to recommend a particular type of urinary diversion. However, most institutions
prefer ileal orthotopic neobladders and ileal conduits based on clinical experience [396, 397]. In selected
patients, such as patients with a single kidney, uretero-cutaneostomy is surgically the least burdensome type of
diversion. Recommendations related to RC and urinary diversions are listed in Section 7.3.10.
7.3.7
Morbidity and mortality
In three long-term studies and one population-based cohort study, the peri-operative mortality was reported
as 1.2–3.2% at 30 days and 2.3–8.0% at 90 days [213, 366, 368, 398, 399]. In a large single-centre series
early complications (within three months of surgery) were seen in 58% of patients [366]. Late morbidity was
usually linked to the type of urinary diversion (see also above) [369, 400]. Early morbidity associated with RC
LIMITED UPDATE MARCH 2021
37
for NMIBC (at high risk for disease progression) is similar and no less than that associated with muscle-invasive
tumours [401]. In general, lower morbidity and (peri-operative) mortality have been observed by surgeons and
in hospitals with a higher case load and therefore more experience [398, 402-406].
Table 7.6: Management of neobladder morbidity (30-64%) [407]
CLAVIEN
System
Grade I
Grade II
Grade III
38
Morbidity
Management
Immediate complications:
Any deviation from the normal
post-operative course without
Post-operative ileus
Nasogastric intubation (usually
the need for pharmacological
removed at day 1)
treatment or surgical, endoscopic
Chewing gum
and radiological interventions.
Avoid fluid excess and
hypovolemia (provoke
Allowed therapeutic regimens
splanchnic hypoperfusion)
are: drugs such as antiemetics,
Post-operative nausea
Antiemetic agent
antipyretics, analgesics,
and vomiting
(decrease opioids)
diuretics and electrolytes and
Nasogastric intubation
physiotherapy.
Urinary infection
Antibiotics, no ureteral catheter
removal
This grade also includes wound
Check the 3 drainages (ureters
infections opened at the bedside.
and neobladdder)
Ureteral catheter
Inject 5 cc saline in the
obstruction
ureteral catheter to resolve the
obstruction
Increase volume infusion to
increase diuresis
Check drainages and watchful
Intra-abdominal urine
waiting
leakage (anastomosis
leakage)
Anaemia well tolerated
Martial treatment
(give iron supplement)
Late complications:
Non compressive
Watchful waiting
lymphocele
Mucus cork
Cough
Indwelling catheter to remove
the obstruction
Incontinence
Urine analysis (infection),
echography (post-void residual)
Physiotherapy
Retention
Drainage and selfcatheterisation education
Transfusion1,2
Anaemia badly tolerated
Requiring pharmacological
or if myocardial
treatment with drugs other
cardiopathy history
than those allowed for grade I
complications. Blood transfusions Pulmonary embolism
Heparinotherapy3
and total parenteral nutrition are
Pyelonephritis
Antibiotics and check kidney
also included.
drainage
(nephrostomy if necessary)
Confusion or neurological Neuroleptics and avoid opioids
disorder
Requiring surgical, endoscopic or Ureteral catheter
Indwelling leader to raise the
radiological intervention
accidentally dislodged
ureteral catheter
Anastomosis stenosis
Renal drainage (ureteral
(7%)
catheter or nephrostomy)
Ureteral reflux
No treatment if asymptomatic
LIMITED UPDATE MARCH 2021
III-a
Intervention not under general
anaesthesia
III-b
Intervention under general
anaesthesia
Grade IV
Life-threatening complication
(including central nervous
system complications: brain
haemorrhage, ischaemic stroke,
subarachnoid bleeding, but
excluding transient ischaemic
attacks) requiring intensive care/
intensive care unit management.
Single organ dysfunction
(including dialysis)
Multi-organ dysfunction
IV-a
IV-b
Grade V
Suffix ‘d’
Compressive lymphocele
Transcutaneous drainage or
intra-operative marsupialisation
(cf grade III)
Ileal anastomosis leakage Ileostomy, as soon as possible
Evisceration
Surgery in emergency
Compressive lymphocele Surgery (marsupialisation)
Rectal necrosis
Colostomy
Neobladder rupture
Nephrostomy and indwelling
catheter/surgery for repairing
neobladder
Severe sepsis
Antibiotics and check all the
urinary drainages and CT scan
in emergency
Non-obstructive renal
Bicarbonate/aetiology treatment
failure
Obstructive pyelonephritis Nephrostomy and antibiotics
and septicaemia
Death of a patient
If the patient suffers from a complication at the time of discharge, the suffix “d” (for ‘disability’)
is added to the respective grade of complication. This label indicates the need for a follow-up to
fully evaluate the complication.
1
systematic review showed that peri-operative blood transfusion (PBT) in patients who undergo RC
A
correlates with increased overall mortality, CSM and cancer recurrence. The authors hypothesised that this
may be caused by the suggested immunosuppressive effect of PBT. The foreign antigens in transfused blood
induce immune suppression, which may lead to tumour cell spread, tumour growth and reduced survival in
already immunosuppressed cancer patients. As other possible causes for this finding increased post-operative
infections and blood incompatibility were mentioned [408]. Buchner and co-workers showed similar results
in a retrospective study. The 5-year CSS decreased in cases where intra-operative blood transfusion (CSS
decreased from 67% to 48%) or post-operative blood transfusion (CSS decreased from 63% to 48%) were
given [409].
2
Intra-operative tranexamin acid infusion reduces peri-operative blood transfusion rates from 57.7% to 31.1%.
There was no increase seen in peri-operative VTE [410].
3
ammond and co-workers reviewed 20,762 cases of VTE after major surgery and found cystectomy patients
H
to have the second highest rate of VTE among all cancers studied [411]. These patients benefit from 30
days low-molecular-weight heparin prophylaxis. Subsequently, it was demonstrated that BMI > 30 and nonurothelial BCs are independently associated with VTE after cystectomy. In these patients extended (90 days)
heparin prophylaxis should be considered [412].
7.3.8
Survival
According to a multi-institutional database of 888 consecutive patients undergoing RC for BC, the 5-year
RFS rate was 58% and CSS was 66% [413]. External validation of post-operative nomograms for BC-specific
mortality showed similar results, with bladder-CSS of 62% [414].
Recurrence-free survival and OS in a large single-centre study of 1,054 patients was 68% and 66%
at five years and 60% and 43%, at ten years, respectively [212]. However, the 5-year RFS in node-positive
patients who underwent cystectomy was considerably less at 34–43% [415, 416]. In a surgery-only study, the
5-year RFS was 76% in patients with pT1 tumours, 74% for pT2, 52% for pT3, and 36% for pT4 [212].
A trend analysis based on 148,315 BC patients identified in the SEER database between 1973 and
2009 showed increased stage-specific 5-year survival rates for all stages, except for metastatic disease [417].
7.3.9
Impact of hospital and surgeon volume on treatment outcomes
Recently, a systemic review was performed to assess the impact of hospital and/or surgeon volume on perioperative outcomes of RC [418]. In total, 40 studies including over 560,000 patients were included. All studies
were retrospective cohort studies.
LIMITED UPDATE MARCH 2021
39
Twenty-two studies reported on hospital volume only, six studies on surgeon volume only and twelve studies
reported on both. The results of this systematic review suggests that a higher hospital volume is likely
associated with lower in-hospital, 30-day and 90-day mortality rates. Also, higher volume hospitals are likely
to have lower positive surgical margins, higher LND and neobladder rates and lower complication rates. For
surgeon volume, less evidence is available and it seems that outcome after RC is mainly hospital-driven. In
spite of the lower quality, the available evidence suggests that performing more than 10 RCs per year per
hospital reduces 30- and 90-day mortality. Performing more than 20 RCs per hospital per year might even
further reduce these mortality rates.
7.3.10
Summary of evidence and guidelines for radical cystectomy and urinary diversion
Summary of evidence
Ensuring that patients are well informed about the various urinary diversion options prior to making a
decision may help prevent or reduce decision regret, independent of the method of diversion selected.
Higher hospital volume likely improves quality of care and reduction in peri-operative mortality and
morbidity.
Radical cystectomy includes removal of regional lymph nodes.
There are data to support that extended lymph node dissection (LND) (vs. standard or limited LND)
improves survival after RC.
Radical cystectomy in both sexes must not include removal of the entire urethra in all cases, which
may then serve as the outlet for an orthotopic bladder substitution. The terminal ileum and colon are
the intestinal segments of choice for urinary diversion.
The type of urinary diversion does not affect oncological outcome.
The use of extended venous thromboembolism (VTE) prophylaxis significantly decreases the incidence
of VTE after RC.
In patients aged > 80 years with MIBC, cystectomy is an option.
Surgical outcome is influenced by comorbidity, age, previous treatment for bladder cancer or other
pelvic diseases, surgeon and hospital volumes of cystectomy, and type of urinary diversion.
Surgical complications of cystectomy and urinary diversion should be reported using a uniform
grading system. Currently, the best-adapted grading system for cystectomy is the Clavien grading
system.
No conclusive evidence exists as to the optimal extent of LND.
Recommendations
Do not delay radical cystectomy (RC) for > 3 months as it increases the risk of progression
and cancer-specific mortality, unless the patient receives neo-adjuvant chemotherapy.
Perform at least 10, and preferably > 20, RCs per hospital/per year.
Before RC, fully inform the patient about the benefits and potential risks of all possible
alternatives. The final decision should be based on a balanced discussion between the
patient and the surgeon.
Do not offer an orthotopic bladder substitute diversion to patients who have a tumour in the
urethra or at the level of urethral dissection.
Pre-operative bowel preparation is not mandatory. “Fast track” measurements may reduce
the time to bowel recovery.
Offer pharmacological prophylaxis, such as low-molecular-weight heparin to RC patients,
starting the first day post-surgery, for a period of 4 weeks.
Offer RC to patients with T2–T4a, N0M0 disease or high-risk non-muscle-invasive bladder
cancer.
Perform a lymph node dissection as an integral part of RC.
Do not preserve the urethra if margins are positive.
40
LE
3
3
3
3
3
3
3
3
2
2
2a
Strength rating
Strong
Strong
Strong
Strong
Strong
Strong
Strong
Strong
Strong
LIMITED UPDATE MARCH 2021
7.3.11
EAU-ESMO consensus statements on the management of advanced- and variant bladder
cancer [8, 9]*
Consensus statement
Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed
by at least an oncologist, a urologist, a radiation oncologist (in case adjuvant radiotherapy or bladder
preservation is considered) and a neutral healthcare professional such as a specialist nurse.
Muscle-invasive pure squamous cell carcinoma of the bladder should be treated with primary radical
cystectomy and lymphadenectomy.
Muscle-invasive pure adenocarcinoma of the bladder should be treated with primary radical cystectomy and
lymphadenectomy.
T1 high-grade bladder urothelial cancer with micropapillary histology (established after complete TURBT and/
or re-TURBT) should be treated with immediate radical cystectomy and lymphadenectomy.
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
TURBT = transurethral resection of bladder tumour.
Figure 7.1: Flow chart for the management of T2–T4a N0M0 urothelial bladder cancer
Diagnosis
• Cystoscopy and tumour resection
• Evaluation of urethra1
• CT imaging of abdomen, chest, UUT
• MRI can be used for local staging
Findings
• cT2-4N0M0
1
– Males: biopsy apical prostatic urethra
or frozen section during surgery if
indicated (see below)
– Females : biopsy of proximal urethra or
frozen section during surgery if indicated
cT2N0M0 selected patients
– Mult modality bladder-sparing therapy
can be considered for T2 tumours
(Note: alternative, not the standard option )
Neo-adjuvant therapy
• Chemotherapy
Recommended in cisplatin-fit patients
(5-8% survival benefit)
• Radiotherapy
Not recommended
• Immunotherapy
Experimental, only in clinical trial setting
Radical cystectomy
• Know general aspects of surgery
- Preparation
- Surgical technique
- Integrated node dissection
- Urinary diversion
- Timing of surgery
• A higher case load improves outcome
Adjuvant chemotherapy
• Consider in high-risk patients only if no
neo-adjuvant therapy was given
CT = computed tomography; MRI = magnetic resonance imaging; UUT = upper urinary tract.
LIMITED UPDATE MARCH 2021
41
7.4
Unresectable tumours
7.4.1
Palliative cystectomy for muscle-invasive bladder carcinoma
Locally advanced tumours (T4b, invading the pelvic or abdominal wall) may be accompanied by several
debilitating symptoms, including bleeding, pain, dysuria and urinary obstruction. These patients are candidates
for palliative treatments, such as palliative RT. Palliative cystectomy with urinary diversion carries the greatest
morbidity and should be considered for symptom relief only if there are no other options [419-421].
Locally advanced MIBC can be associated with ureteral obstruction due to a combination of mechanical
blockage by the tumour and invasion of ureteral orifices by tumour cells. In a series of 61 patients with
obstructive uraemia RC was not an option in 23 patients and obstruction was relieved using permanent
nephrostomy tubes [422]. Another ten patients underwent palliative cystectomy, but local pelvic recurrence
occurred in all ten patients within the first year of follow-up. Another small study (n = 20) showed that primary
cystectomy for T4 BC was technically feasible and associated with a very tolerable therapy-related morbidity
and mortality [423].
7.4.1.1
Guidelines for unresectable tumours
Recommendations
Offer radical cystectomy as a palliative treatment to patients with inoperable locally
advanced tumours (T4b).
Offer palliative cystectomy to patients with symptoms.
7.4.1.2
Strength rating
Weak
Weak
EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*
Consensus statement
In patients with clinical T4 or clinical N+ disease (regional), radical chemoradiation can be offered accepting
that this may be palliative rather than curative in outcome.
Chemoradiation should be given to improve local control in cases of inoperable locally advanced tumours.
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
7.4.2
Supportive care
7.4.2.1
Obstruction of the upper urinary tract
Unilateral (best kidney) or bilateral nephrostomy tubes provide the easiest solution for UUT obstruction, but
patients find the tubes inconvenient and prefer ureteral stenting. However, stenting can be difficult to achieve.
Stents must be regularly replaced and there is the risk of stent obstruction or displacement. Another possible
solution is a urinary diversion with, or without, a palliative cystectomy.
7.4.2.2
Bleeding and pain
In the case of bleeding, the patient must be screened first for coagulation disorders or the patient’s use of
anticoagulant drugs must be reviewed. Transurethral (laser) coagulation may be difficult in a bladder full of
tumour or with a bleeding tumour. Intravesical rinsing of the bladder with 1% silver nitrate or 1–2% alum can
be effective [424]. This can usually be done without any anaesthesia. The instillation of formalin (2.5–4% for 30
minutes) is a more aggressive and painful procedure, requiring anaesthesia. Formalin instillation has a higher
risk of side-effects, e.g., bladder fibrosis, but is more likely to control the bleeding [424]. Vesicoureteral reflux
should be excluded to prevent renal complications.
Radiation therapy is another common strategy to control bleeding and is also used to control pain. An older
study reported control of haematuria in 59% of patients and pain control in 73% [425]. Irritative bladder
and bowel complaints due to irradiation are possible, but are usually mild. Non-conservative options are
embolisation of specific arteries in the small pelvis, with success rates as high as 90% [424]. Radical surgery is
a last resort and includes cystectomy and diversion (see above, Section 7.4.1).
7.5
Bladder-sparing treatments for localised disease
7.5.1
Transurethral resection of bladder tumour
Transurethral resection of bladder tumour alone in MIBC patients is only possible as a therapeutic option if
tumour growth is limited to the superficial muscle layer and if re-staging biopsies are negative for residual
(invasive) tumour [426]. In general, approximately 50% of patients will still have to undergo RC for recurrent
42
LIMITED UPDATE MARCH 2021
MIBC with a disease-specific mortality rate of up to 47% within this group [427]. A disease-free status at
re-staging TURB appears to be crucial in making the decision not to perform RC [428, 429]. A prospective
study by Solsona et al. including 133 patients with radical TURB and re-staging negative biopsies, reported a
15-year follow-up [429]. Thirty per cent of patients had recurrent NMIBC and went on to intravesical therapy,
and 30% (n = 40) progressed, of which 27 died of BC. After five, ten, and fifteen years, the results showed CSS
rates of 81.9%, 79.5%, and 76.7%, respectively and PFS rates with an intact bladder of 75.5%, 64.9%, and
57.8%, respectively.
In conclusion, TURB alone should only be considered as a therapeutic option for muscle-invasive
disease after radical TURB, when the patient is unfit for cystectomy, or refuses open surgery, or as part of a
multimodality bladder-preserving approach.
7.5.1.1
Guideline for transurethral resection of bladder tumour
Recommendation
Do not offer transurethral resection of bladder tumour alone as a curative treatment option
as most patients will not benefit.
7.5.1.2
Strength rating
Strong
EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*
Consensus statement
Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed
by at least an oncologist, a urologist, a radiation oncologist (in case adjuvant radiotherapy or bladder
preservation is considered) and a neutral HCP such as a specialist nurse.
An important determinant for patient eligibility in case of bladder-preserving treatment is absence of
carcinoma in situ.
An important determinant for patient eligibility in case of bladder-preserving treatment is absence or presence
of hydronephrosis.
When assessing patient eligibility for bladder preservation, the likelihood of successful debulking surgery
should be taken into consideration (optimal debulking).
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
HCP = healthcare professional.
7.5.2
External beam radiotherapy
Current RT techniques with soft-tissue matching and image guidance result in superior bladder coverage and
a reduced integral dose to the surrounding tissues. The target total dose (to bladder and/or bladder tumour) for
curative EBRT in BC is 64–66 Gy [430, 431]. A reasonable alternative is moderately hypofractionated EBRT to
55 Gy in 20 fractions which has been suggested to be non-inferior to 64 Gy in 32 fractions in terms of invasive
locoregional control, OS, and late toxicity. In a phase II study, 55 patients (median age 86) with BC, unfit for
cystectomy or even daily RT, were treated with 6-weekly doses of 6 Gy [432]. Forty-eight patients completed
EBRT with acceptable toxicity and 17% showed local progression after two years demonstrating good local
control with this more ultra-hypofractionated schedule.
Elective treatment to the LNs is optional and should take into account patient comorbidities and the
risks of toxicity to adjacent critical structures. For node-positive disease, consider boosting grossly involved
nodes to the highest achievable dose that does not violate normal tissue constraints based on the clinical
scenario.
The use of modern standard EBRT techniques results in major related late morbidity of the urinary
bladder or bowel in less than 5% of patients [433]. Acute diarrhoea is reduced even more with intensitymodulated RT [434]. Important prognostic factors for outcome include response to EBRT, tumour size,
hydronephrosis, presence of CIS, and completeness of the initial TURB. Additional prognostic factors reported
are age and stage [435].
With the use of modern EBRT techniques, efficacy and safely results seem to have improved over time. A 2002
Cochrane analysis demonstrated that RC has an OS benefit compared to RT [436], although this was not the
case in a 2014 retrospective review using a propensity score analysis [437]. In a 2017 retrospective cohort
study of U.S. National Cancer Data Base data, patients over 80 were identified with cT2–4, N0–3, M0 BC, who
were treated with curative EBRT (60–70 Gy, n = 739) or concurrent chemoradiotherapy (n = 630) between 2004
and 2013 [438]. The 2-year OS was 42% for EBRT vs. 56% for chemoradiotherapy (p < 0.001). For EBRT a
higher RT dose and a low stage were associated with improved OS.
LIMITED UPDATE MARCH 2021
43
In conclusion, although EBRT results seem to improve over time, EBRT alone does not seem to be as
effective as surgery or trimodality therapy (see Section 7.5.4). Factors that influence outcome should be
considered. However, EBRT can be an alternative treatment in patients unfit for radical surgery or concurrent
chemotherapy, and it can also be quite effective in helping control bleeding.
7.5.2.1
Summary of evidence and guideline for external beam radiotherapy
Summary of evidence
LE
External beam radiotherapy alone should only be considered as a therapeutic option when the patient 3
is unfit for cystectomy.
Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be
3
achieved by transurethral manipulation because of extensive local tumour growth.
Recommendation
Do not offer radiotherapy alone as primary therapy for localised bladder cancer.
7.5.2.2
Strength rating
Strong
EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*
Consensus statement
Radiotherapy alone (single block) is not the preferred radiotherapeutic schedule.
Radiotherapy for bladder preservation should be performed with IMRT and IGRT to reduce side effects.
Dose escalation above standard radical doses to the primary site in case of bladder preservation, either by
IMRT or brachytherapy, is not recommended.
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiotherapy.
7.5.3
Chemotherapy
Chemotherapy alone rarely produces durable complete remissions. In general, a clinical complete response
rate of up to 56% is reported in some series, which must be weighed against a staging error of > 60% [439,
440]. Response to chemotherapy is a prognostic factor for treatment outcome and eventual survival although it
may be confounded by patient selection [441].
Several groups have reported the effect of chemotherapy on resectable tumours (neoadjuvant approach), as
well as unresectable primary tumours [223, 240, 442, 443]. Neoadjuvant chemotherapy with two to three cycles
of MVAC or CMV has led to a down-staging of the primary tumour in various prospective series [223, 240, 442].
A bladder-conserving strategy with TURB and systemic cisplatin-based chemotherapy has been
reported several years ago and could lead to long-term survival with intact bladder in a highly selected patient
population [441].
A recent large retrospective analysis of a National Cancer Database cohort reported on 1,538
patients treated with TURB and multi-agent chemotherapy [444]. The two and 5-year OS for all patients was
49% and 32.9% and for cT2 patients it was 52.6% and 36.2%, respectively. While these data show that longterm survival with intact bladder can be achieved in a subset of patients it is not recommended for routine use.
7.5.3.1
Summary of evidence and guideline for chemotherapy
Summary of evidence
Complete and partial local responses have been reported with cisplatin-based chemotherapy as
primary therapy for locally advanced tumours in highly selected patients.
Recommendation
Do not offer chemotherapy alone as primary therapy for localised bladder cancer.
44
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Strength rating
Strong
LIMITED UPDATE MARCH 2021
7.5.4
Trimodality bladder-preserving treatment
Trimodality therapy (TMT) combines TURB, chemotherapy and RT. The rationale to combine TURB with RT is
to maximally achieve local tumour control in the bladder and adjacent nodes. The addition of radiosensitising
chemotherapy or other radiosensitisers (mentioned below) is aimed at the potentiation of RT. Micrometastases
are targeted by platinum-based combination chemotherapy (for details see Section 7.1). The aim of TMT is to
preserve the bladder and QoL without compromising oncological outcome.
There are no successfully completed RCTs comparing the outcome of TMT with RC, but TMT using
chemoradiation has been shown to be superior to RT alone [445, 446]. Many of the reported series have
differing characteristics as compared to the larger surgical series, which typically have median ages in the midto-late 60s compared to mid-70s for some large RT series (reviewed by James, et al. [445]). In the case of TMT,
two distinct patterns of care emerge; treatment aimed at patients fit for cystectomy who elect TMT or refuse
cystectomy, and treatment aimed at older, less fit, patients. For the former category, TMT presents selective
bladder preservation and in this case the initial step is a radical TURB where as much tumour as possible
should be resected. In this case appropriate patient selection (e.g., T2 tumours, no CIS) is critical [447, 448].
Even in case of an initial presumed complete resection, a second TUR has been suggested to reveal tumour
in > 50% of patients and subsequently improves 5-year OS in case of TMT [449]. For patients who are not
candidates for cystectomy, less stringent criteria can be applied, but extensive CIS and poor bladder function
should both be regarded as relative contraindications.
A collaborative review has described the principles of TMT [450]. For radiation, two schedules are most
commonly used; historically within the RTOG a split-course format with interval cystoscopy [446] and singlephase treatment which is now more commonly used [445]. A conventional radiation schedule includes EBRT to
the bladder and limited pelvic LNs with an initial dose of 40-45 Gy, with a boost to the whole bladder of 50–54
Gy and a further tumour boost to a total dose of 60–66 Gy. If not boosting the tumour, it is also reasonable for
the whole bladder to be treated to 59.4–66 Gy. For node-positive disease, consider boosting grossly involved
nodes to the highest achievable dose that does not violate normal tissue constraints. Therefore, elective
treatment to the LNs (when node negative) is optional and should take into account patient comorbidities and
the risks of toxicity to adjacent critical structures.
In summary, reasonable radiation fields include pelvis (with bladder and/or bladder tumour boost), bladder only
or partial bladder (tumour) only [445]. A reasonable radiation dosing alternative to conventional fractionation
when treating the bladder-only fields is moderately hypofractionated EBRT to 55 Gy in 20 fractions which has
been suggested to be non-inferior to 64 Gy in 32 fractions (fx) in terms of invasive loco-regional control, OS
and late toxicity [430, 451].
Different chemotherapy regimens have been used, but most evidence exists for cisplatin [452] and mitomycin
C plus 5-FU [445]. In addition to these agents, other regimens have also been used such as gemcitabine
and hypoxic cell sensitisation with nicotinamide and carbogen, without clear preference for a specific
radiosensitiser [8, 9]. In a recently published phase II RCT, twice-a-day radiation plus fluorouracil/cisplatin was
compared to once-daily radiation plus gemcitabine [453]. Both arms were found to result in a > 75% freedom
of distant metastases at 3 years (78% and 84%, respectively). Therefore, there are options for non-cisplatin
candidates such as 5-FU/mitomycin C or low-dose gemcitabine.
To detect non-responders who should be offered salvage cystectomy, bladder biopsies should be performed
after TMT and life-long cystoscopic surveillance is recommended.
Five-year CSS and OS rates vary between 50%–84% and 36%–74%, respectively, with salvage cystectomy
rates of 10–30% [445, 447, 450, 452, 454, 455]. The Boston group reported on their experience in 66 patients
with mixed variant histologies treated with TMT and found similar complete response, OS, DSS and salvage
cystectomy rates as in UC [456]. The majority of recurrences post-TMT are non-invasive and can be managed
conservatively [445]. In contemporary experiences, salvage cystectomy is required in about 10–15% of patients
treated with TMT and can be curative [445, 447, 455]. Current data suggest that major late complication rates
are slightly higher but remain acceptable for salvage- vs. primary cystectomy [457, 458].
A sub-analysis of two RTOG trials looked at complete response (T0) and near-complete response (Ta or
Tis) after TMT [459]. After a median follow-up of 5.9 years 41/119 (35%) of patients experienced a bladder
recurrence, and fourteen required salvage cystectomy. There was no difference between complete and nearcomplete responders. Non-muscle-invasive BC recurrences after complete response to TMT were reported
in 25% of patients by the Boston group, sometimes over a decade after initial treatment [460]. A NMIBC
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45
recurrence was associated with a lower DSS, although in properly selected patients, intravesical BCG could
avoid immediate salvage cystectomy.
The differential impact of RC vs. TMT on long-term OS is lacking a randomised comparison and rigorous
prospective data. A propensity score matched institutional analysis has suggested similar DSS and OS
between TMT and RC [455]. Two retrospective analyses of the National Cancer Database from 2004–2013
with propensity score matching compared RC to TMT. Ritch et al. identified 6,606 RC and 1,773 TMT patients
[461]. Worse survival was linked to higher age, comorbidity and tumour stage. After modelling, TMT resulted
in a lower mortality at one year (HR: 0.84, 95% CI: 0.74–0.96, p = 0.01). However, in years 2 and onwards,
there was a significant and persistent higher mortality after TMT (year 2: HR: 1.4, 95% CI: 1.2–1.6, p < 0.001;
and year 3 onwards: HR: 1.5, 95% CI: 1.2–1.8, p < 0.001). The second analysis was based on a larger cohort,
with 22,680 patients undergoing RC; 2,540 patients received definitive EBRT and 1,489 TMT [462]. Survival
after modelling was significantly better for RC compared to any EBRT, definitive EBRT and TMT (HR: 1.4, 95%
CI: 1.2–1.6) at any time point. In older patients which are potentially less ideal candidates for radical surgery,
Williams et al. found a significantly lower OS (HR :1.49, 1.31–1.69) and CSS (1.55, 1.32–1.83) for TMT as
compared to surgery as well as increased costs [463]. This was a retrospective SEER database study which
included 687 propensity-matched patients in each arm, however, the median number of radiation fractions
was well below what is considered adequate for definitive therapy and as such the radiation patients may have
been treated inadequately or palliatively. In general, such population-based studies are limited by confounding,
misclassification, and selection bias. A systematic review including 57 studies and over 30,000 patients
comparing RC and TMT found improved 10-year OS and DSS for TMT, but for the entire cohort OS and DSS
did not significantly differ between RC and TMT [464]. Complete response after TMT resulted in significantly
better survival, as did down-staging after TURB or NAC in case of RC.
Overall significant late pelvic (GI/genitourinary [GU]) toxicity rates after TMT are low and QoL is good [445, 465,
466]. A combined analysis of survivors from four RTOG trials with a median follow-up of 5.4 years showed that
combined-modality therapy was associated with low rates of late grade 3 toxicity (5.7% GU and 1.9% GI). No
late grade 4 toxicities or treatment-related deaths were recorded [465]. A retrospective study showed QoL to
be good after TMT and in most domains better than after cystectomy, although prospective validations are
needed [467]. One option to reduce side effects after TMT is the use of IMRT and image-guided radiotherapy
(IGRT) [8, 9, 468].
A collaborative review came to the conclusion that data are accumulating, suggesting that bladder preservation
with TMT leads to acceptable outcomes and therefore TMT may be considered a reasonable treatment option
in well-selected patients as compared to RC [450]. Bladder preservation as an alternative to RC is generally
reserved for patients with smaller solitary tumours, negative nodes, no extensive or multifocal CIS, no tumourrelated hydronephrosis, and good pre-treatment bladder function. Trimodality bladder-preserving treatment
should also be considered in all patients with a contraindication for surgery, either a relative or absolute
contraindication since the factors that determine fitness for surgery and chemoradiotherapy differ. There are no
definitive contemporary data supporting the benefit of using neoadjuvant or adjuvant chemotherapy combined
with chemoradiation. Patient selection is critical in achieving good outcomes [450]. Whether a node dissection
should be performed before TMT as in RC remains unclear [8, 9].
A bladder-preserving trimodality strategy requires very close multidisciplinary cooperation [8, 9]. This was also
highlighted by a Canadian group [469]. In Ontario between 1994 and 2008 only 10% (370/3,759) of patients
with cystectomy had a pre-operative radiation oncology consultation, with high geographical variations.
Independent factors associated with this consultation included advanced age (p < 0.001), greater comorbidity
(p < 0.001) and earlier year of diagnosis (p < 0.001). A bladder-preserving trimodality strategy also requires
a high level of patient compliance. Even if a patient has shown a clinical response to a trimodality bladderpreserving strategy, the bladder remains a potential source of recurrence, hence long-term life-long bladder
monitoring is essential and patients should be counselled that this will be required.
7.5.4.1
Summary of evidence and guidelines for trimodality bladder-preserving treatment
Summary of evidence
In a selected patient population, long-term survival rates of trimodality bladder-preserving treatment
are comparable to those of early cystectomy.
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LIMITED UPDATE MARCH 2021
Recommendations
Strength rating
Offer surgical intervention or trimodality bladder-preserving treatments (TMT) to appropriate Strong
candidates as primary curative therapeutic approaches since they are more effective than
radiotherapy alone.
Offer TMT as an alternative to selected, well-informed and compliant patients, especially for Strong
whom radical cystectomy is not an option or not acceptable.
7.5.4.2
EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8, 9]*
Consensus statement
Candidates for curative treatment, such as cystectomy or bladder preservation, should be clinically assessed
by at least an oncologist, a urologist, a radiation oncologist (in case adjuvant radiotherapy or bladder
preservation is considered) and a neutral HCP such as a specialist nurse.
An important determinant for patient eligibility in case of bladder-preserving treatment is absence of
carcinoma in situ.
An important determinant for patient eligibility in case of bladder-preserving treatment is absence or presence
of hydronephrosis.
When assessing patient eligibility for bladder preservation, the likelihood of successful debulking surgery
should be taken into consideration (optimal debulking).
Bladder urothelial carcinoma with small cell neuroendocrine variant should be treated with neoadjuvant
chemotherapy followed by consolidating local therapy.
In case of bladder preservation with radiotherapy, combination with a radiosensitiser is always recommended
to improve clinical outcomes, such as cisplatin, 5FU/TMC, carbogen/nicotinamide or gemcitabine.
Radiotherapy for bladder preservation should be performed with IMRT and IGRT to reduce side effects.
Dose escalation above standard radical doses to the primary site in case of bladder preservation, either by
IMRT or by brachytherapy, is not recommended.
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
HCP = healthcare professional; IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiotherapy;
5FU = 5-fluorouracil; MMC = mitomycin-C.
7.6
Adjuvant therapy
7.6.1
Role of adjuvant platinum-based chemotherapy
Adjuvant chemotherapy after RC for patients with pT3/4 and/or LN positive (N+) disease without clinically
detectable metastases (M0) is still under debate [457, 470].
The general benefits of adjuvant chemotherapy include:
•
chemotherapy is administered after accurate pathological staging, therefore, treatment in patients at low
risk for micrometastases is avoided;
•
no delay in definitive surgical treatment.
The drawbacks of adjuvant chemotherapy are:
•
assessment of in vivo chemosensitivity of the tumour is not possible and overtreatment is an unavoidable
problem;
•
delay or intolerability of chemotherapy, due to post-operative morbidity [471].
There is limited evidence from adequately conducted and accrued phase III RCTs in favour of the routine use
of adjuvant chemotherapy [470, 472-477]. An individual patient data meta-analysis [472] of survival data from
six RCTs of adjuvant chemotherapy [454, 478-481] included 491 patients (unpublished data from Otto et al.,
were included in the analysis). All included trials suffered from significant methodological flaws including small
sample size (underpowered), incomplete accrual, use of inadequate statistical methods and design flaws
(irrelevant endpoints and failing to address salvage chemotherapy in case of relapse or metastases) [470]. In
these trials, three or four cycles of CMV, cisplatin, cyclophosphamide, and adriamycin (CISCA), methotrexate,
vinblastine, adriamycin or epirubicin, and cisplatin (MVA(E)C) and cisplatin and methotrexate (CM) were used
[482], and one trial used cisplatin monotherapy [480]. The data were not convincing to support an unequivocal
recommendation for the use of adjuvant chemotherapy. In 2014, this meta-analysis was updated with an
additional three studies [474-476] resulting in the inclusion of 945 patients from nine trials [473]. None of the
trials had fully accrued and individual patient data were not used in the analysis [473]. For one trial only an
abstract was available at the time of the meta-analysis [475] and none of the included individual trials were
significantly positive for OS in favour of adjuvant chemotherapy. In two of the trials more modern chemotherapy
LIMITED UPDATE MARCH 2021
47
regimens were used (gemcitabine/cisplatin and paclitaxel/gemcitabine/cisplatin) [474, 475]. The HR for OS was
0.77 (95% CI: 0.59–0.99, p = 0.049) and for DFS 0.66 (95% CI: 0.45–0.91, p = 0.014) with a stronger impact on
DFS in case of nodal positivity.
A retrospective cohort analysis including 3,974 patients after cystectomy and LND showed an OS benefit in
high-risk subgroups (extravesical extension and nodal involvement) (HR: 0.75, CI: 0.62–0.90) [483]. A recent
publication of the largest RCT (EORTC 30994), although not fully accrued, showed a significant improvement
of PFS for immediate, compared with deferred, cisplatin-based chemotherapy (HR: 0.54, 95% CI: 0.4–0.73,
p < 0.0001), but there was no significant OS benefit [484].
Furthermore, a large observational study including 5,653 patients with pathological T3–4 and/
or pathological node-positive BC, treated between 2003 and 2006 compared the effectiveness of adjuvant
chemotherapy vs. observation. Twenty-three percent of patients received adjuvant chemotherapy with a 5-year
OS of 37% for the adjuvant arm vs. 29.1% (HR: 0.70, 95% CI: 0.64–0.76) in the observation group [485].
Another large retrospective analysis based on National Cancer Data Base including 15,397 patients
with locally advanced (pT3/4) or LN-positive disease also demonstrated an OS benefit in patients with UC
histology [486]. In patients with concomitant variant or pure variant histology, however, no benefit was found.
From the currently available evidence it is still unclear whether immediate adjuvant chemotherapy or
chemotherapy at the time of relapse is superior, or if the two approaches are equivalent with respect to
the endpoint of OS. The most recent meta-analysis from 2014 showed a therapeutic benefit of adjuvant
chemotherapy, but the level of evidence of this review is still very low, with significant heterogeneity and
methodological flaws in the only nine included trials [473]. Patients should be informed about potential
chemotherapy options before RC, including neoadjuvant and adjuvant chemotherapy, and the limited evidence
for adjuvant chemotherapy.
7.6.2
Role of adjuvant immunotherapy
To evaluate the benefit of PD-1/PD-L1 checkpoint inhibitors, a number of randomised phase III trials
comparing checkpoint inhibitor monotherapy with atezolizumab, nivolumab or pembrolizumab are under way.
Preliminary results of two phase III trials have been presented (atezolizumab at ASCO 2020; nivolumab at
ASCO GU 2021): the primary endpoint of improved DFS was not achieved with atezolizumab but was achieved
with adjuvant nivolumab. Further results and longer follow-up have to be awaited.
So far, adjuvant immunotherapy is not standard of care and should only be given within a clinical
trial [487].
7.6.3
Guidelines for adjuvant therapy
Recommendations
Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or
pN+ disease if no neoadjuvant chemotherapy has been given.
Only offer immunotherapy with a checkpoint inhibitor in a clinical trial setting.
7.7
Strength rating
Strong
Strong
Metastatic disease
7.7.1
Introduction
Approximately 50% of patients with muscle-invasive UC relapse after RC, depending on the pathological stage
of the primary tumour and the nodal status. Local recurrence accounts for 30% of relapses, whereas distant
metastases are more common. Ten to fifteen percent of patients are already metastatic at diagnosis [488].
Before the development of effective chemotherapy patients with metastatic UC had a median survival rarely
exceeding three to six months [489].
7.7.1.1
Prognostic factors and treatment decisions
Prognostic factors are crucial for assessing phase II study results and stratifying phase III trials [490, 491]. In a
multivariate analysis, Karnofsky PS of ≤ 80% and presence of visceral metastases were independent prognostic
factors of poor survival after treatment with MVAC [491]. These prognostic factors have also been validated for
newer combination chemotherapy regimens [492-496]. Two additional prognostic models have been developed
in the past years including the variables leukocyte count, number of sites of visceral metastases, site of primary
tumour, PS, LN metastasis [496] and visceral metastasis, albumin and haemoglobin [495], respectively.
For patients refractory to, or progressing shortly after, platinum-based combination chemotherapy,
four prognostic groups have been established based on three adverse factors that have developed in patients
treated with vinflunine and that have been validated in an independent data set; Hb < 10 g/dL presence of liver
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LIMITED UPDATE MARCH 2021
metastases and ECOG PS ≥ 1 [497]. It is important to acknowledge that these prognostic models have not
been validated in the context of newer agents including immunotherapy.
7.7.1.2
Comorbidity in metastatic disease
Comorbidity is defined as “the presence of one or more disease(s) in addition to an index disease” (see
Section 5.3). Comorbidity increases with age. However, chronological age does not necessarily correlate with
functional impairment. Different evaluation systems are being used to screen patients as potentially fit or unfit
for chemotherapy, but age alone should not be used as the basis for treatment selection [498].
7.7.2
First-line systemic therapy for metastatic disease
In general, patients with untreated metastatic BC can be divided into three broad categories: fit for cisplatinbased chemotherapy, fit for carboplatin-based chemotherapy (but unfit for cisplatin) and unfit for any platinumbased chemotherapy.
7.7.2.1
Definitions: ‘Fit for cisplatin, fit for carboplatin, unfit for any platinum-based chemotherapy’
An international survey among BC experts [499] was the basis for a consensus statement on how to classify
patients unfit for cisplatin-based chemotherapy. At least one of the following criteria has to be present: PS > 1;
GFR ≤ 60 mL/min; grade ≥ 2 audiometric loss; grade ≥ 2 peripheral neuropathy or New York Heart Association
(NYHA) class III heart failure [500]. More than 50% of patients with UC are not eligible for cisplatin-based
chemotherapy [501-504]. Renal function assessment in UC is of utmost importance for treatment selection
[501, 505]. In case of doubt, measuring GFR with radioisotopes (99mTc DTPA or 51Cr-EDTA) is recommended.
Cisplatin has also been administered in patients with a lower GFR (40–60 mL/min) using different split-dose
schedules. The respective studies were mostly small phase I and II trials in different settings (neoadjuvant
and advanced disease) demonstrating that the use of split-dose cisplatin is feasible and appears to result in
encouraging efficacy [506-509]. However, no prospective randomised trial has compared split-dose cisplatin
with conventional dosing.
Most patients that are deemed unfit for cisplatin are able to receive carboplatin-based chemotherapy. However,
some patients are deemed unfit for any platinum-based chemotherapy (both cisplatin and carboplatin) in case
of PS > 2, impaired renal function with a GFR < 30 mL/min or the combination of PS 2 and GFR < 60 mL/min
since the outcome in this patient population is poor regardless of platinum-based treatment or not [510].
Patients with multiple comorbidities may also be poor candidates for platinum-based chemotherapy.
7.7.2.2
Chemotherapy in patients fit for cisplatin
Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s
demonstrating an OS of twelve to fourteen months in different series (for a review see [511]). Methotrexate,
vinblastine, adriamycin plus cisplatin (MVAC) and GC prolonged survival to up to 14.8 and 13.8 months,
respectively, compared to monotherapy and older chemotherapy combinations. Neither of the two
combinations is superior to the other but equivalence has not been tested. Response rates were 46% and 49%
for MVAC and GC, respectively. The long-term survival results have confirmed the efficacy of the two regimens
[512]. The major difference between the above-mentioned combinations is toxicity. The lower toxicity of GC
[174] compared to standard MVAC has resulted in it becoming a new standard regimen [513]. Methotrexate,
vinblastine, adriamycin plus cisplatin is better tolerated when combined with granulocyte colony-stimulating
factor (G-CSF) [513, 514].
High-dose intensity MVAC (HD-MVAC) combined with G-CSF is less toxic and more efficacious than standard
MVAC in terms of dose density, complete response (CR), and 2-year survival rate. However, there is no
significant difference in median survival between the two regimens [515, 516]. In general, all disease sites have
been shown to respond to cisplatin-based combination chemotherapy. A response rate of 66% and 77% with
MVAC and HD-MVAC, respectively, has been reported in retroperitoneal LNs vs. 29% and 33% at extranodal
sites [515]. The disease sites also have an impact on long-term survival. In LN-only disease, 20.9% of patients
were alive at five years compared to only 6.8% of patients with visceral metastases [512].
Further intensification of treatment using paclitaxel, cisplatin and gemcitabine (PCG) triple regimen
did not result in a significant improvement in OS in the intention-to-treat (ITT) population of a large phase III
RCT, comparing PCG triple regimen to GC [517]. However, the overall response rate (ORR) was higher with the
triple regimen (56% vs. 44%, p = 0.0031), and the trend for OS improvement in the ITT population (15.8 vs.
12.7 months; HR = 0.85, p = 0.075) became significant in the eligible population.
Carboplatin-containing chemotherapy has not been proven to be equivalent to cisplatin combinations, and
should not be considered interchangeable or standard in patients fit for cisplatin. Several phase II RCTs of
LIMITED UPDATE MARCH 2021
49
carboplatin vs. cisplatin combination chemotherapy have produced lower CR rates and shorter OS for the
carboplatin arms [518]. Recently, a retrospective International Study of Advanced/Metastatic Cancer of the
Urothelium (RISC) group highlighted the importance of applying the cisplatin-eligibility criteria in order to
maintain benefit [519].
7.7.2.3
Chemotherapy in patients fit for carboplatin (but unfit for cisplatin)
Up to 50% of patients are not fit for cisplatin-containing chemotherapy but may be candidates for carboplatin
[500]. The first randomised phase II/III trial in this setting was conducted by the EORTC and compared two
carboplatin-containing regimens (methotrexate/carboplatin/vinblastine [M-CAVI] and carboplatin/gemcitabine
[GemCarbo]) in patients unfit for cisplatin. The EORTC definitions for eligibility were GFR < 60 mL/min and/or
PS 2. Both regimens were active. Severe acute toxicity was 13.6% in patients treated with GemCarbo vs. 23%
with M-CAVI, while the ORR was 42% for GemCarbo and 30% for M-CAVI. Further analysis showed that in
patients with PS 2 and impaired renal function, combination chemotherapy provided very limited benefit [510].
The ORR and severe acute toxicity were both 26% for the former group, and 20% and 24%, respectively, for
the latter group [510]. Phase III data have confirmed these results [494]. The combination of carboplatin and
gemcitabine can be considered a standard of care in this patient group.
A randomised, international phase II trial (JASINT1; JAVLOR Association Study in CDDP-unfit
Patients With Advanced Transitional Cell Carcinoma: Gemcitabine Versus Carboplatin) assessed the efficacy
and tolerability profile of two vinflunine-based regimens (vinflunine/gemcitabine vs. vinflunine/carboplatin).
Both regimens showed equal ORR and OS with less haematologic toxicity for the combination vinflunine/
gemcitabine [520].
7.7.2.4
Integration of immunotherapy in the first-line treatment of patients fit for platinum-based
chemotherapy
7.7.2.4.1 Immunotherapy combination approaches
In 2020 the results of three phase III trials have been presented and published investigating the use of
immunotherapy in the first-line setting for platinum-eligible patients.
The first trial to report was IMvigor130 investigating the combination of the PD-L1 inhibitor
atezolizumab plus platinum-gemcitabine chemotherapy vs. chemotherapy plus placebo vs. atezolizumab
alone [521]. The primary endpoint of PFS benefit for the combination vs. chemotherapy alone in the ITT group
was reached (8.2 months vs. 6.3 months [HR: 0.82, 95% CI: 0.70–0.96; one-sided, p = 0.007]) while OS was
not significant at the interim analysis after a median follow-up of 11.8 months. The small PFS benefit in the
absence of an OS benefit has raised questions of its clinical significance. Due to the sequential testing design,
the comparison of chemotherapy vs. atezolizumab alone has not yet been formally performed.
The KEYNOTE 361 study had a very similar design using the PD-1 inhibitor pembrolizumab plus
platinum-gemcitabine vs. chemotherapy alone vs. pembrolizumab alone. The results of the primary endpoints
of PFS and OS for the comparison of pembrolizumab plus chemotherapy vs. chemotherapy in the ITT
population have been presented but are not yet fully published and show no benefit for the combination [522].
DANUBE compared the immunotherapy combination (IO-IO) of CTLA-4 inhibitor tremelimumab and
PD-L1 inhibitor durvalumab with chemotherapy alone or durvalumab alone [523]. The co-primary endpoint of
improved OS for the IO-IO combination vs. chemotherapy was not reached in the ITT group nor was the OS
improved for durvalumab monotherapy vs. chemotherapy in the PD-L1-positive population.
In conclusion; at this time these three trials do not support the use of combination of PD-1/L1 checkpoint
inhibitors plus chemotherapy or the IO-IO combination.
7.7.2.4.2 Use of single-agent immunotherapy
Based on the results of two single-arm phase II trials [524, 525] the checkpoint inhibitors pembrolizumab and
atezolizumab have been approved by the FDA and the EMA for first-line treatment in cisplatin-unfit patients
in case of positive PD-L1 status. Programmed death-ligand-1 positivity for use of pembrolizumab is defined
by immunohistochemistry as a combined positive score (CPS) of ≥ 10 using the Dako 22C33 platform and for
atezolizumab as positivity of ≥ 5% tumour-infiltrating immune cells using Ventana SP142.
The PD-1 inhibitor pembrolizumab was tested in 370 patients with advanced or metastatic UC
ineligible for cisplatin, showing an ORR of 29% and complete remission in 7% of patients [524]. The PD-L1
inhibitor atezolizumab was also evaluated in the same patient population in a phase II trial (n = 119) showing
an ORR of 23% with 9% of patients achieving a complete remission; median OS was 15.9 months [525]. The
results are difficult to interpret due to the missing control arm and the heterogeneity of the study population
with regards to PD-L1 status.
The trials IMvigor 130, Keynote 361 and DANUBE all included an experimental arm with
immunotherapy alone using atezolizumab, pembrolizumab and durvalumab, respectively [521-523]. The
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LIMITED UPDATE MARCH 2021
results presented so far have not demonstrated a benefit in terms of PFS or OS compared to platinum-based
chemotherapy but no subgroup comparisons for cisplatin-unfit patients were analysed.
7.7.2.4.3 Switch maintenance with immunotherapy
The JAVELIN Bladder 100 study investigated the impact of switch maintenance with the PD-L1 inhibitor
avelumab after initial treatment with platinum-gemcitabine combination [526]. Patients achieving at least stable
disease, or better, after 4–6 cycles of platinum-gemcitabine were randomised to avelumab or best supportive
care (BSC). Overall survival was the primary endpoint which improved to 21.4 months with avelumab compared
to 14.3 months with BSC (HR: 0.69, 95% CI: 0.56–0.86; p < 0.001). Of patients who discontinued BSC and
received subsequent treatment 53% received immunotherapy. Grade 3 or higher side effects occurred in 47%
of avelumab patients compared to 25% of BSC patients. Immune-related adverse events occurred in 29% of
all patients and 7% experienced grade 3 complications which included colitis, pneumonitis, rash, increased
liver enzymes, hyperglycaemia, myositis and hypothyroidism.
A randomised phase II trial evaluated switch maintenance treatment with pembrolizumab in patients
achieving at least stable disease on platinum-based first-line chemotherapy [527]. One hundred and eight
patients were randomised to pembrolizumab or placebo. At a median follow-up of 12.9 months (range 0.9–34.5
months), the primary endpoint of PFS was met (5.4 months vs. 3.0 months, HR: 0.65, p = 0.04) but not the
secondary endpoint of OS (22 months vs. 18.7 months, HR: 0.91, 95% CI: 0.52–1.59).
7.7.2.5
Treatment of patients unfit for any platinum-based chemotherapy
Limited data exists regarding the optimal treatment for this patient population which is characterised by
impaired PS (PS > 2) and/or impaired renal function (GFR < 30 mL/min). Historically, the outcome in this
patient group has been poor. Often BSC has been chosen instead of systemic therapy. Most trials evaluating
alternative treatment options to cisplatinum-based chemotherapy did not focus specifically on this patient
population thereby making interpretation of data difficult. The FDA (but not EMA) has approved pembrolizumab
and atezolizumab as first-line treatment for patients not fit to receive any platinum-based chemotherapy
regardless of PD-L1 status based on the results of two single-arm phase II trials [524, 525]. It has not been
reported how many patients in these two studies were unfit for any platinum-based chemotherapy.
7.7.2.6
Non-platinum combination chemotherapy
The use of single-agent chemotherapy has been associated with varying response rates. Responses with
single agents are usually short-lived, complete responses are rare, and no long-term DFS/OS has been
reported.
Different combinations of gemcitabine and paclitaxel have been studied as first- and second-line treatments.
Apart from severe pulmonary toxicity with a weekly schedule of both drugs, this combination is well tolerated
and produces response rates between 38% and 60% in both lines. Non-platinum combination chemotherapy
has not been compared to standard platinum-based chemotherapy in RCTs; therefore, it is not recommended
for first-line use in platinum-eligible patients [528-535].
7.7.3
Second-line systemic therapy for metastatic disease
7.7.3.1
Second-line chemotherapy
Second-line chemotherapy data are highly variable and mainly derive from small single-arm phase II trials
apart from a single randomised phase III study [497]. A reasonable strategy has been to re-challenge former
cisplatin-sensitive patients if progression occurred at least six to twelve months after first-line cisplatin-based
combination chemotherapy. Second-line response rates of single-agent treatment with paclitaxel (weekly),
docetaxel, nab-paclitaxel (nanoparticle albumin-bound) [536] oxaliplatin, ifosfamide, topotecan, pemetrexed,
lapatinib, gefitinib and bortezomib have ranged between 0% and 28% in small phase II trials [537-539].
Gemcitabine has also shown response in second-line use but most patients receive this drug as part of their
first-line treatment [535].
The paclitaxel/gemcitabine combination has shown response rates of 38–60% in small single-arm
studies. No phase III RCT with an adequate comparator arm has been conducted to assess the true value and
OS benefit of this second-line combination [489, 533, 540].
Vinflunine, a third-generation vinca alkaloid, was tested in a phase III RCT and compared against
BSC in patients progressing after first-line treatment with platinum-containing combination chemotherapy for
metastatic disease [541]. The results showed a modest ORR (8.6%), a clinical benefit with a favourable safety
profile and a survival benefit in favour of vinflunine, which was, however, only statistically significant in the
eligible patient population (not in the ITT population).
Vinflunine was approved as second-line treatment in Europe (not in the U.S.). More recently,
second-line therapy with PD-1/PD-L1 checkpoint inhibitors has been established as standard second-line
LIMITED UPDATE MARCH 2021
51
therapy and vinflunine is reserved for patients with contraindications to immunotherapy and may be considered
as third- or later-line treatment option although no randomised data for these indications exist.
A randomised phase III trial evaluated the addition of the angiogenesis inhibitor ramucirumab to
docetaxel chemotherapy vs. docetaxel alone, which resulted in improved PFS (4.07 vs. 2.76 months) and
higher response rates (24.5% vs. 14%), respectively [542]. While the primary endpoint of PFS prolongation was
reached, the clinical benefit appears small and no OS benefit has been shown [543].
7.7.3.2
Second-line immunotherapy for platinum-pre-treated patients
The immune checkpoint inhibitors pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab have
demonstrated similar efficacy and safety in patients progressing during, or after, standard platinum-based
chemotherapy in phase I, II and III trials.
Pembrolizumab, a PD-1 inhibitor, has been tested in patients progressing during or after platinum-based firstline chemotherapy in a phase III RCT and demonstrated a significant OS benefit leading to approval. In the trial,
patients (n = 542) were randomised to receive either pembrolizumab monotherapy or chemotherapy (paclitaxel,
docetaxel or vinflunine). The median OS in the pembrolizumab arm was 10.3 months (95% CI: 8.0–11.8) vs.
7.4 months (95% CI: 6.1–8.3) for the chemotherapy arm (HR for death, 0.73, 95% CI: 0.59–0.91, p = 0.002)
independent of PD-L1 expression levels [544]. This trial was recently updated with a longer follow-up of 27.7
months showing consistent improvement of OS [545]. In addition, HRQoL analysis showed that patients on
pembrolizumab experience stable, or improved, HRQoL, whereas it deteriorated on chemotherapy [546].
Atezolizumab, a PD-L1 inhibitor, tested in patients progressing during, or after, previous platinum-based
chemotherapy in phase I, phase II and phase III trials, was the first checkpoint inhibitor approved for BC [204,
547, 548]. The phase III RCT (IMvigor211) included 931 patients comparing atezolizumab with second-line
chemotherapy (either paclitaxel, docetaxel or vinflunine) did not meet its primary endpoint of improved OS for
patients with high PD-L1 expression (immune cells [IC] score 2/3) with 11.1 months (atezolizumab) vs. 10. 6
(chemotherapy) months (stratified HR: 0.87, 95% CI: 0.63–1.21, p = 0.41) but OS was numerically improved
in the ITT population in an exploratory analysis (8.6 months vs. 8.0 months, HR: 0.85, 95% CI: 0.73–0.99). A
phase IV single-arm safety study was conducted with atezolizumab including 1,004 patients confirming the
efficacy and tolerability profile [549].
The PD-1 inhibitor nivolumab was approved based on the results of a single-arm phase II trial (CheckMate
275), enrolling 270 platinum pre-treated patients. The first endpoint was ORR. Objective response rate was
19.6%, and OS was 8.74 months for the entire group [550]. Based on results of phase I/II and phase IB trials,
two additional PD-L1 inhibitors, durvalumab and avelumab, are currently only approved for this indication in the
U.S. [551-553].
7.7.3.2.1 Side-effect profile of immunotherapy
Checkpoint inhibitors including PD-1 or PD-L1 antibodies and CTLA-4 antibodies have a distinct side effect
profile associated with their mechanism of action leading to enhanced immune system activity. These adverse
events can affect any organ in the body leading to mild, moderate or severe side effects. The most common
organs affected are the skin, gastrointestinal tract, liver, lung, thyroid, adrenal and pituitary gland. Other
systems that may be affected include musculoskeletal, renal, nervous, haematologic, ocular and cardiovascular
system. Any change during immunotherapy treatment should raise suspicion about a possible relation to the
treatment. The nature of immune-related adverse events has been very well characterised and published [554].
The timely and appropriate treatment of immune-related side effects is crucial to achieve optimal
benefit from the treatment while maintaining safety. Clear guidelines for side effect management have been
published [555]. Immunotherapy treatment should be applied and supervised by trained clinicians only to
ensure early side effect recognition and treatment.
In case of interruption of immunotherapy, re-challenge will require close monitoring for adverse
events [556].
7.7.4
Novel agents for second- or later-line therapy
Genomic profiling of urothelial carcinoma has revealed common potentially actionable genomic alterations
including alterations in FGFR [557]. Erdafitinib is a pan-FGFR tyrosine kinase inhibitor and the first FDAapproved targeted therapy for metastatic urothelial carcinoma with susceptible FGFR2/3 alterations following
platinum-containing chemotherapy. The phase II trial of erdafitinib included 99 patients whose tumour
harboured an FGFR3 mutation or FGFR2/3 fusion and who had disease progression following chemotherapy
[202]. The confirmed ORR was 40% and an additional 39% of patients had stable disease. A total of 22
patients had previously received immunotherapy with only one patient achieving a response, yet the response
52
LIMITED UPDATE MARCH 2021
rate for erdafitinib for this subgroup was 59%. At a median follow-up of 24 months, the median PFS was
5.5 months (95% CI: 4.0–6.0) and the median OS was 11.3 months (95% CI: 9.7–15.2) [202]. Treatmentrelated adverse events of ≥ grade 3 occurred in 46% of patients. Common adverse events of ≥ grade 3 were
hyponatraemia (11%), stomatitis (10%), and asthenia (7%) and 13 patients discontinued erdafitinib due to
adverse events, including retinal pigment epithelial detachment, hand-foot syndrome, dry mouth, and skin/nail
events. In addition to erdafitinib, several other FGFR inhibitors are being evaluated including infigratinib which
has demonstrated promising activity [203]. The increased identification of FGFR3 mutations/fusion in UTUCs
and in NMIBC has led to several ongoing trials.
Another promising drug is enfortumab vedotin, an antibody-drug conjugate (ADC) targeting Nectin-4, a
cell adhesion molecule which is highly expressed in UC conjugated to monomethyl auristatin E (MMAE). A
published phase-II single-arm study (n = 125) in patients previously treated with platinum chemotherapy and
checkpoint inhibition showed a confirmed objective response rate of 44%, including 12% complete responses
[558]. Responses were seen across patient subgroups including 41% in checkpoint inhibitor non-responders
and 38% in patients with liver metastases. The most common treatment-related AEs included fatigue (50%),
alopecia (48%), and decreased appetite (41%). Treatment-related AEs of interest included any rash (48% all
grade, 11% ≥ G3) and any peripheral neuropathy (50% all grade, 3% ≥ G3). This data led to the accelerated
FDA approval for enfortumab vedotin in locally advanced or metastatic UC patients who have previously
received a PD-1 or PD-L1 inhibitor, and platinum-containing chemotherapy in the neoadjuvant/adjuvant,
locally advanced or metastatic setting [559]. A phase III RCT comparing enfortumab vedotin with single-agent
chemotherapy has reported preliminary results (ASCO GU 2021), reporting a significant survival benefit [558].
Another ongoing trial has reported promising activity for the combination of enfortumab vedotin in combination
with pembrolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced/metastatic UC
(ORR: 73.3% with 15.6% complete responses) [560]. Another promising ADC is sacituzumab govitecan, targeting
trophoblast cell surface antigen 2 (Trop-2) conjugated to SN-38, the active metabolite of irinotecan [561].
7.7.5
Post-chemotherapy surgery and oligometastatic disease
With cisplatin-containing combination chemotherapy, excellent response rates may be obtained in patients
with LN metastases only, good PS and adequate renal function, including a high number of complete
responses with up to 20% of patients achieving long-term DFS [512, 516, 562, 563]. The role of surgery of
residual LNs after chemotherapy is still unclear. Although some studies suggest a survival benefit and QoL
improvement, the level of evidence supporting this practice is mainly anecdotal [564-578]. Retrospective
studies of post-chemotherapy surgery after partial or complete remission have indicated that surgery may
contribute to long-term DFS in selected patients [579-582]. These findings have been confirmed in a recent
systematic review including 28 studies [582].
In the absence of data from RCTs, patients should be evaluated on an individual basis and
discussed by an interdisciplinary tumour board [582].
7.7.6
Treatment of patients with bone metastases
The prevalence of metastatic bone disease (MBD) in patients with advanced/metastatic UC is 30–40% [583].
Skeletal complications due to MBD have a detrimental effect on pain and QoL and are also associated
with increased mortality [584]. Bisphosphonates such as zoledronic acid reduce and delay skeletal-related
events (SREs) due to bone metastases by inhibiting bone resorption, as shown in a small pilot study [585].
Denosumab, a fully human monoclonal antibody that binds to and neutralises RANKL (receptor activator
of nuclear factor κB ligand), was shown to be non-inferior to zoledronic acid in preventing or delaying SREs
in patients with solid tumours and advanced MBD, including patients with UC [586]. Patients with MBD,
irrespective of the cancer type, should be considered for bone-targeted treatment [584].
Patients treated with zoledronic acid or denosumab should be informed about possible side effects including
osteonecrosis of the jaw and hypocalcaemia. Supplementation with calcium and vitamin D is mandatory.
Dosing regimens of zoledronic acid should follow regulatory recommendations and have to be adjusted
according to pre-existing medical conditions, especially renal function [587]. For denosumab, no dose
adjustments are required for variations in renal function.
LIMITED UPDATE MARCH 2021
53
7.7.7
Summary of evidence and guidelines for metastatic disease
Summary of evidence
In a first-line setting, performance status (PS) and the presence or absence of visceral metastases are
independent prognostic factors for survival.
In a second-line setting, negative prognostic factors are: liver metastasis, PS ≥ 1 and low haemoglobin
(< 10 g/dL).
Cisplatin-containing combination chemotherapy can achieve median survival of up to 14 months, with
long-term disease-free survival (DFS) reported in ~15% of patients with nodal disease and good PS.
Single-agent chemotherapy provides low response rates of usually short duration.
Carboplatin combination chemotherapy is less effective than cisplatin-based chemotherapy in terms
of complete response and survival.
Non-platinum combination chemotherapy has not been tested against standard chemotherapy in
patients who are fit or unfit for cisplatin-combination chemotherapy.
There is no defined standard therapy for platinum chemotherapy-unfit patients with advanced or
metastatic urothelial cancer (UC).
Post-chemotherapy surgery after partial or complete response may contribute to long-term DFS in
selected patients.
Zoledronic acid and denosumab have been approved for supportive treatment in case of bone
metastases of all cancer types including UC, as they reduce and delay skeletal related events.
PD-1 inhibitor pembrolizumab has been approved for patients that have progressed during or after
previous platinum-based chemotherapy based on the results of a phase III trial.
PD-L1 inhibitors atezolizumab, nivolumab, durvalumab and avelumab have been FDA approved for
patients that have progressed during or after previous platinum-based chemotherapy based on the
results of a phase II trial.
PD-1 inhibitor pembrolizumab and PD-L1 inhibitor atezolizumab have been approved for patients
with advanced or metastatic UC unfit for cisplatinum-based first-line chemotherapy and with
overexpression of PD-L1 based on the results of single-arm phase II trials.
The combination of chemotherapy plus pembrolizumab or atezolizumab and the combination of
durvalumab and tremelimumab have not demonstrated OS survival benefit compared to platinumbased chemotherapy alone.
Switch maintenance with the PD-L1 inhibitor avelumab has demonstrated significant OS benefit in
patients achieving at least stable disease on first-line platinum-based chemotherapy.
Recommendations
First-line treatment for platinum-fit patients
Use cisplatin-containing combination chemotherapy with GC or HD-MVAC.
In patients unfit for cisplatin but fit for carboplatin use the combination of carboplatin and
gemcitabine.
In patients achieving stable disease, or better, after first-line platinum-based chemotherapy
use maintenance treatment with PD-L1 inhibitor avelumab.
First-line treatment in patients unfit for platinum-based chemotherapy
Consider checkpoint inhibitors pembrolizumab or atezolizumab.
Second-line treatment
Offer checkpoint inhibitor pembrolizumab to patients progressing during, or after, platinumbased combination chemotherapy for metastatic disease. If this is not possible, offer
atezolizumab, nivolumab (EMA, FDA approved); avelumab or durvalumab (FDA approved).
Further treatment after platinum- and immunotherapy
Offer treatment in clinical trials testing novel antibody drug conjugates (enfortumab vedotin,
sacituzumab govitecan); or in case of patients with FGFR3 alterations, FGFR tyrosine kinase
inhibitors.
LE
1b
1b
1b
2a
2a
4
2b
3
1b
1b
2a
2a
1b
1b
Strength rating
Strong
Strong
Strong
Weak
Strong
Strong
GC = gemcitabine plus cisplatin; FGFR = fibroblast growth factor receptor; HD-MVAC = high-dose intensity
methotrexate, vinblastine, adriamycin plus cisplatin.
54
LIMITED UPDATE MARCH 2021
Figure 7.2: Flow chart for the management of metastatic urothelial cancer*
PLATINUM-INELIGIBLE
PLATINUM-ELIGIBLE
cisplatin
PS 2 and GFR < 60 mL/min
PS > 2; GFR < 30 mL/min
carboplatin
PS 0-1 and
GFR > 50-60 mL/min
PS 2 or GFR 30-60
mL/min
cisplatin/gemcitabine
or DD-MVAC 4-6 cycles
carboplatin/gemcitabine
4-6 cycles
PD
PD-L1 +
PD-L1 -
CR/PR/SD
2nd line therapy
PD
Watchful
waiting
Maintenance
• pembrolizumab
(atezolizumab, avelumab,
durvalumab, nivolumab)
• Trials
Switch
maintenance:
avelumab
Immunotherapy
• atezolizumab
• pembrolizumab
Best
supportive
care
LATER-LINE THERAPY
UC patients refractory to platinum-based
chemotherapy and IO
FGFR3 mutation UC progressing on
platinum-based chemotherapy ± prior IO
•
•
•
erdafitinib (FDA) – in trial
chemotherapy:
o paclitaxel
o Docetaxel
o vinflunine
Trials
•
•
•
enfortumab vedotin (FDA) – in trial
chemotherapy:
o paclitaxel
o docetaxel
o vinflunine
Trials
*Treatment within clinical trials is highly encouraged.
BSC = best supportive care; CR = complete response; DD-MVAC = dose dense methotrexate vinblastine
doxorubicin cisplatin; EV = enfortumab vedotin; FDA = US Food and Drug Administration;
FGFR = pan-fibroblast growth factor receptor tyrosine kinase inhibitor; GFR = glomerular filtration rate;
IO = immunotherapy; PR = partial response; PS = performance status; SD = stable disease.
7.8
Quality of life
7.8.1
Introduction
The evaluation of HRQoL considers physical, psychological, emotional and social functioning. In patients with
MIBC, HRQoL declines in particular in the physical and social functioning domains [588]. Several questionnaires
have been validated for assessing HRQoL in patients with BC, including FACT (Functional Assessment of
Cancer Therapy)-G [589], EORTC QLQ-C30 [590], EORTC QLQ-BLM (MIBC module) [591], and SF (Short Form)36 [592, 593] and recently the BCI questionnaire specifically designed and validated for BC patients [594].
7.8.2
Neoadjuvant chemotherapy
The impact of NAC on patient-reported outcomes (using EORTC QLQ questionnaires) was investigated by
Feuerstein et al. [595]. A propensity-matched analysis of 101 patients who completed NAC and 54 patients
who did not undergo NAC, showed no negative effect of NAC on patient-reported outcomes. Similar results
were reported by Huddart et al. based on data from the BC2001 trial [466].
LIMITED UPDATE MARCH 2021
55
7.8.3
Radical cystectomy and urinary diversion
Two systematic reviews and meta-analyses focused on HRQoL after RC and urinary diversion [351, 596].
Yang et al. compared HRQoL of incontinent and continent urinary diversions (all types) including
29 studies (n = 3,754) of which 9 had a prospective design (one of which was randomised) [351]. Only three
studies reported HRQoL data both pre- and post-operatively. In these three studies, an initial deterioration in
overall HRQoL was reported but general health, functional and emotional domains at 12 months post-surgery
were equal or better than baseline. After 12 months, the HRQoL benefits diminished in all domains. Overall,
no difference in HRQoL between continent and incontinent urinary diversion was reported although an ileal
conduit may confer a small physical health benefit [596].
Cerruto et al. reported HRQoL comparing ileal conduit with orthotopic neobladder reconstruction
[596]. A pooled analysis was performed including 18 studies (n = 1,553) of which the vast majority
were retrospective studies. The analysis showed no statistical significant difference in overall HRQoL, but
methodological limitations need to be considered.
Clifford et al. prospectively evaluated continence outcomes in male patients undergoing orthotopic neobladder
diversion [597]. Day-time continence increased from 59% at less than three months post-operatively to 92%
after 12 to 18 months. Night-time continence increased from 28% at less than three months post-operatively
to 51% after 18 to 36 months. Also of interest is the urinary bother in females with an orthotopic neobladder.
Bartsch and co-workers reported day-time and night-time continence rates of 70.4% and 64.8%, respectively,
in 56 female neobladder patients. Thirty-five patients (62.5%) performed clean intermittent catheterisation,
which is much worse when compared to male neobladder patients. Moreover, patients with non-organconfined disease (p = 0.04) and patients with a college degree (p = 0.001) showed worse outcomes on HRQoL
scores [598].
Altogether, there is no superior type of urinary diversion in terms of overall HRQoL in unselected patients.
Health-related QoL outcomes are most likely a result of good patient selection. An older, more isolated, patient
is probably better served with an ileal conduit, whereas a younger patient with a likely higher level of interest
in body image and sexuality is better off with an orthotopic diversion. The patient’s choice is the key to the
selection of reconstruction method [351].
7.8.4
Bladder sparing trimodality therapy
The only HRQoL data in bladder sparing treatment collected in an RCT setting was published by Huddart et al.
[466]. The primary endpoint was the change in the Bladder Cancer Subscale (BLCS), as part of the FACT-BL
questionnaire, at one year post-treatment. Questionnaire return rate at one and five years was 70% and 60%,
respectively. The remaining patients did mostly not respond as a result of recurrence or RC. The data show a
reduction in HRQoL in the majority of the domains immediately following radiotherapy but in most patients the
HRQoL scores returned to baseline 6 months after RT and maintained at this level for five years. Approximately
33% of patients reported persistent lower Bladder Cancer Subscale scores after five years. Addition of
chemotherapy did not affect the HRQoL outcomes.
7.8.5
Non-curative or metastatic bladder cancer
In non-curative or metastatic BC, HRQoL is reduced because of associated micturition problems, bleeding,
pain and therefore disturbance of social and sexual life [599]. There is limited literature describing HRQoL in BC
patients receiving palliative care [600] but there are reports of bladder-related symptoms relieved by palliative
surgery [423], RT [601], and/or chemotherapy [602].
A HRQoL analysis was performed in platinum-refractory patients who were randomised to pembrolizumab
vs. another line of chemotherapy (KEYNOTE-45 trial) [546]. It was reported that patients treated with
pembrolizumab had stable or improved global health status/QoL, whereas those treated with investigators’
choice of chemotherapy experienced declines in global health [546].
7.8.6
Summary of evidence and recommendations for health-related quality of life
Summary of evidence
Compared to non-cancer controls, the diagnosis and treatment of bladder cancer has a negative
impact on HRQoL.
There is no significant difference in overall QoL between patients with continent or incontinent
diversion.
In patients with MIBC treated with RC, overall HRQoL declines immediately after treatment and
recovers to baseline at 12 months post-operatively.
56
LE
2a
2a
1a
LIMITED UPDATE MARCH 2021
In patients with MIBC treated with radiotherapy, overall HRQoL declines immediately after treatment. 1b
In most patients, overall HRQoL then recovers to baseline at 6 months and maintains at this level to 5
years.
In patients with MIBC treated with radiotherapy, concomitant chemotherapy or neo-adjuvant
1b
chemotherapy has no significant impact on HRQoL.
In patients with platinum-refractory advanced urothelial carcinoma, pembrolizumab may be superior in 1b
terms of HRQoL compared to another line of chemotherapy.
Recommendations
Use validated questionnaires to assess health-related quality of life in patients with muscleinvasive bladder cancer.
Discuss the type of urinary diversion taking into account a patient preference, existing
comorbidities, tumour variables and coping abilities.
8.
FOLLOW-UP
8.1
Follow-up in muscle invasive bladder cancer
Strength rating
Strong
Strong
An appropriate schedule for disease monitoring should be based on natural timing of recurrence; probability
and site of recurrence; functional monitoring after urinary diversion and the potential available management
options [603].
Nomograms on CSS following RC have been developed and externally validated, but their wider
use cannot be recommended until further data become available [604, 605].
Current surveillance protocols are based on patterns of recurrence drawn from retrospective series
only. Combining this data is not possible since most retrospective studies use different follow-up regimens and
imaging techniques. Additionally, reports of asymptomatic recurrences diagnosed during routine oncological
follow-up and results from retrospective studies are contradictory [606-608]. From the Volkmer B, et al.
series of 1,270 RC patients, no differences in OS were observed between asymptomatic and symptomatic
recurrences [607]. Conversely, in the Giannarini, et al. series of 479 patients; those with recurrences detected
during routine follow-up (especially in the lungs) and with secondary urothelial tumours as the site of
recurrence, had a slightly higher survival [606]. Boorjian, et al. included 1,599 RC patients in their series, with
77% symptomatic recurrences. On multivariate analysis, patients who were symptomatic at recurrence had a
60% increased risk of death as compared to asymptomatic patients [608].
However, at this time, no data from prospective trials demonstrating the potential benefit of early
detection of recurrent disease and its impact on OS are available [609]. For details see Section 7.5.4.
8.2
Site of recurrence
8.2.1
Local recurrence
Local recurrence takes place in the soft tissues of the original surgical site or in LNs. Contemporary cystectomy
has a 5–15% probability of pelvic recurrence which usually occurs during the first 24 months, most often
within 6 to 18 months after surgery. However, late recurrences can occur up to five years after RC. Risk factors
described are pathological stage, LNs, positive margins, extent of LND and peri-operative chemotherapy [610].
Patients generally have a poor prognosis after pelvic recurrence. Even with treatment, median
survival ranges from four to eight months following diagnosis. Definitive therapy can prolong survival, but
mostly provides significant palliation of symptoms. Trimodality management generally involves a combination
of chemotherapy, radiation and surgery [609].
8.2.2
Distant recurrence
Distant recurrence is seen in up to 50% of patients treated with RC for MIBC. As with local recurrence,
pathological stage and nodal involvement are risk factors [611]. Systemic recurrence is more common in locally
advanced disease (pT3/4), ranging from 32 to 62%, and in patients with LN involvement (range 52–70%) [612].
The most likely sites for distant recurrence are LNs, lungs, liver and bone. Nearly 90% of distant
recurrences appear within the first three years after RC, mainly in the first two years, although late recurrence
has been described after more than 10 years. Median survival of patients with progressive disease treated
with platinum-based chemotherapy is 9–26 months [613-615]. However, longer survival (28–33% at 5 years)
has been reported in patients with minimal metastatic disease undergoing trimodality management, including
metastasectomy [565, 573].
LIMITED UPDATE MARCH 2021
57
8.2.3
Urothelial recurrences
After RC, the incidence of new urethral tumours was 4.4% (1.3–13.7%). Risk factors for secondary urethral
tumours are urethral malignancy in the prostatic urethra/prostate (in men) and bladder neck (in women).
Orthotopic neobladder was associated with a significant lower risk of urethral tumours after RC (OR: 0.44)
[616].
There is limited data, and agreement, about urethral follow-up, with some authors recommending routine
surveillance with urethral wash and urine cytology and others doubting the need for routine urethral
surveillance. However, there is a significant survival advantage in men with urethral recurrence diagnosed
asymptomatically vs. symptomatically, so follow-up of the male urethra is indicated in patients at risk of urethral
recurrence [609]. Treatment is influenced by local stage and grade of urethral occurrence. In urethral CIS, BCG
instillations have success rates of 83% [617]. In invasive disease, urethrectomy should be performed if the
urethra is the only site of disease; in case of distant disease, systemic chemotherapy is indicated [3].
Upper urinary tract UCs occur in 4–10% of cases and represent the most common sites of late recurrence
(3-year DFS following RC) [618]. Median OS is 10–55 months, and 60–67% of patients die of metastatic
disease [609]. A meta-analysis found that 38% of UTUC recurrence was diagnosed by follow-up investigations,
whereas in the remaining 62%, diagnosis was based on symptoms. When urine cytology was used during
surveillance, the rate of primary detection was 7% vs. 29.6% with UUT imaging. The meta-analysis concluded
that patients with non-invasive cancer are twice as likely to have UTUC as patients with invasive disease [619].
Multifocality increases the risk of recurrence by three-fold, while positive ureteral or urethral margins increase
the risk by seven-fold. Radical nephroureterectomy can prolong survival [620].
8.3
Time schedule for surveillance
Although, based on low level evidence only, some follow-up schedules have been suggested, guided by the
principle that recurrences tend to occur within the first years following initial treatment. A schedule suggested
by the EAU Guidelines Panel includes a CT scan (every 6 months) until the third year, followed by annual
imaging thereafter. Patients with multifocal disease, NMIBC with CIS or positive ureteral margins are at
higher risk of developing UTUC, which can develop late (> 3 years). In those cases, monitoring of the UUT is
mandatory during follow-up. Computed tomography is to be used for imaging of the UUT [619].
The exact time to stop follow-up is not well known and recently a risk-adapted schedule has been proposed,
based on the interaction between recurrence risk and competing health factors that could lead to individualised
recommendations and may increase recurrence detection. Elderly and very low-risk patients (those with NMIBC
or pT0 disease at final cystectomy report) showed a higher competing risk of non-BC mortality when compared
with their level of BC recurrence risk. On the other hand, patients with locally advanced disease or LN
involvement are at a higher risk of recurrence for more than 20 years [621]. However, this model has not been
validated and does not incorporate several risk factors related to non-BC mortality. Furthermore, the prognostic
implications of the different sites of recurrence should be considered. Local and systemic recurrences have a
poor prognosis and early detection of the disease will not influence survival [622]. Despite this, the rationale for
a risk-adapted schedule for BC surveillance appears to be promising and deserves further investigation.
Since data for follow-up strategies are sparse, a number of key questions were included in a
recently held consensus project [8, 9]. Outcomes for all statements for which consensus was achieved are
listed in Section 8.6.
8.4
Follow-up of functional outcomes and complications
Apart from oncological surveillance, patients with a urinary diversion need functional follow-up. Complications
related to urinary diversion are detected in 45% of patients during the first five years of follow-up. This rate
increases over time, and exceeds 54% after 15 years of follow-up. In a single-centre series of 259 male
patients, long-term follow-up after orthotopic bladder substitution (median 121 months [range 60–267]),
showed that excellent long-term functional outcomes can be achieved in high-volume centres with dedicated
teams [623]. A smaller multi-centre series including women only (n = 102) showed complication rates between
5–12% after orthotopic neobladder (median follow up of 24 months [range 1.5–100 months]). Both early (5%)
and late (12%) complications related to the urinary diversion [624].
The functional complications are diverse and include: vitamin B12 deficiency, metabolic acidosis, worsening of
renal function, urinary infections, urolithiasis, stenosis of uretero-intestinal anastomosis, stoma complications
in patients with ileal conduit, neobladder continence problems, and emptying dysfunction [609]. Functional
complications are especially common in women: approximately two-thirds need to catheterise their
neobladder, while almost 45% do not void spontaneously at all [598]. There seems to be a correlation between
58
LIMITED UPDATE MARCH 2021
voiding patterns and nerve preservation; in 66 women bilateral preservation of autonomic nerves decreased the
need for catheterisation to between 3.4–18.7% (CI: 95%) [624].
Recently a 21% increased risk of fractures was also described as compared to no RC due to chronic metabolic
acidosis and subsequent long-term bone loss [622].
Since low vitamin B12 levels have been reported in 17% of patients with bowel diversion, in case of
cystectomy and bowel diversion, vitamin B12 levels should be measured annually [8, 9, 378].
8.5
Summary of evidence and recommendations for specific recurrence sites
Site of recurrence
Local recurrence
Distant recurrence
Upper urinary tract
recurrence
Secondary urethral
tumour
8.6
Summary of evidence
Poor prognosis.
Treatment should be
individualised depending on
the local extent of tumour.
Poor prognosis.
Recommendation
Offer radiotherapy, chemotherapy
and possibly surgery as options
for treatment, either alone or in
combination.
Offer chemotherapy as the first
option, and consider metastasectomy
or radiotherapy in case of unique
metastasis site.
See EAU Guidelines on Upper Urinary
Tract Urothelial Carcinomas.
Risk factors are multifocal
disease (NMIBC/CIS or
positive ureteral margins).
Staging and treatment should See EAU Guidelines on Primary
Urethral Carcinoma.
be done as for primary
urethral tumour.
Strength rating
Strong
Strong
Strong
Strong
EAU-ESMO consensus statements on the management of advanced- and variant
bladder cancer [8, 9]*
Consensus statement
After radical cystectomy with curative intent, regular follow-up is needed.
After radical cystectomy with curative intent, follow-up for the detection of second cancers in the urothelium
is recommended.
After radical cystectomy with curative intent, follow-up of the urethra with cytology and/or cystoscopy is
recommended in selected patients (e.g., multifocality, carcinoma in situ and tumour in the prostatic urethra).
After trimodality treatment with curative intent, follow-up for the detection of relapse is recommended every
3–4 mos initially; then after 3 yrs, every 6 mos in the majority of patients.
After trimodality treatment with curative intent, regular follow-up for the detection of relapse is needed in the
majority of patients.
After trimodality treatment with curative intent, follow-up imaging to assess distant recurrence or recurrence
outside the bladder is needed.
After trimodality treatment with curative intent, assessment of the urothelium to detect recurrence is
recommended every 6 mos in the majority of patients.
After trimodality treatment with curative intent, in addition to a CT scan, other investigations of the bladder are
recommended.
In patients with a partial or complete response after chemotherapy for metastatic urothelial cancer, regular
follow-up is needed. Imaging studies may be done according to signs/symptoms.
To detect relapse (outside the bladder) after trimodality treatment with curative intent, CT of the thorax and
abdomen is recommended as the imaging method for follow-up in the majority of patients.
To detect relapse (outside the bladder) after trimodality treatment with curative intent, routine imaging with CT
of the thorax and abdomen should be stopped after 5 yrs in the majority of patients.
In patients treated with radical cystectomy with curative intent and who have a neobladder, management of
acid bases household includes regular measurements of pH and sodium bicarbonate substitution according
to the measured value.
To detect relapse after radical cystectomy with curative intent, routine imaging with CT of the thorax and
abdomen should be stopped after 5 yrs in the majority of patients.
LIMITED UPDATE MARCH 2021
59
To detect relapse after radical cystectomy with curative intent, a CT of the thorax and abdomen is
recommended as the imaging method for follow-up in the majority of patients.
Levels of LDH and CEA are not essential in the follow-up of patients with urothelial cancer to detect
recurrence.
Vitamin B12 levels have to be measured annually in the follow-up of patients treated with radical cystectomy
and bowel diversion with curative intent.
*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed
(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).
CEA = carcinoembryonic antigen; CT = computed tomography; LDH = lactate dehydrogenase; mos = months;
yrs = years.
9.
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CONFLICT OF INTEREST
All members of the Muscle-invasive and Metastatic Bladder Cancer Guidelines Working Group have provided
disclosure statements of all relationships that they have that might be perceived as a potential source of
a conflict of interest. This information is publicly accessible through the European Association of Urology
website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/?type=panel.
This guidelines document was developed with the financial support of the European Association of
Urology. No external sources of funding and support have been involved. The EAU is a non-profit organization
and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other
reimbursements have been provided.
11.
CITATION INFORMATION
The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the
citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location,
or an ISBN number may vary.
The compilation of the complete Guidelines should be referenced as:
EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4.
If a publisher and/or location is required, include:
EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/
References to individual guidelines should be structured in the following way:
Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.
94
LIMITED UPDATE MARCH 2021
EAU Guidelines on
Upper Urinary
Tract Urothelial
Carcinoma
M. Rouprêt, M. Babjuk (Chair), M. Burger (Vice-chair),
E. Compérat, N.C. Cowan, P. Gontero, F. Liedberg,
A. Masson-Lecomte, A.H. Mostafid, J. Palou,
B.W.G. van Rhijn, S.F. Shariat, R. Sylvester
Guidelines Associates: O. Capoun, D. Cohen,
J.L. Dominguez-Escrig, T. Seisen, V. Soukup
© European Association of Urology 2021
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION
1.1
Aim and scope
1.2
Panel composition
1.3
Available publications
1.4
Publication history & summary of changes
1.4.1
Summary of changes
4
4
4
4
4
4
2.
5
5
6
METHODS
2.1
Data identification
2.2
Review
3.
EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY
3.1
Epidemiology
3.2
Risk factors 3.3
Histology and classification
3.3.1
Histological types
3.4
Summary of evidence and recommendations for epidemiology, aetiology and pathology
6
6
7
8
8
8
4.
8
8
9
9
9
STAGING AND CLASSIFICATION SYSTEMS
4.1
Classification
4.2
Tumour Node Metastasis staging
4.3
Tumour grade
4.4
Future developments
5.
DIAGNOSIS
5.1
Symptoms
5.2
Imaging
5.2.1
Computed tomography urography
5.2.2
Magnetic resonance urography
5.3
Cystoscopy
5.4
Cytology
5.5
Diagnostic ureteroscopy
5.6
Distant metastases
5.6.1
18F-Fluorodeoxglucose positron emission tomography/computed tomography
5.7
Summary of evidence and guidelines for the diagnosis of UTUC
9
9
9
9
10
10
10
10
10
10
11
6.
11
11
11
11
11
11
11
11
12
12
12
12
12
12
12
12
12
12
12
13
14
14
PROGNOSIS
6.1
Prognostic factors
6.1.1
Patient-related factors
6.1.1.1
Age and gender
6.1.1.2
Ethnicity
6.1.1.3
Tobacco consumption
6.1.1.4
Surgical delay
6.1.1.5
Other factors
6.1.2
Tumour-related factors
6.1.2.1
Tumour stage and grade
6.1.2.2
Tumour location, multifocality, size and hydronephrosis
6.1.2.3
Variant histology
6.1.2.4
Lymph node involvement
6.1.2.5
Lymphovascular invasion
6.1.2.6
Surgical margins
6.1.2.7
Other pathological factors
6.1.3
Molecular markers
6.2
Risk stratification for clinical decision making
6.2.1
Low- versus high-risk UTUC
6.2.2
Peri-operative predictive tools for high-risk disease
6.3
Bladder recurrence
6.4
Summary of evidence and guidelines for the prognosis of UTUC
2
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
7.
DISEASE MANAGEMENT
7.1
Localised non-metastatic disease
7.1.1
Kidney-sparing surgery
7.1.1.1
Ureteroscopy
7.1.1.2
Percutaneous access
7.1.1.3
Ureteral resection
7.1.1.4
Upper urinary tract instillation of topical agents
7.1.1.5
Guidelines for kidney-sparing management of UTUC
7.1.2
Management of high-risk non-metastatic UTUC
7.1.2.1
Surgical approach
7.1.2.1.1
Open radical nephroureterectomy
7.1.2.1.2
Minimal invasive radical nephroureterectomy
7.1.2.1.3
Management of bladder cuff
7.1.2.1.4
Lymph node dissection
7.1.3
Peri-operative chemotherapy
7.1.3.1
Neoadjuvant chemotherapy
7.1.3.2
Adjuvant chemotherapy 7.1.4
Adjuvant radiotherapy after radical nephroureterectomy
7.1.5
Post-operative bladder instillation
7.1.6Summary of evidence and guidelines for the management of high-risk nonmetastatic UTUC
7.2
Metastatic disease
7.2.1
Radical nephroureterectomy
7.2.2
Metastasectomy
7.2.3
Systemic treatments
7.2.3.1
First-line setting
7.2.3.2
Second-line setting
7.2.4
Summary of evidence and guidelines for the treatment of metastatic UTUC
14
14
14
14
14
15
15
15
15
15
15
15
16
16
16
16
16
16
17
17
20
20
20
20
20
20
21
8.
FOLLOW-UP
8.1
Summary of evidence and guidelines for the follow-up of UTUC
22
22
9.
REFERENCES
23
10.
CONFLICT OF INTEREST
38
11.
CITATION INFORMATION
38
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
3
1.
INTRODUCTION
1.1
Aim and scope
The European Association of Urology (EAU) Non-muscle-invasive Bladder Cancer (NMIBC) Guidelines
Panel has compiled these clinical guidelines to provide urologists with evidence-based information and
recommendations for the management of upper urinary tract urothelial carcinoma (UTUC). Separate EAU
guidelines documents are available addressing non-muscle-invasive bladder cancer [1], muscle-invasive and
metastatic bladder cancer (MIBC) [2], and primary urethral carcinoma [3].
It must be emphasised that clinical guidelines present the best evidence available to the experts
but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.
1.2
Panel composition
The European Association of Urology (EAU) Guidelines Panel on NMIBC consists of an international
multidisciplinary group of clinicians, including urologists, uro-oncologists, a radiologist, a pathologist and
a statistician. Members of this panel have been selected based on their expertise and to represent the
professionals treating patients suspected of harbouring urothelial carcinoma (UC). All experts involved in the
production of this document have submitted potential conflict of interest statements, which can be viewed on
the EAU website Uroweb: https://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/.
1.3
Available publications
A quick reference document (Pocket guidelines) is available in print and as an app for iOS and Android
devices, presenting the main findings of the UTUC Guidelines. These are abridged versions which may require
consultation together with the full text version. Several scientific publications are available as are a number of
translations of all versions of the EAU UTUC Guidelines, the most recent scientific summary was published in
2020 [4]. All documents are accessible through the EAU website Uroweb: https://uroweb.org/guideline/upperurinary-tract-urothelial-cell-carcinoma/.
1.4
Publication history & summary of changes
The first EAU Guidelines on UTUC were published in 2011. This 2021 publication presents a substantial update
of the 2020 version.
1.4.1
Summary of changes
The literature for the complete document has been assessed and updated, whenever relevant. Conclusions
and recommendations have been rephrased and added to throughout the current document.
Key changes for the 2021 print:
•
Chapter 5 – Diagnosis, new section 5.3 – 18F-Fluorodeoxglucose positron emission tomography/
computed tomography (FDT-PET/CT) was added resulting in a change of a recommendation.
5.7 Summary of evidence and guidelines for the diagnosis of UTUC
Recommendation
Magnetic resonance urography or FDG-PET/CT may be used when CT is contraindicated.
•
Strength rating
Weak
Chapter 6 – Prognosis, additional information has been addeded and this section was restructured,
resulting in changes to Figures 6.1 and 6.2 and the Summary of evidence. New sections 6.2.2 – Perioperative predictive tools for high risk disease and 6.3 – Bladder recurrence were added.
6.4 Summary of evidence and guidelines for the prognosis of UTUC
Summary of evidence
Models are available to predict non-organ confined disease and altered prognosis after RNU.
Patient, tumour and treatment-related factors impact risk of bladder recurrence.
4
LE
3
3
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
•
Chapter 7 – Treatment, Sections 7.1.2 – Management of high-risk non-metastatic UTUC and 7.1.3.3 –
Induction chemotherapy were added. Section 7.1.5 – Post-operative bladder instillation was expanded,
resulting in a changed recommendation.
7.1.6Summary of evidence and guidelines for the management of high-risk non-metastatic UTUC
Summary of evidence
Post-operative chemotherapy improves disease-free survival.
Recommendation
Offer post-operative systemic platinum-based chemotherapy to patients with
muscle-invasive UTUC.
•
LE
1b
Strength rating
Strong
Section 7.2 – Metastatic disease, systemic treatments, considerable new data has been added in both
the first-line and second-line setting, not resulting in a change to the recommendations. A change was
made to Figure 7.2 – Surgical treatment according to location and status, to include post-operative
chemotherapy as an option for high-risk tumours.
2.
METHODS
2.1
Data identification
Standard procedure for EAU Guidelines includes an annual assessment of newly published literature in the
field to guide future updates. For the 2021 UTUC Guidelines, new and relevant evidence has been identified,
collated and appraised through a structured assessment of the literature. The search was restricted to articles
published between May 30th 2019 and May 29th 2020. Databases searched included Pubmed, Ovid, EMBASE
and both the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
After deduplication, a total of 614 unique records were identified, retrieved and screened for relevance.
Excluded from the search were basic research studies, case series, reports and editorial comments.
Only articles published in the English language, addressing adults were included. The publications identified
were mainly retrospective, including some large multicentre studies. Owing to the scarcity of randomised data,
articles were selected based on the following criteria: evolution of concepts, intermediate- and long-term clinical
outcomes, study quality, and relevance. Older studies were only included if they were historically relevant.
A total of 35 new publications were added to the 2021 UTUC Guidelines print. A detailed search strategy is
available online: https://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/?type=appendicespublications.
For Chapters 3-6 (Epidemiology, Aetiology and Pathology, Staging and Classification systems, Diagnosis and
Prognosis) references used in this text are assessed according to their level of evidence (LE) based on the 2009
Oxford Centre for Evidence-Based Medicine (CEBM) Levels of Evidence [5]. For the Disease Management and
Follow-up chapters (Chapters 7 and 8) a system modified from the 2009 CEBM LEs has been used [5]. For
each recommendation within the guidelines there is an accompanying online strength rating form, based on a
modified GRADE methodology [6, 7]. These forms address a number of key elements, namely:
1.
2.
3.
4.
5.
6.
he overall quality of the evidence which exists for the commendation references used in
T
this text are graded according to the CEBM Levels of Evidence (see above) [5];
the magnitude of the effect (individual or combined effects);
the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
the balance between desirable and undesirable outcomes;
the impact of patient values and preferences on the intervention;
the certainty of those patient values and preferences.
These key elements are the basis which panels use to define the strength rating of each recommendation.
The strength of each recommendation is represented by the words ‘strong’ or ‘weak’. The strength of each
recommendation is determined by the balance between desirable and undesirable consequences of alternative
management strategies, the quality of the evidence (including certainty of estimates), and nature and variability
of patient values and preferences [8].
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
5
Additional information can be found in the general Methodology section of this print, and online at
the EAU website; https://uroweb.org/guidelines/policies-and-methodological-documents/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
2.2
Review
The 2021 UTUC Guidelines have been peer-reviewed prior to publication.
3.
EPIDEMIOLOGY, AETIOLOGY AND
PATHOLOGY
3.1
Epidemiology
Urothelial carcinomas (UCs) are the sixth most common tumours in developed countries [9]. They can be
located in the lower (bladder and urethra) and/or the upper (pyelocaliceal cavities and ureter) urinary tract.
Bladder tumours account for 90–95% of UCs and are the most common urinary tract malignancy [1]. Upper
urinary tract UCs are uncommon and account for only 5–10% of UCs [9] with an estimated annual incidence
in Western countries of almost two cases per 100,000 inhabitants. This rate has risen in the past few decades
as a result of improved detection and improved bladder cancer survival [10]. Pyelocaliceal tumours are
approximately twice as common as ureteral tumours and multifocal tumours are found in approximately
10–20% of cases [11]. The presence of concomitant carcinoma in situ of the upper tract is between 11 and
36% [10]. In 17% of cases, concurrent bladder cancer is present [12] whilst a prior history of bladder cancer
is found in 41% of American men but in only 4% of Chinese men [13]. This, along with genetic and epigenetic
factors, may explain why Asian patients present with more advanced and higher grade disease compared to
other ethnic groups [10]. Following treatment, recurrence in the bladder occurs in 22–47% of UTUC patients,
depending on initial tumour grade [14] compared with 2–5% in the contralateral upper tract [15].
With regards to UTUC occurring following an initial diagnosis of bladder cancer, a series of 82
patients treated with bacillus Calmette-Guérin (BCG) who had regular upper tract imaging between years 1
and 3 showed a 13% incidence of UTUC, all of which were asymptomatic [16], whilst in another series of
307 patients without routine upper tract imaging the incidence was 25% [17]. A multicentre cohort study
(n = 402) with a 50 month follow-up has demonstrated a UTUC incidence of 7.5% in NMIBC receiving BCG
with predictors being intravesical recurrence and non-papillary tumour at transurethral resection of the bladder
[18]. Following radical cystectomy for MIBC, 3–5% of patients develop a metachronous UTUC [19, 20].
Approximately two-thirds of patients who present with UTUCs have invasive disease at diagnosis
compared to 15–25% of patients presenting with muscle-invasive bladder tumours [21]. This is probably due
to the absence of muscularis propria layer in the upper tract, so tumours are more likely to upstage at an earlier
time-point. Approximately 9% of patients present with metastasis [10, 22]. Upper urinary tract UCs have a peak
incidence in individuals aged 70–90 years and are twice as common in men [23].
Upper tract UC and bladder cancer exhibit significant differences in the prevalence of common
genomic alterations. In individual patients with a history of both tumours, bladder cancer and UTUC were
always clonally related. Genomic characterisation of UTUC provides information regarding the risk of bladder
recurrence and can identify tumours associated with Lynch syndrome [24].
The Amsterdam criteria are a set of diagnostic criteria used by doctors to help identify families
which are likely to have Lynch syndrome [25]. In Lynch-related UTUC, immunohistochemistry analysis showed
loss of protein expression corresponding to the disease-predisposing MMR (mismatch repair) gene mutation
in 98% of the samples (46% were microsatellite instable and 54% microsatellite stable) [26]. The majority of
tumours develop in MSH2 mutation carriers [26]. Patients identified at high risk for Lynch syndrome should
undergo DNA sequencing for patient and family counselling [27, 28]. Germline mutations in DNA MMR genes
defining Lynch syndrome, are found in 9% of patients with UTUC compared to 1% of patients with bladder
cancer, linking UTUC to Lynch syndrome [29]. A study of 115 consecutive UTUC patients, reported that 13.9%
screened positive for potential Lynch syndrome and 5.2% had confirmed Lynch syndrome [30]. This is one of
the highest rates of undiagnosed genetic disease in urological cancers, which justifies screening of all patients
under 65 presenting with UTUC and those with a family history of UTUC (see Figure 3.1) [31, 32].
6
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
Figure 3.1: S
election of patients with UTUC for Lynch syndrome screening during the first medical
Interview
UTUC
Systemac screening during medical interview
Suspicion of hereditary UTUC
- Age < 65 yr
- Personal history of Lynch-spectrum cancer
or
- First-degree relave < 50 yr with Lynch-spectrum cancer
or
- Two first-degree relaves with Lynch-spectrum cancer
Sporadic UTUC
Germ-line DNA sequencing: mutaon (5-9%)
- Clinical evaluaon for other Lynch-related cancer:
colorectal, gastrointesnal, endometrial ovarian and skin
- Close monitoring and follow-up
- Familial genec counselling
UTUC = upper urinary tract urothelial carcinoma.
3.2
Risk factors
A number of environmental factors have been implicated in the development of UTUC [11, 33]. Published
evidence in support of a causative role for these factors is not strong, with the exception of smoking and
aristolochic acid. Tobacco exposure increases the relative risk of developing UTUC from 2.5 to 7.0 [34-36].
A large population-based study assessing familial clustering in relatives of UC patients, including 229,251
relatives of case subjects and 1197,552 relatives of matched control subjects, has demonstrated genetic
or environmental roots independent of smoking-related behaviours. With more than 9% of the cohort being
UTUC patients, clustering was not seen in upper tract disease. This may suggest that the familial clustering of
urothelial cancer is specific to lower tract cancers [37].
In Taiwan, the presence of arsenic in drinking water has been tentatively linked to UTUC [38].
Aristolochic acid, a nitrophenanthrene carboxylic acid produced by Aristolochia plants, exerts multiple
effects on the urinary system. Aristolochic acid irreversibly injures renal proximal tubules resulting in chronic
tubulointerstitial disease, while the mutagenic properties of this chemical carcinogen lead predominantly
to UTUC [39-41]. Aristolochic acid has been linked to bladder cancer, renal cell carcinoma, hepatocellular
carcinoma and intrahepatic cholangiocarcinoma [42]. Two routes of exposure to aristolochic acid are known:
(i) environmental contamination of agricultural products by Aristolochia plants, as reported for Balkan endemic
nephropathy [43]; and (ii) ingestion of Aristolochia-based herbal remedies [44, 45]. Aristolochia herbs are
used worldwide, especially in China and Taiwan [41]. Following bioactivation, aristolochic acid reacts with
genomic DNA to form aristolactam-deoxyadenosine adducts [46]; these lesions persist for decades in target
tissues, serving as robust biomarkers of exposure [9]. These adducts generate a unique mutational spectrum,
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
7
characterised by A>T transversions located predominately on the non-transcribed strand of DNA [42, 47].
However, fewer than 10% of individuals exposed to aristolochic acid develop UTUC [40].
Two retrospective series found that aristolochic acid-associated UTUC is more common in females
[48, 49]. However, females with aristolochic acid UTUC have a better prognosis than their male counterparts.
Alcohol consumption is associated with development of UTUC. A large case-control study (1,569 cases
and 506,797 controls) has evidenced a significantly higher risk of UTUC in ever-drinkers compared to neverdrinkers (OR: 1.23; 95% CI: 1.08–1.40, p = 0.001). Compared to never-drinkers, the risk threshold for UTUC
was > 15 g of alcohol/day. A dose-response was observed [50].
Differences in the ability to counteract carcinogens may contribute to host susceptibility to UTUC. Some
genetic polymorphisms are associated with an increased risk of cancer or faster disease progression that
introduces variability in the inter-individual susceptibility to the risk factors previously mentioned. Upper urinary
tract UCs may share some risk factors and described molecular pathways with bladder UC [24]. So far, two
UTUC-specific polymorphisms have been reported [51].
A history of bladder cancer is associated with higher risk of UTUCs (see Section 3.1). Patients who
undergo ureteral stenting prior to radical cystectomy are at higher risk for upper tract recurrence [52].
3.3
Histology and classification
3.3.1
Histological types
Upper urinary tract tumours are almost always urothelial carcinomas and pure non-urothelial histology is rare
[53, 54]. However, variants are present in approximately 25% of UTUCs [55, 56]. Pure squamous cell carcinoma
of the urinary tract is often assumed to be associated with chronic inflammatory diseases and infections
arising from urolithiasis [57, 58]. Urothelial carcinoma with divergent squamous differentiation is present in
approximately 15% of cases [57]. Keratinising squamous metaplasia of urothelium is a risk factor for squamous
cell cancers and therefore mandates surveillance. Upper urinary tract UCs with variant histology are highgrade and have a worse prognosis compared with pure UC [56, 59, 60]. Other variants, although rare, include
sarcomatoid and UCs with inverted growth [60].
However, collecting duct carcinomas, which may seem to share similar characteristics with UCs,
display a unique transcriptomic signature similar to renal cancer, with a putative cell of origin in the distal
convoluted tubules. Therefore, collecting duct carcinomas are considered as renal tumours [61].
3.4
Summary of evidence and recommendations for epidemiology, aetiology and
pathology
Summary of evidence
Aristolochic acid and smoking exposure increases the risk for UTUC.
Patients with Lynch syndrome are at risk for UTUC.
LE
2a
3
Recommendations
Strength rating
Evaluate patient and family history based on the Amsterdam criteria to identify patients with Weak
upper tract urothelial carcinoma.
Evaluate patient exposure to smoking and aristolochic acid.
Weak
4.
STAGING AND CLASSIFICATION SYSTEMS
4.1
Classification
The classification and morphology of UTUC and bladder carcinoma are similar [1]. However, it is not possible
to distinguish between non-invasive papillary tumours (papillary urothelial tumours of low malignant potential
and low- and high-grade papillary UC) [62], flat lesions (carcinoma in situ [CIS]), and invasive carcinoma. This
is in most cases due to the size of biopsy specimens that do not include deep tissue required for pathological
staging. With UTUC, histological grade is a surrogate for pathological stage, as it strongly correlates [63].
8
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
4.2
Tumour Node Metastasis staging
The tumour, node, metastasis (TNM) classification is shown in Table 1 [64]. The regional lymph nodes (LNs)
are the hilar and retroperitoneal nodes and, for the mid- and distal ureter, the pelvic nodes. Laterality does not
affect N classification.
4.3
Tumour grade
In 2004, the WHO and the International Society of Urological Pathology published a new histological
classification of UCs which provides a different patient stratification between individual categories compared
to the older 1973 WHO classification [65, 66]. In 2016, an update of the 2004 WHO grading classification was
published without major changes [65]. These guidelines are still based on both the 1973 and 2004/2016 WHO
classifications since most published data use the 1973 classification [62].
4.4
Future developments
A number of studies focussing on molecular classification have been able to demonstrate genetically different
groups of UTUC by evaluating DNA, RNA and protein expression. Four molecular subtypes with distinct
clinical behaviours were identified, but, as yet, it is unclear whether these subtypes will respond differently to
treatment [67].
Table 1: TNM classification 2017 for upper tract urothelial cell carcinoma [64]
T - Primary tumour
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
Ta
Non-invasive papillary carcinoma
Tis
Carcinoma in situ
T1
Tumour invades subepithelial connective tissue
T2
Tumour invades muscularis
T3
(Renal pelvis) Tumour invades beyond muscularis into peripelvic fat or renal parenchyma
(Ureter) Tumour invades beyond muscularis into periureteric fat
T4
Tumour invades adjacent organs or through the kidney into perinephric fat
N - Regional lymph nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single lymph node 2 cm or less in the greatest dimension
N2
Metastasis in a single lymph node more than 2 cm, or multiple lymph nodes
M - Distant metastasis
M0
No distant metastasis
M1
Distant metastasis
TNM = Tumour, Node, Metastasis (classification).
5.
DIAGNOSIS
5.1
Symptoms
The diagnosis of UTUC may be incidental or symptom related. The most common symptom is visible or
nonvisible haematuria (70–80%) [68, 69]. Flank pain, due to clot or tumour tissue obstruction or less often due
to local growth, occurs in approximately 20–32% of cases [69, 70]. Systemic symptoms (including anorexia,
weight loss, malaise, fatigue, fever, night sweats, or cough) associated with UTUC should prompt evaluation for
metastases associated with a worse prognosis [70].
5.2
Imaging
5.2.1
Computed tomography urography
Computed tomography (CT) urography has the highest diagnostic accuracy of the available imaging techniques
[71]. A meta-analysis of 13 studies comprising 1,233 patients revealed a pooled sensitivity of CT urography for
UTUC of 92% (CI: 0.85–0.96) and a pooled specificity of 95% (CI: 0.88–0.98) [72].
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
9
Rapid acquisition of thin sections allows high-resolution isotropic images that can be viewed in
multiple planes to assist with diagnosis without loss of resolution. Epithelial “flat lesions” without mass effect or
urothelial thickening are generally not visible with CT.
The presence of enlarged LNs is highly predictive of metastases in UTUC [73, 74].
5.2.2
Magnetic resonance urography
Magnetic resonance (MR) urography is indicated in patients who cannot undergo CT urography, usually when
radiation or iodinated contrast media are contraindicated [75]. The sensitivity of MR urography is 75% after
contrast injection for tumours < 2 cm [75]. The use of MR urography with gadolinium-based contrast media
should be limited in patients with severe renal impairment (< 30 mL/min creatinine clearance), due to the risk
of nephrogenic systemic fibrosis. Computed tomography urography is more sensitive and specific for the
diagnosis and staging of UTUC as compared with MR urography [76].
5.3
Cystoscopy
Urethrocystocopy is an integral part of UTUC diagnosis to rule out concomitant bladder cancer [10, 12].
5.4
Cytology
Abnormal cytology may indicate high-grade UTUC when bladder cystoscopy is normal, and in the absence of
CIS in the bladder and prostatic urethra [1, 77, 78]. Cytology is less sensitive for UTUC than bladder tumours
and should be performed selectively for the affected upper tract [79]. In a recent study, barbotage cytology
detected up to 91% of cancers [80]. Barbotage cytology taken from the renal cavities and ureteral lumina is
preferred before application of a contrast agent for retrograde ureteropyelography as it may cause deterioration
of cytological specimens [81]. Retrograde ureteropyelography remains an option to detect UTUCs [71, 82, 83].
The sensitivity of fluorescence in situ hybridisation (FISH) for molecular abnormalities characteristic
of UTUCs is approximately 50% and therefore its use in clinical practice remains unproven [84, 85].
5.5
Diagnostic ureteroscopy
Flexible ureteroscopy (URS) is used to visualise the ureter, renal pelvis and collecting system and for biopsy
of suspicious lesions. Presence, appearance and size of tumour can be determined using URS. In addition,
ureteroscopic biopsies can determine tumour grade in more than 90% of cases with a low false-negative
rate, regardless of sample size [86]. Undergrading may occur following diagnostic biopsy, making intensive
follow-up necessary if kidney-sparing treatment is chosen [87]. Ureteroscopy also facilitates selective ureteral
sampling for cytology in situ [83, 88, 89]. Stage assessment using ureteroscopic biopsy is inaccurate.
Combining ureteroscopic biopsy grade, imaging findings such as hydronephrosis, and urinary
cytology may help in the decision-making process between radical nephroureterectomy (RNU) and kidneysparing therapy [89, 90]. While some studies suggest a higher rate of intravesical recurrence after RNU in
patients who underwent diagnostic URS pre-operatively [91, 92], one study did not [93].
Technical developments in flexible ureteroscopes and the use of novel imaging techniques improve
visualisation and diagnosis of flat lesions [94]. Narrow-band imaging is a promising technique, but results are
preliminary [95]. Optical coherence tomography and confocal laser endomicroscopy (Cellvizio®) have been
used in vivo to evaluate tumour grade and/or for staging purposes, with a promising correlation with definitive
histology in high-grade UTUC [96, 97]. Recommendations for the diagnosis of UTUC are listed in Section 5.6.
5.6
Distant metastases
Prior to any treatment with curative intent, it is essential to rule out distant metastases. Computed tomography
is the diagnostic technique of choice for lung- and abdominal staging for metastases [72].
18F-Fluorodeoxglucose positron emission tomography/computed tomography
5.6.1
A retrospective multi-centre publication on the use of 18F-Fluorodeoxglucose positron emission tomography/
computed tomography (FDG-PET/CT) for the detection of nodal metastasis in 117 surgically-treated UTUC
patients reported a promising sensitivity and specificity of 82% and 84%, respectively. Suspicious LNs on
FDG-PET/CT were associated with worse recurrence-free survival [98]. These results warrant further validation
and comparison to MR and CT.
10
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
5.7
Summary of evidence and guidelines for the diagnosis of UTUC
Summary of evidence
The diagnosis and staging of UTUC is best done with computed tomography urography and URS.
Selective urinary cytology has high sensitivity in high-grade tumours, including carcinoma in situ.
Urethrocystoscopy can detect concomitant bladder cancer.
Recommendations
Perform a urethrocystoscopy to rule out bladder tumour.
Perform a computed tomography (CT) urography for diagnosis and staging.
Use diagnostic ureteroscopy and biopsy if imaging and cytology are not sufficient for the
diagnosis and/or risk-stratification of the tumour.
Magnetic resonance urography or 18F-Fluorodeoxglucose positron emission tomography/
computed tomography may be used when CT is contra-indicated.
6.
PROGNOSIS
6.1
Prognostic factors
LE
2a
3
2a
Strength rating
Strong
Strong
Strong
Weak
Upper urinary tract UCs that invade the muscle wall usually have a very poor prognosis. The 5-year specific
survival is < 50% for pT2/pT3 and < 10% for pT4 UTUC [99-102]. Many prognostic factors have been identifed
and can be used to risk-stratify patients in order to decide on the most appropriate local treatment (radical vs.
conservative) and discuss peri-operative systemic therapy. Factors can be divided into patient-related factors
and tumour-related factors.
6.1.1
Patient-related factors
6.1.1.1
Age and gender
Older age at the time of RNU is independently associated with decreased cancer-specific survival (CSS) [100,
103, 104] (LE: 3). However, even elderly patients can be cured with RNU [105]. Therefore, chronological age alone
should not be a contraindication to RNU [104, 105]. Gender has no impact on prognosis of UTUC [23, 100, 106].
6.1.1.2
Ethnicity
One multicentre study of academic centres did not show any difference in outcomes between races [107],
but U.S. population-based studies have indicated that African-American patients have worse outcomes
than other ethnicities (LE: 3). Whether this is related to access to care or biological and/or patterns of care
remains unknown. Another study has demonstrated differences between Chinese and American patients at
presentation (risk factor, disease characteristics and predictors of adverse oncologic outcomes) [13].
6.1.1.3
Tobacco consumption
Being a smoker at diagnosis increases the risk for disease recurrence and mortality after RNU [108, 109] and
recurrence within the bladder [110] (LE: 3). There is a close relationship between tobacco consumption and
prognosis [111] (LE: 3); smoking cessation improves cancer control [109].
6.1.1.4
Surgical delay
A delay between diagnosis of an invasive tumour and its removal may increase the risk of disease progression.
Once a decision regarding RNU has been made, the procedure should be carried out within twelve weeks,
when possible [112-116] (LE: 3).
6.1.1.5
Other factors
A higher American Society of Anesthesiologists score confers worse CSS after RNU [117] (LE: 3), as does poor
performance status [118]. Obesity and higher body mass index adversely affect cancer-specific outcomes in
patients treated with RNU [119] (LE: 3), with potential differences between races [120]. Several blood-based
biomarkers have been associated with locally advanced disease and cancer-specific mortality such as high
pre-treatment-derived neutrophil-lymphocyte ratio [121-124], low albumin [123, 125], high C-reactive protein
[123] or modified Glasgow score [126], high De Ritis (AST/ALT) ratio [127], altered renal function [123, 128] and
high fibrinogen [123, 129] (LE: 3).
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
11
6.1.2
Tumour-related factors
6.1.2.1
Tumour stage and grade
The main prognostic factors are tumour stage and grade [21, 89, 100, 130, 131].
6.1.2.2
Tumour location, multifocality, size and hydronephrosis
Initial location of the UTUC is a prognostic factor in some studies [132, 133] (LE: 3). After adjustment for the
effect of tumour stage, patients with ureteral and/or multifocal tumours seem to have a worse prognosis than
patients diagnosed with renal pelvic tumours [100, 132-138]. Hydronephrosis is associated with advanced
disease and poor oncological outcome [73, 81, 139]. A large multi-institutional retrospective study including
932 RNUs for non-metastatic UTUC demonstrated that a 2 cm cut-off appears to be most useful in identifying
patients at risk of harbouring ≥ pT2 UTUC [140].
6.1.2.3
Variant histology
Pathological variants are associated with worse cancer-specific and overall survival (OS) [56] (LE: 3). Most
studied variants are micropapillary [59], squamous [141] and carcomatoid [59] which are consistently
associated with locally advanced disease and worse outcome.
6.1.2.4
Lymph node involvement
Patients with nodal metastasis experience very poor survival after surgery [142]. Lymph node density (cut-off
30%) and extranodal extension are powerful predictors of survival outcomes in N+ UTUC [143-145]. Lymph
node dissection (LND) performed at the time of RNU allows for optimal tumour staging, although its curative
role remains controversial [102, 144, 146, 147] (LE: 3).
6.1.2.5
Lymphovascular invasion
Lymphovascular invasion (LVI) is present in approximately 20% of UTUCs and is an independent predictor of
survival [148-150]. Lymphovascular invasion status should be specifically reported in the pathological reports
of all UTUC specimens [148, 151, 152] (LE: 3).
6.1.2.6
Surgical margins
Positive soft tissue surgical margin is associated with a higher disease recurrence after RNU. Pathologists
should look for and report positive margins at the level of ureteral transection, bladder cuff, and around the
tumour [153] (LE: 3).
6.1.2.7
Other pathological factors
Extensive tumour necrosis (> 10% of the tumour area) is an independent prognostic predictor in patients who
undergo RNU [154, 155] (LE: 3). In case neoadjuvant treatment was administered, pathological downstaging is
associated with better OS [156] (LE: 3). The architecture of UTUC is also a strong prognosticator with sessile
growth pattern being associated with worse outcome [157, 158] (LE: 3). Concomitant CIS in organ-confined
UTUC and a history of bladder CIS are associated with a higher risk of recurrence and cancer-specific mortality
[159, 160] (LE: 3). Macroscopic infiltration or invasion of peri-pelvic adipose tissue confers a higher risk of
disease recurrence after RNU compared to microscopic infiltration of renal parenchyma [55, 161].
6.1.3
Molecular markers
Because of the rarity of UTUC, the main limitations of molecular studies are their retrospective design and, for
most studies, small sample size. None of the investigated markers have been validated yet to support their
introduction in daily clinical decision making [100, 162].
6.2
Risk stratification for clinical decision making
6.2.1
Low- versus high-risk UTUC
As tumour stage is difficult to assess clinically in UTUC, it is useful to “risk stratify” UTUC between lowand high risk of progression to identify those patients who are more likely to benefit from kidney-sparing
treatment and those who should be treated radically [163, 164] (see Figure 6.2). The factors to consider for risk
stratification are presented in Figure 6.1.
12
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
Figure 6.1: Risk stratification of non-metastatic UTUC
UTUC
High-risk UTUC**
Low-risk UTUC*
•
•
•
•
•
•
•
•
•
•
•
•
Unifocal disease
Tumour size < 2 cm
Negave for high-grade cytology
Low-grade URS biopsy
No invasive aspect on CT
•
Mulfocal disease
Tumour size ≥ 2 cm
High-grade cytology
High-grade URS biopsy
Local invasion on CT
Hydronephrosis
Previous radical cystectomy for highgrade bladder cancer
Variant histology
CT = computed tomography; URS = ureteroscopy; UTUC = upper urinary tract urothelial carcinoma.
* All these factors need to be present.
**Any of these factors need to be present.
6.2.2
Peri-operative predictive tools for high-risk disease
There are several pre-RNU models aiming at predicting which patient has muscle-invasive/non-organconfined disease [165-168] (LE: 3). Prognostic nomograms based on pre-operative factors and pathological
characteristics are available [102, 168-174]. The main factors included in these models, which may be used
when counselling patients regarding follow-up and administration of peri-operative chemotherapy, are detailed
in Figure 6.2.
Figure 6.2: U
pper urinary tract urothelial cell carcinoma - prognostic factors included in prognostic
models
High-risk UTUC
Prognosc factors
Post-operave
Pre-operave
•
•
•
•
•
•
•
•
Advanced age
Poor social status
Chronic kidney disease
Ureteral tumour locaon
Sessile tumor architecture
Advanced clinical stage
High grade (biopsy, cytology)
Blood based biomarkers
•
•
•
•
•
•
Advanced stage
High grade
Carcinoma in situ
Lymphovascular invasion
Lymph node involvement
Sessile tumour architecture
UTUC = upper tract urothelial carcinoma.
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
13
6.3
Bladder recurrence
A meta-analysis of available data has identified significant predictors of bladder recurrence after RNU [175]
(LE: 3). Three categories of predictors for increased risk of bladder recurrence were identified:
1.
Patient-specific factors such as male gender, previous bladder cancer, smoking and preoperative chronic kidney disease.
2.
Tumour-specific factors such as positive pre-operative urinary cytology, tumour grade,
ureteral location, multifocality, tumour diameter, invasive pT stage, and necrosis [176].
3.
Treatment-specific factors such as laparoscopic approach, extravesical bladder cuff
removal, and positive surgical margins [175].
In addition, the use of diagnostic URS has been associated with a higher risk of developing bladder recurrence
after RNU [91, 92] (LE: 3). Based on low-level evidence only, a single dose of intravesical chemotherapy
after diagnostic/therapeutic ureteroscopy of non-metastatic UTUC has been suggested to lower the rate of
intravesical recurrence, similarly to that after RNU [175].
6.4
Summary of evidence and guidelines for the prognosis of UTUC
Summary of evidence
Important prognostic factors for risk stratification include tumour multifocality, size, stage, grade,
hydronephrosis and variant histology.
Models are available to predict non-organ confined disease and altered prognosis after RNU.
Patient, tumour and treatment-related factors impact risk of bladder recurrence.
Currently, no prognostic biomarkers are validated for clinical use.
Recommendation
Use prognostic factors to risk-stratify patients for therapeutic guidance.
7.
DISEASE MANAGEMENT
7.1
Localised non-metastatic disease
LE
3
3
3
3
Strength rating
Weak
7.1.1
Kidney-sparing surgery
Kidney-sparing surgery for low-risk UTUC reduces the morbidity associated with radical surgery (e.g., loss
of kidney function), without compromising oncological outcomes [177]. In low-risk cancers, it is the preferred
approach as survival is similar to that after RNU [177]. This option should therefore be discussed in all lowrisk cases, irrespective of the status of the contralateral kidney. In addition, it can also be considered in select
patients with a serious renal insufficiency or having a solitary kidney (LE: 3). Recommendations for kidneysparing management of UTUC are listed in Section 7.1.1.5.
7.1.1.1
Ureteroscopy
Endoscopic ablation should be considered in patients with clinically low-risk cancer [178, 179]. A flexible
ureteroscope is useful in the management of pelvicalyceal tumours [180]. The patient should be informed of
the need and be willing to comply with an early second-look URS [181] and stringent surveillance; complete
tumour resection or destruction is necessary [181]. Nevertheless, a risk of disease progression remains with
endoscopic management due to the suboptimal performance of imaging and biopsy for risk stratification and
tumour biology [182].
7.1.1.2
Percutaneous access
Percutaneous management can be considered for low-risk UTUC in the renal pelvis [179, 183] (LE: 3). This may
also be offered for low-risk tumours in the lower caliceal system that are inaccessible or difficult to manage by
flexible URS. However, this approach is being used less due to the availability of improved endoscopic tools
such as distal-tip deflection of recent ureteroscopes [179, 183]. Moreover, a risk of tumour seeding remains
with a percutaneous access [183].
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UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
7.1.1.3
Ureteral resection
Segmental ureteral resection with wide margins provides adequate pathological specimens for staging and
grading while preserving the ipsilateral kidney. Lymphadenectomy can also be performed during segmental
ureteral resection [177]. Segmental resection of the proximal two-thirds of ureter is associated with higher
failure rates than for the distal ureter [184, 185] (LE: 3).
Distal ureterectomy with ureteroneocystostomy are indicated for low-risk tumours in the distal ureter
that cannot be removed completely endoscopically and for high-risk tumours when kidney-sparing surgery
for renal function preservation is desired (in case of an imperative indication) [101, 184, 185] (LE: 3). A total
ureterectomy with an ileal-ureteral substitution is technically feasible, but only in selected cases when a renalsparing procedure is mandatory and the tumour is low risk [186].
7.1.1.4
Upper urinary tract instillation of topical agents
The antegrade instillation of BCG or mitomycin C in the upper urinary tract via percutaneous nephrostomy
after complete tumour eradication has been studied for CIS after kidney-sparing management [160, 187]
(LE: 3). Retrograde instillation through a single J open-ended ureteric stent is also used. Both the antegrade
and retrograde approach can be dangerous due to possible ureteric obstruction and consecutive pyelovenous
influx during instillation/perfusion. The reflux obtained from a double-J stent has been used but this approach
is suboptimal because the drug often does not reach the renal pelvis [188-191].
A systematic review and meta-analysis assessing the oncologic outcomes of patients with papillary
UTUC or CIS of the upper tract treated with kidney-sparing surgery and adjuvant endocavitary treatment
analysed the effect of adjuvant therapies (i.e., chemotherapeutic agents and/or immunotherapy with BCG)
after kidney-sparing surgery for papillary non-invasive (Ta-T1) UTUCs and of adjuvant BCG for the treatment
of upper tract CIS, finding no difference between the method of drug administration (antegrade vs. retrograde
vs. combined approach) in terms of recurrence, progression, CSS, and OS. Furthermore, the recurrence
rates following adjuvant instillations are comparable to those reported in the literature in untreated patients,
questioning their efficacy [192]. The analyses were based on retrospective small studies suffering from
publication and reporting bias.
A single-arm phase III RCT showed that the use of mitomycin-containing reverse thermal gel
(UGN-101) instillations via retrograde catheter to the renal pelvis and calyces was associated with a complete
response rate in a total of 42 patients (59%) in biopsy-proven low-grade UTUC measuring less than 15 mm.
The median follow-up of patients with a complete response was 11 months. The most frequently reported
all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%),
haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). A total of 19 (27%) of 71 patients had
drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment
[193].
7.1.1.5
Guidelines for kidney-sparing management of UTUC
Recommendations
Offer kidney-sparing management as primary treatment option to patients with low-risk
tumours.
Offer kidney-sparing management (distal ureterectomy) to patients with high-risk tumours
limited to the distal ureter.
Offer kidney-sparing management to patients with solitary kidney and/or impaired renal
function, providing that it will not compromise survival. This decision will have to be made
on a case-by-case basis in consultation with the patient.
Strength rating
Strong
Weak
Strong
7.1.2
Management of high-risk non-metastatic UTUC
7.1.2.1
Surgical approach
7.1.2.1.1 Open radical nephroureterectomy
Open RNU with bladder cuff excision is the standard treatment of high-risk UTUC, regardless of tumour
location [21] (LE: 3). Radical nephroureterectomy must be performed according to oncological principles
preventing tumour seeding [21]. Section 7.1.6 lists the recommendations for RNU.
7.1.2.1.2 Minimal invasive radical nephroureterectomy
Retroperitoneal metastatic dissemination and metastasis along the trocar pathway following manipulation
of large tumours in a pneumoperitoneal environment have been reported in few cases [194, 195]. Several
precautions may lower the risk of tumour spillage:
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
15
1.
2.
3.
4.
5.
avoid entering the urinary tract;
avoid direct contact between instruments and the tumour;
perform the procedure in a closed system. Avoid morcellation of the tumour and use an
endobag for tumour extraction;
the kidney and ureter must be removed en bloc with the bladder cuff;
Invasive or large (T3/T4 and/or N+/M+) tumours are contraindications for minimal-invasive
RNU as the outcome is worse compared to an open approach [196, 197].
Laparoscopic RNU is safe in experienced hands when adhering to strict oncological principles. There is a
tendency towards equivalent oncological outcomes after laparoscopic or open RNU [195, 198-201] (LE:
3). One prospective randomised study has shown that laparoscopic RNU is inferior to open RNU for nonorgan confined UTUC. However, this was a small trial (n = 80), which was likely underpowered [197] (LE: 2).
Oncological outcomes after RNU have not changed significantly over the past three decades despite staging
and surgical refinements [202] (LE: 3). A robot-assisted laparoscopic approach can be considered with recent
data suggesting oncologic equivalence with the other approaches [203-205].
7.1.2.1.3 Management of bladder cuff
Resection of the distal ureter and its orifice is performed because there is a considerable risk of tumour
recurrence in this area and in the bladder [175, 184, 206-208]. Several techniques have been considered to
simplify distal ureter resection, including the pluck technique, stripping, transurethral resection of the intramural
ureter, and intussusception. None of these techniques has convincingly been shown to be equal to complete
bladder cuff excision [15, 206, 207] (LE: 3).
7.1.2.1.4 Lymph node dissection
The use of a LND template is likely to have a greater impact on patient survival than the number of removed
LNs [209]. Template-based and completeness of LND improves CSS in patients with muscle-invasive disease
and reduces the risk of local recurrence [210]. Even in clinically [211] and pathologically [212] node-negative
patients, LND improves survival. The risk of LN metastasis increases with advancing tumour stage [146].
Lymph node dissection appears to be unnecessary in cases of TaT1 UTUC because of the low risk of LN
metastasis [213-216], however, tumour staging is inaccurate pre-operatively; therefore a template-based LND
should be offered to all patients who are scheduled for RNU. The templates for LND have been described [210,
217, 218].
7.1.3
Peri-operative chemotherapy
7.1.3.1
Neoadjuvant chemotherapy
In patients treated prior to losing their renal reserve several retrospective studies evaluating the role of
neoadjuvant chemotherapy have shown promising pathological downstaging and complete response rates
[156, 219-222]. In addition, neoadjuvant chemotherapy has been shown to result in lower disease recurrence
and mortality rates compared to RNU alone without compromising the use of definitive surgical treatment
[221, 223-225]. No RCTs have been published yet but prospective data from a phase II trial showed that the
use of neoadjuvant chemotherapy was associated with a 14% pathological complete response rate for highgrade UTUC [226]. In addition, final pathological stage was ≤ ypT1 in more than 60% of included patients with
acceptable toxicity profile.
7.1.3.2
Adjuvant chemotherapy
A phase III prospective randomised trial (n = 261) evaluating the benefit of adjuvant gemcitabine-platinum
combination chemotherapy initiated within 90 days after RNU vs. surveillance has reported a significant
improvement in disease-free survival in patients with pT2–pT4, N (any) or LN-positive (pT any, N1–3) M0 UTUC
[227] (LE: 1).
The main limitation of using adjuvant chemotherapy for advanced UTUC remains the limited ability
to deliver full dose cisplatin-based regimen after RNU, given that this surgical procedure is likely to impact renal
function [228, 229]. In a retrospective study histological variants of UTUC exhibit different survival rates and
adjuvant chemotherapy was only associated with an OS benefit in patients with pure urothelial carcinoma [230]
(LE: 3).
7.1.4
Adjuvant radiotherapy after radical nephroureterectomy
Adjuvant radiation therapy has been suggested to control loco-regional disease after surgical removal.
The data remains controversial and insufficient for conclusions [232-235]. Moreover, its added value to
chemotherapy remains questionable [234].
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UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
7.1.5
Post-operative bladder instillation
The rate of bladder recurrence after RNU for UTUC is 22–47% [164, 207]. Two prospective randomised
trials [236, 237] and two meta-analyses [238, 239] have demonstrated that a single post-operative dose of
intravesical chemotherapy (mitomycin C, pirarubicin) 2–10 days after surgery reduces the risk of bladder
tumour recurrence within the first years post-RNU (LE: 2). Prior to instillation, a cystogram might be considered
in case of any concerns about drug extravasation.
Based on current evidence it is unlikely that additional instillations beyond one peri-operative instillation of
chemotherapy further substantially reduces the risk of intravesical recurrence [240]. Whilst there is no direct
evidence supporting the use of intravesical instillation of chemotherapy after kidney-sparing surgery, singledose chemotherapy might be effective in that setting as well (LE: 4). Management is outlined in Figures 7.1 and
7.2. One low-level evidence study suggested that bladder irrigation might reduce the risk of bladder recurrence
after RNU [241].
7.1.6
Summary of evidence and guidelines for the management of high-risk non-metastatic UTUC
Summary of evidence
Radical nephroureterectomy is the standard treatment for high-risk UTUC, regardless of tumour
location.
Open, laparoscopic and robotic approaches have similar oncological outcomes for organ-confined
UTUC.
Failure to completely remove the bladder cuff increases the risk of bladder cancer recurrence.
Lymphadenectomy improves survival in muscle-invasive UTUC.
Post-operative chemotherapy improves disease-free survival.
Single post-operative intravesical instillation of chemotherapy lowers the bladder cancer recurrence
rate.
Recommendations
Perform radical nephroureterectomy (RNU) in patients with high-risk non-metastatic upper
tract urothelial carcinoma (UTUC).
Perform open RNU in non-organ confined UTUC.
Remove the bladder cuff in its entirety.
Perform a template-based lymphadenectomy in patients with muscle-invasive UTUC.
Offer post-operative systemic platinum-based chemotherapy to patients with muscleinvasive UTUC.
Deliver a post-operative bladder instillation of chemotherapy to lower the intravesical
recurrence rate.
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
LE
2a
2a
3
3
1b
1
Strength rating
Strong
Weak
Strong
Strong
Strong
Strong
17
Figure 7.1: Proposed flowchart for the management of UTUC
UTUC
Diagnosc evaluaon:
CTU, urinary cytology, cystoscopy
+/- Flexible ureteroscopy with biopsies
High-risk UTUC*
Low-risk UTUC
RNU +/- template lymphadenectomy
+/- peri-operave planum-based
combinaon chemotherapy
Kidney-sparing surgery:
flexible ureteroscopy or segmental
resecon
or percutaneous approach
Open
(prefer open in cT3, cN+)
Laparoscopic
Recurrence
Close and stringent follow-up
Single post-operave dose of intravesical
chemotherapy
*In patients with solitary kidney, consider a more conservative approach.
CTU = computed tomography urography; RNU = radical nephroureterectomy;
UTUC = upper urinary tract urothelial carcinoma.
18
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
1. URS
2. Ureteroureterostomy*
Low-risk
Low-risk
1. URS
or
2. Distal
ureterectomy
High-risk
• RNU
+/- LND
+/- perioperave
chemo
Mid & Proximal
Ureter
Distal
1. RNU
or
2. Distal
ureterectomy
+/- LND
+/- perioperave
chemo
High-risk
UTUC
1. URS
2. RNU*
Low-risk
Calyx
• RNU
+/- LND
+/- postoperave
chemo
High-risk
Low-risk
High-risk
• RNU
+/- LND
+/- postoperave
chemo
Renal pelvis
1. URS
2. Percutaneous
Kidney
Figure 7.2: Surgical treatment according to location and risk status
1 = first treatment option; 2 = secondary treatment option.
*In case not amendable to endoscopic management.
LND = lymph node dissection; RNU = radical nephroureterectomy; URS = ureteroscopy;
UTUC = upper urinary tract urothelial carcinoma.
19
7.2
Metastatic disease
7.2.1
Radical nephroureterectomy
The role of RNU in the treatment of patients with metastatic UTUC has recently been explored in several
observational studies [242-245]. Although evidence remains very limited, RNU may be associated with cancerspecific [242, 244, 245] and OS benefit in selected patients, especially those fit enough to receive cisplatinbased chemotherapy [243, 244]. It is noteworthy that these benefits may be limited to those patients with only
one metastatic site [244]. Nonetheless, given the high risk of bias of the observational studies addressing RNU
for metastatic UTUC, indications for RNU in this setting should mainly be reserved for palliative patients, aimed
at controlling symptomatic disease [17, 108] (LE: 3).
7.2.2
Metastasectomy
There is no UTUC-specific study supporting the role of metastasectomy in patients with advanced disease.
However, several reports including both UTUC and bladder cancer patients suggested that resection of
metastatic lesions could be safe and oncologically beneficial in selected patients with a life expectancy of more
than six months [246-248]. This was confirmed in the most recent and largest study to date [249]. Nonetheless,
in the absence of data from randomised controlled trials, patients should be evaluated on an individual basis
and the decision to perform a metastasectomy (surgically or otherwise) should be done in a shared decisionmaking process with the patient.
7.2.3
Systemic treatments
7.2.3.1
First-line setting
Extrapolating from the bladder cancer literature and small, single-centre, UTUC studies, platinum-based
combination chemotherapy, especially using cisplatin, is likely to be efficacious as first-line treatment of
metastatic UTUC. A retrospective analysis of three RCTs showed that primary tumour location in the lower- or
upper urinary tract had no impact on progression-free or OS in patients with locally advanced or metastatic UC
treated with platinum-based combination chemotherapy [250].
The efficacy of immunotherapy using programmed death-1 (PD1) or programmed death-ligand 1 (PD-L1)
inhibitors has been evaluated in the first-line setting for the treatment of patients with metastactic urothelial
carcinoma, including those with UTUC.
Data from a phase III RCT showed that the use of avelumab maintenance therapy after 4 to 6
cycles of gemcitabin plus cisplatin or carboplatin significantly prolonged OS as compared to best supportive
care alone in those patients with advanced or metastatic urothelial carcinoma who did not progress during,
or responded to, first-line chemotherapy [251]. Although no subgroup analysis based on tumour location was
available in this study, almost 30% of the included patients had UTUC.
Atezolizumab was associated with an objective response rate of 39% in 33 (28%) cisplatin-ineligible
patients with metastatic UTUC included in a single-arm phase II trial (n = 119) [252]. Median OS in the overall
cohort was 15.9 months and toxicity was acceptable.
However, data from a phase III RCT including 1,213 patients with metastatic urothelial carcinoma,
of which 312 (26%) were diagnosed with UTUC patients showed that the combination of atezolizumab with
platinum-based chemotherapy was associated with limited PFS benefit as compared to platinum-based
chemotherapy alone and no significant impact was observed on OS.
In a single-arm phase II trial (n = 370) pembrolizumab was associated with an objective response
rate of 22% in 69 (19%) cisplatin-ineligible patients with metastatic UTUC [253]. In the overall cohort, a PD-L1
expression of 10% was associated with a greater response rate to pembrolizumab, which had acceptable
toxicity. However, addition of pembrolizumab to platinum-based chemotherapy did not reach statistical
significance for PFS and OS benefits as compared to platinum-based chemotherapy alone in a phase III RCT
in 351 patients with metastatic urothelial carcinoma including 64 (18%) UTUC patients [254]. Another negative
phase III RCT showed that durvalumab alone, or in combination with tremelimumab, did not prolong OS as
compared to platinum-based chemotherapy for metastatic urothelial carcinoma [255]. This study included 221
(21%) UTUC patients and subgroup analyses suggested that durvalumab alone may have better efficacy for
these individuals as compared to those with bladder cancer.
No other data are currently available in the first-line setting but several trials are currently testing
immunotherapy combinations with nivolumab (NCT03036098 [256]), pembrolizumab (NCT02178722 [257]) or
durvalumab (NCT03682068 [258]) in patients with metastatic UC, including those with UTUC.
7.2.3.2
Second-line setting
Similar to the bladder cancer setting, second-line treatment of metastatic UTUC remains challenging. In a
post-hoc subgroup analysis of locally advanced or metastatic UC, vinflunine was reported to be as effective in
UTUC as for bladder cancer progressing after cisplatin-based chemotherapy [259].
20
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
More importantly, a phase III RCT including 542 patients who received prior platinum-based
chemotherapy for advanced UC showed that pembrolizumab could decrease the risk of death by almost 50%
in those with UTUC (n = 75, 13.8%), although these results were borderline significant [260]. The objective
response rate was 21.1% in the overall cohort and median OS was 10.3 months. Interestingly, although no
subgroup analysis was available for UTUC patients (n = 65/21%), a single-arm phase II trial demonstrated
that atezolizumab has durable activity associated with PD-L1 expression on immune cells in patients with
metastatic UC [261]. The objective response rate was 26% in the group of those overexpressing PD-L1 and
15% in the overall population. However, a phase III RCT, including 51 (21.8%) patients with UTUC, showed
that it was not associated with prolonged OS as compared to chemotherapy in patients overexpressing PD-L1,
despite a more favourable safety profile [262].
Other immunotherapies such as nivolumab [263], avelumab [264, 265] and durvalumab [266] have
shown objective response rates ranging from 17.8% [266] to 19.6% [263] and median OS ranging from 7.7
months to 18.2 months in patients with platinum-resistant metastatic UC, overall. These results were obtained
from single-arm phase I or II trials only and the number of UTUC patients included in these studies was only
specified for avelumab (n = 7/15.9%) [265] without any subgroup analysis based on primary tumour location.
The immunotherapy combination of nivolumab plus ipilimumab has shown significant anti-tumour
activity with objective response rate up to 38% in a phase I/II multicentre trial including 78 patients with
metastatic UC progressing after platinum-based chemotherapy [267]. Although UTUC patients were included
in this trial, no subgroup analysis was available. Other immunotherapy combinations may be effective in the
second-line setting but data are currently limited [268].
In a recent phase II study the use of erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, was associated with a
40% response rate in 99 patients with metastatic urothelial carcinoma and prespecified FGFR alterations who
progressed after first-line chemotherapy [269]. This study included 23 UTUC patients with visceral metastases
showing a 43% response rate.
7.2.4
Summary of evidence and guidelines for the treatment of metastatic UTUC
Summary of evidence
Radical nephroureterectomy may improve quality of life and oncologic outcomes in select metastatic
patients.
Cisplatin-based combination chemotherapy can improve median survival.
Single-agent and carboplatin-based combination chemotherapy are less effective than cisplatin-based
combination chemotherapy in terms of complete response and survival.
Non-platinum combination chemotherapy has not been tested against standard chemotherapy in
patients who are fit or unfit for cisplatin combination chemotherapy.
PD-1 inhibitor pembrolizumab has been approved for patients who have progressed during or after
previous platinum-based chemotherapy based on the results of a phase III trial.
PD-L1 inhibitor atezolizumab has been FDA approved for patients that have progressed during or after
previous platinum-based chemotherapy based on the results of a phase II trial.
PD-1 inhibitor nivolumab has been approved for patients that have progressed during or after previous
platinum-based chemotherapy based on the results of a phase II trial.
PD-1 inhibitor pembrolizumab has been approved for patients with advanced or metastatic UC
ineligible for cisplatin-based first-line chemotherapy based on the results of a phase II trial but use of
pembrolizumab is restricted to PD-L1 positive patients.
PD-L1 inhibitor atezolizumab has been approved for patients with advanced or metastatic UC
ineligible for cisplatin-based first-line chemotherapy based on the results of a phase II trial but use of
atezolizumab is restricted to PD-L1 positive patients.
Recommendations
Offer radical nephroureterectomy as a palliative treatment to symptomatic patients with
resectable locally advanced tumours.
First-line treatment for cisplatin-eligible patients
Use cisplatin-containing combination chemotherapy with GC or HD-MVAC.
Do not offer carboplatin or non-platinum combination chemotherapy.
First-line treatment in patients unfit for cisplatin
Offer checkpoint inhibitors pembrolizumab or atezolizumab depending on PD-L1 status.
Offer carboplatin combination chemotherapy if PD-L1 is negative.
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
LE
3
2
3
4
1b
2a
2a
2a
2a
Strength rating
Weak
Strong
Strong
Weak
Strong
21
Second-line treatment
Offer checkpoint inhibitor (pembrolizumab) to patients with disease progression during or
after platinum-based combination chemotherapy for metastatic disease.
Offer checkpoint inhibitor (atezolizumab or nivolumab) to patients with disease progression
during or after platinum-based combination chemotherapy for metastatic disease.
Only offer vinflunine to patients for metastatic disease as second-line treatment if
immunotherapy or combination chemotherapy is not feasible. Alternatively, offer vinflunine
as third- or subsequent-line treatment.
Strong
Strong
Strong
GC = gemcitabine plus cisplatin; HD-MVAC = high-dose intensity methotrexate, vinblastine, adriamycin plus
cisplatin; PD-L1 = programmed death ligand 1; PCG = paclitaxel, cisplatin, gemcitabine.
8.
FOLLOW-UP
The risk of recurrence and death evolves during the follow-up period after surgery [270]. Stringent follow-up is
mandatory to detect metachronous bladder tumours (probability increases over time [271]), local recurrence,
and distant metastases. Section 8.1 presents the summary of evidence and recommendations for follow-up of
UTUC.
Surveillance regimens are based on cystoscopy and urinary cytology for > 5 years [12, 14, 15, 164].
Bladder recurrence is not considered a distant recurrence. When kidney-sparing surgery is performed, the
ipsilateral UUT requires careful and long-term follow-up due to the high risk of disease recurrence [180, 272,
273] and progression to RNU beyond 5 years [274]. Despite endourological improvements, follow-up after
kidney-sparing management is difficult and frequent, and repeated endoscopic procedures are necessary.
Following kidney-sparing surgery, and as done in bladder cancer, an early repeated (second look) ureteroscopy
within six to eight weeks after primary endoscopic treatment has been proposed, but is not yet routine practice
[2, 181].
8.1
Summary of evidence and guidelines for the follow-up of UTUC
Summary of evidence
Follow-up is more frequent and more stringent in patients who have undergone kidney-sparing
treatment compared to radical nephroureterectomy.
Recommendations
After radical nephroureterectomy
Low-risk tumours
Perform cystoscopy at three months. If negative, perform subsequent cystoscopy nine
months later and then yearly, for five years.
High-risk tumours
Perform cystoscopy and urinary cytology at three months. If negative, repeat subsequent
cystoscopy and cytology every three months for a period of two years, and every six
months thereafter until five years, and then yearly.
Perform computed tomography (CT) urography and chest CT every six months for two years,
and then yearly.
After kidney-sparing management
Low-risk tumours
Perform cystoscopy and CT urography at three and six months, and then yearly for five
years.
Perform ureteroscopy (URS) at three months.
High-risk tumours
Perform cystoscopy, urinary cytology, CT urography and chest CT at three and six months,
and then yearly.
Perform URS and urinary cytology in situ at three and six months.
22
LE
3
Strength rating
Weak
Weak
Weak
Weak
Weak
Weak
Weak
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
9.
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O’Brien, T., et al. Prevention of bladder tumours after nephroureterectomy for primary upper
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Ito, A., et al. Prospective randomized phase II trial of a single early intravesical instillation of
pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary
tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol, 2013. 31: 1422.
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nephroureterectomy for primary upper urinary tract urothelial carcinomas: a systematic review and
meta-analysis. Urol Int, 2013. 91: 291.
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Harraz, A.M., et al. Single Versus Maintenance Intravesical Chemotherapy for the Prevention of
Bladder Recurrence after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A
Randomized Clinical Trial. Clin Genitourin Cancer, 2019. 17: e1108.
https://pubmed.ncbi.nlm.nih.gov/31594736
Yamamoto, S., et al. Intravesical irrigation might prevent bladder recurrence in patients undergoing
radical nephroureterectomy for upper urinary tract urothelial carcinoma. Int J Urol, 2019. 26: 791.
https://pubmed.ncbi.nlm.nih.gov/31081198
Dong, F., et al. How do organ-specific metastases affect prognosis and surgical treatment for
patients with metastatic upper tract urothelial carcinoma: first evidence from population based data.
Clin Exp Metastasis, 2017. 34: 467.
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Metastatic Upper Tract Urothelial Carcinoma. European Urology, 2017. 71: 714.
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Analysis of an International, Multicenter, Multidisciplinary Database. Eur Urol Oncol, 2020. 3: 94.
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Carcinoma. Clin Genitourin Cancer, 2019. 17: e602.
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Siefker-Radtke, A.O., et al. Is there a role for surgery in the management of metastatic urothelial
cancer? The M. D. Anderson experience. J Urol, 2004. 171: 145.
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cancer. Eur Urol, 2007. 52: 1106.
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experience (AUO AB 30/05). Eur Urol, 2009. 55: 1293.
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Moschini, M., et al. Impact of Primary Tumor Location on Survival from the European Organization for
the Research and Treatment of Cancer Advanced Urothelial Cancer Studies. J Urol, 2018. 199: 1149.
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Powles, T., et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.
N Engl J Med, 2020. 383: 1218.
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advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet,
2017. 389: 67.
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Balar, A.V., et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and
unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2
study. Lancet Oncol, 2017. 18: 1483.
https://pubmed.ncbi.nlm.nih.gov/28967485
Alva, A., et al. LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line
(1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Ann Oncol 2020. 31: S1142.
https://www.annalsofoncology.org/article/S0923-7534(20)42334-8/abstract
Powles, T., et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in
previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma
(DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol, 2020. 21: 1574.
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of an Observational Study. Anticancer Res, 2017. 37: 6437.
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10.
CONFLICT OF INTEREST
273.
All members of the Non-Muscle-Invasive Bladder Cancer Guidelines working panel have provided disclosure
statements on all relationships that they have that might be perceived to be a potential source of a conflict of
interest. This information is publically accessible through the European Association of Urology website:
http://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/.
This guidelines document was developed with the financial support of the European Association of
Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation,
and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other
reimbursements have been provided.
11.
CITATION INFORMATION
The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the
citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location,
or an ISBN number may vary.
The compilation of the complete Guidelines should be referenced as:
EAU Guidelines. Edn. presented at the EAU Annual Congress Milan, 2021. ISBN 978-94-92671-13-4.
If a publisher and/or location is required, include:
EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/
References to individual guidelines should be structured in the following way:
Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.
38
UPPER URINARY TRACT UROTHELIAL CARCINOMA - LIMITED UPDATE 2021
EAU - EANM - ESTRO ESUR - ISUP - SIOG
Guidelines on
Prostate Cancer
N. Mottet (Chair), P. Cornford (Vice-chair), R.C.N. van den Bergh,
E. Briers, Expert Patient Advocate (European Prostate Cancer
Coalition/Europa UOMO), M. De Santis, S. Gillessen,
J. Grummet, A.M. Henry, T.H. van der Kwast, T.B. Lam,
M.D. Mason, S. O’Hanlon, D.E. Oprea-Lager, G. Ploussard,
H.G. van der Poel, O. Rouvière, I.G. Schoots. D. Tilki, T. Wiegel
Guidelines Associates: T. Van den Broeck, M. Cumberbatch,
A. Farolfi, N. Fossati, G. Gandaglia, N. Grivas, M. Lardas,
M. Liew, L. Moris, P-P.M. Willemse
© European Association of Urology 2021
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION
1.1
Aims and scope
1.2
Panel composition
1.2.1
Acknowledgement
1.3
Available publications
1.4
Publication history and summary of changes
1.4.1
Publication history
1.4.2
Summary of changes
10
10
10
10
10
10
10
10
2.
15
15
16
16
METHODS
2.1
Data identification
2.2
Review
2.3
Future goals
3.
EPIDEMIOLOGY AND AETIOLOGY
3.1
Epidemiology
3.2
Aetiology
3.2.1
Family history / hereditary prostate cancer
3.2.1.1
Germline mutations and prostate cancer
3.2.2
Risk factors
3.2.2.1
Metabolic syndrome
3.2.2.1.1
Diabetes/metformin
3.2.2.1.2
Cholesterol/statins
3.2.2.1.3
Obesity
3.2.2.2
Dietary factors
3.2.2.3
Hormonally active medication
3.2.2.3.1
5-alpha-reductase inhibitors (5-ARIs)
3.2.2.3.2
Testosterone
3.2.2.4
Other potential risk factors
3.2.3
Summary of evidence for epidemiology and aetiology
16
16
16
16
17
17
17
17
18
18
18
18
18
18
19
19
4.
19
19
20
21
21
5.
CLASSIFICATION AND STAGING SYSTEMS
4.1
Classification
4.2
Gleason score and International Society of Urological Pathology 2014 grade
4.3
Prognostic relevance of stratification
4.4
Guidelines for classification and staging systems
DIAGNOSTIC EVALUATION 5.1
Screening and early detection
5.1.1
Screening
5.1.2
Early detection
5.1.3
Genetic testing for inherited prostate cancer
5.1.4
Guidelines for germline testing*
5.1.5
Guidelines for screening and early detection
5.2
Clinical diagnosis
5.2.1
Digital rectal examination
5.2.2
Prostate-specific antigen
5.2.2.1
PSA density
5.2.2.2
PSA velocity and doubling time
5.2.2.3
Free/total PSA ratio
5.2.3
Biomarkers in prostate cancer
5.2.3.1
Blood based biomarkers: PHI/4K score/IsoPSA
5.2.3.2
Urine biomarkers: PCA3/SelectMDX/Mi Prostate score (MiPS)/ExoDX
5.2.3.3
Tests to select men for a repeat biopsy
5.2.3.4
Guidelines for risk-assessment of asymptomatic men
5.2.4
The role of imaging in clinical diagnosis
5.2.4.1
Transrectal ultrasound and ultrasound-based techniques
5.2.4.2
Multiparametric magnetic resonance imaging
2
21
21
21
23
24
25
25
25
25
25
26
26
26
26
26
27
27
28
28
28
28
PROSTATE CANCER - LIMITED UPDATE 2021
5.2.4.2.1
Multiparametric magnetic resonance imaging
performance in detecting PCa
28
5.2.4.2.2Targeted biopsy improves the detection of ISUP
grade > 2 cancer as compared to systematic biopsy.
28
5.2.4.2.3MRI-TBx without systematic biopsy reduces the detection
of ISUP grade 1 PCa as compared to systematic biopsy. 29
5.2.4.2.4
The added value of systematic and targeted biopsy
29
5.2.4.2.5
Number of biopsy procedures potentially avoided in
the ‘MR pathway’
30
5.2.4.2.6
Other considerations
30
5.2.4.2.6.1 Multiparametric magnetic resonance
imaging reproducibility
30
5.2.4.2.6.2 Targeted biopsy accuracy and reproducibility 31
5.2.4.2.6.3 Role of risk-stratification
31
5.2.4.2.6.4 Pre-biopsy MRI and MRI-TBx may induce
an ISUP prostate cancer grade shift, as a
result of improved diagnosis
33
5.2.4.2.7
Summary of evidence and practical considerations on
pre-biopsy MRI and MRI-TBx
33
5.2.4.3
Guidelines for imaging in PCa detection
33
5.2.5
Baseline biopsy
34
5.2.6
Repeat biopsy
34
5.2.6.1
Repeat biopsy after previously negative biopsy
34
5.2.6.2
Saturation biopsy
34
5.2.7
Prostate biopsy procedure 34
5.2.7.1
Sampling sites and number of cores
34
5.2.7.2
Antibiotics prior to biopsy
35
5.2.7.2.1
Transperineal prostate biopsy
35
5.2.7.2.2
Transrectal prostate biopsy
35
5.2.7.3
Summary of evidence and recommendations for performing prostate
biopsy (in line with the Urological Infections Guidelines Panel)
36
5.2.7.4
Local anaesthesia prior to biopsy
37
5.2.7.5
Complications
38
5.2.7.6
Seminal vesicle biopsy
38
5.2.7.7
Transition zone biopsy
38
5.2.8
Pathology of prostate needle biopsies
38
5.2.8.1
Processing
38
5.2.8.2
Microscopy and reporting
38
5.2.8.2.1
Recommended terminology for reporting prostate
biopsies
39
5.2.8.3
Tissue-based prognostic biomarker testing
39
5.2.8.4
Histopathology of radical prostatectomy specimens
40
5.2.8.4.1
Processing of radical prostatectomy specimens
40
5.2.8.4.1.1 Guidelines for processing prostatectomy
specimens
40
5.2.8.4.2
Radical prostatectomy specimen report
40
5.2.8.4.3
ISUP grade in prostatectomy specimens
41
5.2.8.4.4
Definition of extraprostatic extension
41
5.2.8.4.5
PCa volume
42
5.2.8.4.6
Surgical margin status
42
5.3
Diagnosis - Clinical Staging 42
5.3.1
T-staging
42
5.3.1.1
TRUS
42
5.3.1.2
MRI
42
5.3.2
N-staging
43
5.3.2.1
Computed tomography and magnetic resonance imaging
43
5.3.2.2
Risk calculators incorporating MRI findings
43
5.3.2.3
Choline PET/CT
43
5.3.2.4
Prostate-specific membrane antigen-based PET/CT
43
5.3.3
M-staging
44
PROSTATE CANCER - LIMITED UPDATE 2021
3
5.3.3.1
Bone scan
5.3.3.2
Fluoride PET and PET/CT, choline PET/CT and MRI
5.3.3.3
Prostate-specific membrane antigen-based PET/CT
5.3.4
Summary of evidence and practical considerations on initial N/M staging
5.3.5
Summary of evidence and guidelines for staging of prostate cancer
5.4
Estimating life expectancy and health status
5.4.1
Introduction
5.4.2
Life expectancy
5.4.3
Health status screening
5.4.3.1
Co-morbidity
5.4.3.2
Nutritional status
5.4.3.3
Cognitive function
5.4.3.4
Physical function
5.4.3.5
Shared decision-making
5.4.4
Conclusion
5.4.5
Guidelines for evaluating health status and life expectancy
44
44
45
45
46
46
46
46
47
47
47
48
48
48
48
50
6.
50
50
50
51
51
52
TREATMENT
6.1
Treatment modalities 6.1.1
Deferred treatment (active surveillance/watchful waiting)
6.1.1.1
Definitions
6.1.1.2
Active surveillance
6.1.1.3
Watchful Waiting
6.1.1.3.1
Outcome of watchful waiting compared with active
treatment
6.1.1.4
The ProtecT study
6.1.2
Radical prostatectomy
6.1.2.1
Introduction
6.1.2.2
Pre-operative preparation
6.1.2.2.1
Pre-operative patient education
6.1.2.3
Surgical techniques
6.1.2.3.1
Robotic anterior versus Retzius-sparing dissection
6.1.2.3.2
Pelvic lymph node dissection
6.1.2.3.3
Sentinel node biopsy analysis
6.1.2.3.4
Prostatic anterior fat pad dissection and histologic
analysis
6.1.2.3.5
Management of the dorsal venous complex
6.1.2.3.6
Nerve-sparing surgery
6.1.2.3.7
Lymph-node-positive patients during radical
prostatectomy
6.1.2.3.8
Removal of seminal vesicles
6.1.2.3.9
Techniques of vesico-urethral anastomosis
6.1.2.3.10 Bladder neck management
6.1.2.3.11 Urethral length preservation
6.1.2.3.12 Cystography prior to catheter removal
6.1.2.3.13 Urinary catheter
6.1.2.3.14 Use of a pelvic drain
6.1.2.4
Acute and chronic complications of surgery
6.1.2.4.1
Effect of anterior and posterior reconstruction on
continence
6.1.2.4.2
Deep venous thrombosis prophylaxis
6.1.2.4.3
Early complications of extended lymph node dissection
6.1.3
Radiotherapy
6.1.3.1
External beam radiation therapy
6.1.3.1.1Technical aspects: intensity-modulated external-beam
radiotherapy and volumetric arc external-beam
radiotherapy 6.1.3.1.2
Dose escalation
6.1.3.1.3
Hypofractionation
6.1.3.1.4Neoadjuvant or adjuvant hormone therapy plus
radiotherapy
4
52
52
53
53
53
53
54
54
55
55
55
56
56
56
56
56
57
57
57
58
58
58
58
59
59
59
59
59
60
61
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6.1.3.1.5
Combined dose-escalated radiotherapy and androgen
deprivation therapy
64
6.1.3.2
Proton beam therapy
65
6.1.3.3
Spacer during external beam radiation therapy
65
6.1.3.4
Brachytherapy
65
6.1.3.4.1
Low-dose rate (LDR) brachytherapy
65
6.1.3.4.2
High-dose rate brachytherapy
66
6.1.3.5
Acute side effects of external beam radiotherapy and brachytherapy 66
6.1.4
Hormonal therapy
67
6.1.4.1
Introduction
67
6.1.4.1.1
Different types of hormonal therapy
67
6.1.4.1.1.1 Testosterone-lowering therapy (castration) 67
6.1.4.1.1.1.1 Castration level
67
6.1.4.1.1.1.2 Bilateral orchiectomy
67
6.1.4.1.1.1.3 Oestrogens
67
6.1.4.1.1.1.4 Luteinising-hormone-releasing
hormone agonists
67
6.1.4.1.1.1.5 Luteinising-hormone-releasing
hormone antagonists
67
6.1.4.1.1.1.6 Anti-androgens
68
6.1.4.1.1.1.6.1 Steroidal anti-androgens
68
6.1.4.1.1.1.6.2 Non-steroidal anti-androgens
68
6.1.4.1.1.2 New androgen receptor pathway targetting
agents (ARTA)
68
6.1.4.1.1.2.1 Abiraterone acetate
68
6.1.4.1.1.2.2 Apalutamide, darolutamide,
enzalutamide (alphabetical order)
68
6.1.4.1.1.3 New compounds
69
6.1.4.1.1.3.1 PARP inhibitors
69
6.1.4.1.1.3.2 Immune checkpoint inhibitors
69
6.1.4.1.1.3.3 Protein kinase B (AKT) inhibitors
69
6.1.5
Investigational therapies
69
6.1.5.1
Background
69
6.1.5.2
Cryotherapy
69
6.1.5.3
High-intensity focused ultrasound
70
6.1.5.4
Focal therapy
70
6.1.6
General guidelines for the treatment of prostate cancer
71
6.2
Treatment by disease stages
72
6.2.1
Treatment of low-risk disease
72
6.2.1.1
Active surveillance 72
6.2.1.1.1
Active surveillance - inclusion criteria
72
6.2.1.1.2
Tissue-based prognostic biomarker testing
72
6.2.1.1.3
Imaging for treatment selection
72
6.2.1.1.4
Monitoring during active surveillance
73
6.2.1.1.5
Active Surveillance - when to change strategy
74
6.2.1.2
Alternatives to active surveillance for the treatment of low-risk disease 74
6.2.1.3
Summary of evidence and guidelines for the treatment of low-risk
disease
74
6.2.2
Treatment of intermediate-risk disease
75
6.2.2.1
Active Surveillance
75
6.2.2.2
Surgery
75
6.2.2.3
Radiation therapy
75
6.2.2.3.1
Recommended IMRT for intermediate-risk PCa
75
6.2.2.3.2
Brachytherapy monotherapy
75
6.2.2.4
Other options for the primary treatment of intermediate-risk PCa (experimental therapies)
75
6.2.2.5
Guidelines for the treatment of intermediate-risk disease
76
6.2.3
Treatment of high-risk localised disease
76
6.2.3.1
Radical prostatectomy 76
6.2.3.1.1
ISUP grade 4–5
76
6.2.3.1.2
Prostate-specific antigen > 20 ng/mL
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5
6.2.3.1.3Radical prostatectomy in cN0 patients who are found to
have pathologically confirmed lymph node invasion (pN1) 77
6.2.3.2
External beam radiation therapy
77
6.2.3.2.1
Recommended external beam radiation therapy
treatment policy for high-risk localised PCa
77
6.2.3.2.2
Lymph node irradiation in cN0
77
6.2.3.2.3
Brachytherapy boost
77
6.2.3.3
Options other than surgery and radiotherapy for the primary
treatment of localised PCa
77
6.2.3.4
Guidelines for radical treatment of high-risk localised disease
78
6.2.4
Treatment of locally advanced PCa
78
6.2.4.1
Surgery
78
6.2.4.2
Radiotherapy for locally advanced PCa
78
6.2.4.3
Treatment of cN1 M0 PCa 78
6.2.4.3.1
Guidelines for the management of cN1 M0 prostate
cancer
80
6.2.4.4
Options other than surgery and radiotherapy for primary treatment
80
6.2.4.4.1
Investigational therapies
80
6.2.4.4.2
Androgen deprivation therapy monotherapy
80
6.2.4.5
Guidelines for radical treatment of locally-advanced disease
80
6.2.5
Adjuvant treatment after radical prostatectomy
80
6.2.5.1
Introduction
80
6.2.5.2
Risk factors for relapse
81
6.2.5.2.1
Biomarker-based risk stratification after radical
prostatectomy
81
6.2.5.3
Immediate (adjuvant) post-operative external irradiation after RP
(cN0 or pN0)
81
6.2.5.4
Comparison of adjuvant- and salvage radiotherapy
82
6.2.5.5
Adjuvant androgen ablation in men with N0 disease
83
6.2.5.6
Adjuvant treatment in pN1 disease
83
6.2.5.6.1
Adjuvant androgen ablation alone
83
6.2.5.6.2
Adjuvant radiotherapy combined with ADT in pN1 disease 83
6.2.5.6.3
Observation of pN1 patients after radical prostatectomy
and extended lymph node dissection
84
6.2.5.7
Guidelines for adjuvant treatment in pN0 and pN1 disease after
radical prostatectomy
84
6.2.5.8
Guidelines for non-curative or palliative treatments in prostate cancer 84
6.2.6
Persistent PSA after radical prostatectomy
85
6.2.6.1
Natural history of persistently elevated PSA after RP
85
6.2.6.2
Imaging in patients with persistently elevated PSA after RP
86
6.2.6.3
Impact of post-operative RT and/or ADT in patients with persistent PSA 87
6.2.6.4
Conclusion
87
6.2.6.5
Recommendations for the management of persistent PSA after
radical prostatectomy
88
6.3
Management of PSA-only recurrence after treatment with curative intent
88
6.3.1
Background
88
6.3.2
Definitions of clinically relevant PSA relapse
88
6.3.3
Natural history of biochemical recurrence
88
6.3.4
The role of imaging in PSA-only recurrence
89
6.3.4.1
Assessment of metastases
89
6.3.4.1.1
Bone scan and abdominopelvic CT
89
6.3.4.1.2
Choline PET/CT
89
6.3.4.1.3
Fluoride PET and PET/CT
89
6.3.4.1.4
Fluciclovine PET/CT
89
6.3.4.1.5
Prostate-specific membrane antigen based PET/CT
90
6.3.4.1.6
Whole-body and axial MRI
90
6.3.4.2
Assessment of local recurrences
90
6.3.4.2.1
Local recurrence after radical prostatectomy
90
6.3.4.2.2
Local recurrence after radiation therapy
91
6.3.4.3
Summary of evidence on imaging in case of biochemical recurrence 91
6
PROSTATE CANCER - LIMITED UPDATE 2021
6.3.4.4
Guidelines for imaging in patients with biochemical recurrence
91
6.3.5
Treatment of PSA-only recurrences
91
6.3.5.1
Treatment of PSA-only recurrences after radical prostatectomy
91
6.3.5.1.1
Salvage radiotherapy for PSA-only recurrence after
radical prostatectomy (cTxcN0M0, without PET/ CT)
91
6.3.5.1.2
Salvage radiotherapy combined with androgen
deprivation therapy (cTxcN0, without PET/CT)
93
6.3.5.1.2.1 Target volume, dose, toxicity
94
6.3.5.1.2.2 Salvage RT with or without ADT
(cTx CN0/1) (with PET/CT)
95
6.3.5.1.2.3 Metastasis-directed therapy for
rcN+ (with PET/CT)
95
6.3.5.1.3
Salvage lymph node dissection
95
6.3.5.1.4
Comparison of adjuvant- and salvage radiotherapy
96
6.3.5.2
Management of PSA failures after radiation therapy
96
6.3.5.2.1
Salvage radical prostatectomy
96
6.3.5.2.1.1 Oncological outcomes
96
6.3.5.2.1.2 Morbidity
97
6.3.5.2.1.3 Summary of salvage radical prostatectomy 97
6.3.5.2.2
Salvage cryoablation of the prostate
97
6.3.5.2.2.1 Oncological outcomes
97
6.3.5.2.2.2 Morbidity
98
6.3.5.2.2.3 Summary of salvage cryoablation of the
prostate
98
6.3.5.2.3
Salvage re-irradiation
98
6.3.5.2.3.1 Salvage brachytherapy for radiotherapy
failure
98
6.3.5.2.3.2 Salvage stereotactic ablative body
radiotherapy for radiotherapy failure
99
6.3.5.2.3.2.1Oncological outcomes and morbidity 99
6.3.5.2.3.2.2 Morbidity
99
6.3.5.2.3.2.3Summary of salvage stereotactic
ablative body radiotherapy
99
6.3.5.2.4
Salvage high-intensity focused ultrasound
99
6.3.5.2.4.1 Oncological outcomes
99
6.3.5.2.4.2 Morbidity
100
6.3.5.2.4.3Summary of salvage high-intensity focused
ultrasound
100
6.3.6
Hormonal therapy for relapsing patients
100
6.3.7
Observation
101
6.3.8
Guidelines for second-line therapy after treatment with curative intent
101
6.4
Treatment: Metastatic prostate cancer
101
6.4.1
Introduction
101
6.4.2
Prognostic factors
101
6.4.3
First-line hormonal treatment
102
6.4.3.1
Non-steroidal anti-androgen monotherapy
102
6.4.3.2
Intermittent versus continuous androgen deprivation therapy
102
6.4.3.3
Immediate versus deferred androgen deprivation therapy
103
6.4.4
Combination therapies
103
6.4.4.1
‘Complete’ androgen blockade
103
6.4.4.2
Androgen deprivation combined with other agents
103
6.4.4.2.1
Androgen deprivation therapy combined with
chemotherapy
103
6.4.4.2.2
Combination with the new hormonal treatments
(abiraterone, apalutamide, enzalutamide)
104
6.4.5
Treatment selection and patient selection
106
6.4.6
Deferred treatment for metastatic PCa (stage M1)
106
6.4.7
Treatment of the primary tumour in newly diagnosed metastatic disease
106
6.4.8
Metastasis-directed therapy in M1-patients
107
6.4.9
Guidelines for the first-line treatment of metastatic disease
107
PROSTATE CANCER - LIMITED UPDATE 2021
7
6.5
Treatment: Castration-resistant PCa (CRPC)
6.5.1
Definition of CRPC
6.5.2
Management of mCRPC - general aspects
6.5.2.1
Molecular diagnostics
6.5.3
Treatment decisions and sequence of available options
6.5.4
Non-metastatic CRPC
6.5.5
Metastatic CRPC
6.5.5.1
Conventional androgen deprivation in CRPC
6.5.6
First-line treatment of metastatic CRPC
6.5.6.1
Abiraterone
6.5.6.2
Enzalutamide
6.5.6.3
Docetaxel
6.5.6.4
Sipuleucel-T
6.5.6.5
Ipatasertib
6.5.7
Second-line treatment for mCRPC and sequence
6.5.7.1
Cabazitaxel
6.5.7.2
Abiraterone acetate after prior docetaxel
6.5.7.3
Enzalutamide after docetaxel
6.5.7.4
Radium-223
6.5.8
Treatment after docetaxel and one line of hormonal treatment for mCRPC
6.5.8.1
PARP inhibitors for mCRPC
6.5.8.2
Sequencing treatment
6.5.8.2.1
ARTA -> ARTA (chemotherapy-naïve patients)
6.5.8.2.2
ARTA -> PARP inhibitor/olaparib
6.5.8.2.3
Docetaxel for mHSPC -> docetaxel rechallenge
6.5.8.2.4
ARTA -> docetaxel or docetaxel -> ARTA followed by
PARP inhibitor
6.5.8.2.5
ARTA before or after docetaxel
6.5.8.2.6
ARTA –> docetaxel -> cabazitaxel or docetaxel –>
ARTA -> cabazitaxel
6.5.9
Prostate-specific membrane antigen (PSMA) therapy
6.5.9.1
Background
6.5.9.2
PSMA-based therapy 6.5.10 Immunotherapy for mCRPC
6.5.11 Monitoring of treatment
6.5.12 When to change treatment
6.5.13 Symptomatic management in metastatic CRPC
6.5.13.1 Common complications due to bone metastases
6.5.13.2 Preventing skeletal-related events
6.5.13.2.1 Bisphosphonates
6.5.13.2.2 RANK ligand inhibitors
6.5.14 Summary of evidence and guidelines for life-prolonging treatments of
castrate-resistant disease
6.5.15 Guidelines for systematic treatments of castrate-resistant disease
6.5.16 Guidelines for supportive care of castrate-resistant disease
6.5.17 Guideline for non-metastatic castrate-resistant disease
6.6
Summary of guidelines for the treatment of prostate cancer
6.6.1
General guidelines recommendations for treatment of prostate cancer
6.6.2
Guidelines recommendations for the various disease stages
6.6.3
Guidelines for metastatic disease, second-line and palliative treatments
7.
FOLLOW-UP
7.1
Follow-up: After local treatment
7.1.1
Definition
7.1.2
Why follow-up?
7.1.3
How to follow-up?
7.1.3.1
Prostate-specific antigen monitoring
7.1.3.1.1
Active surveillance follow-up
7.1.3.1.2
Prostate-specific antigen monitoring after radical
prostatectomy
8
108
108
108
108
108
108
109
109
110
110
110
111
111
111
112
112
113
113
113
113
114
114
114
115
115
115
115
115
115
115
115
115
115
116
116
116
116
116
117
117
118
118
118
118
119
119
122
124
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124
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PROSTATE CANCER - LIMITED UPDATE 2021
7.1.3.1.3
Prostate-specific antigen monitoring after radiotherapy
7.1.3.1.4
Digital rectal examination
7.1.3.1.5
Transrectal ultrasound, bone scintigraphy, CT, MRI and
PET/CT
7.1.4
How long to follow-up?
7.1.5
Summary of evidence and guidelines for follow-up after treatment with curative
intent
7.2
Follow-up: During first line hormonal treatment (androgen sensitive period)
7.2.1
Introduction
7.2.2
Purpose of follow-up
7.2.3
General follow-up of men on ADT
7.2.3.1
Testosterone monitoring
7.2.3.2
Liver function monitoring
7.2.3.3
Serum creatinine and haemoglobine
7.2.3.4
Monitoring of metabolic complications
7.2.3.5
Monitoring bone problems
7.2.3.6
Monitoring lifestyle and cognition
7.2.4
Methods of follow-up in men on ADT without metastases
7.2.4.1
Prostate-specific antigen monitoring
7.2.4.2
Imaging
7.2.5
Methods of follow-up in men under ADT for metastatic hormone-sensitive PCa
7.2.5.1
PSA monitoring
7.2.5.2
Imaging as a marker of response in metastatic PCa
7.2.6
Guidelines for follow-up during hormonal treatment
8.
124
125
125
125
125
125
125
125
126
126
126
126
126
126
127
127
127
127
127
127
127
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QUALITY OF LIFE OUTCOMES IN PROSTATE CANCER
8.1
Introduction
8.2
Adverse effects of PCa therapies
8.2.1
Surgery
8.2.2
Radiotherapy
8.2.2.1
Side-effects of external beam radiotherapy
8.2.2.2
Side effects from brachytherapy
8.2.3
Local primary whole-gland treatments other than surgery or radiotherapy
8.2.3.1
Cryosurgery
8.2.3.2
High-intensity focused ultrasound
8.2.4
Hormonal therapy
8.2.4.1
Sexual function
8.2.4.2
Hot flushes
8.2.4.3
Non-metastatic bone fractures
8.2.4.4
Metabolic effects
8.2.4.5
Cardiovascular morbidity
8.2.4.6
Fatigue
8.2.4.7
Neurological side effects
8.3
Overall quality of life in men with PCa
8.3.1
Long-term (> 12 months) quality of life outcomes in men with localised disease
8.3.1.1
Men undergoing local treatments
8.3.1.2
Guidelines for quality of life in men undergoing local treatments
8.3.2
Improving quality of life in men who have been diagnosed with PCa
8.3.2.1
Men undergoing local treatments
8.3.2.2
Men undergoing systemic treatments
8.3.2.3
Decision regret
8.3.2.4
Decision aids in prostate cancer
8.3.2.5
Guidelines for quality of life in men undergoing systemic treatments
128
128
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128
129
129
129
129
129
129
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130
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131
131
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134
135
9.
REFERENCES
135
10.
CONFLICT OF INTEREST
211
11.
CITATION INFORMATION
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PROSTATE CANCER - LIMITED UPDATE 2021
9
1.
INTRODUCTION
1.1
Aims and scope
The Prostate Cancer (PCa) Guidelines Panel have prepared this guidelines document to assist medical
professionals in the evidence-based management of PCa.
It must be emphasised that clinical guidelines present the best evidence available to the experts
but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.
1.2
Panel composition
The PCa Guidelines Panel consists of an international multidisciplinary group of urologists, radiation
oncologists, medical oncologists, radiologists, a pathologist, a geriatrician and a patient representative.
All imaging sections in the text have been developed jointly with the European Society of Urogenital Radiology
(ESUR) and the European Association of Nuclear Medicine (EANM). Representatives of the ESUR and the
EANM in the PCa Guidelines Panel are (in alphabetical order): Dr. D. Oprea-Lager, Prof.Dr. O Rouvière and
Dr. I.G. Schoots.
All radiotherapy sections have been developed jointly with the European Society for Radiotherapy
& Oncology (ESTRO). Representatives of ESTRO in the PCa Guidelines Panel are (in alphabetical order):
Prof.Dr. A.M. Henry, Prof.Dr. M.D. Mason and Prof.Dr. T. Wiegel.
The International Society of Urological Pathology is represented by Prof.Dr. T. van der Kwast.
Dr. S. O’Hanlon, consultant geriatrician, representing the International Society of Geriatric Oncology
(SOIG) contributed to the sections addressing life expectancy, health status and quality of life in particular.
Dr. E. Briers, expert Patient Advocate Hasselt-Belgium representing the patient voice as delegated
by the European Prostate Cancer Coalition/Europa UOMO.
All experts involved in the production of this document have submitted potential conflict of interest
statements which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/prostate-cancer/.
1.2.1
Acknowledgement
The PCa Guidelines Panel gratefully acknowledges the assistance and general guidance provided by
Prof.Dr. M. Bolla, honorary member of the PCa Guidelines Panel.
1.3
Available publications
A quick reference document (Pocket guidelines) is available, both in print and as an app for iOS and Android
devices. These are abridged versions which may require consultation together with the full text version. Several
scientific publications are available [1, 2] as are a number of translations of all versions of the PCa Guidelines.
All documents can be accessed on the EAU website: http://uroweb.org/guideline/prostate-cancer/.
1.4
Publication history and summary of changes
1.4.1
Publication history
The EAU PCa Guidelines were first published in 2001. This 2021 document presents an update of the 2020
PCa Guidelines publication.
1.4.2
Summary of changes
The literature for the complete document has been assessed and updated based upon a review of all
recommendations and creation of appropriate GRADE forms. Evidence summaries and recommendations have
been amended throughout the current document and several new sections have been added.
All chapters of the 2021 PCa Guidelines have been updated. New data have been included in the following
sections, resulting in new sections and added and revised recommendations in:
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5.1.4 Guidelines for germline testing*
Recommendations
Consider germline testing in men with metastatic PCa.
Consider germline testing in men with high-risk PCa who have a family member
diagnosed with PCa at age < 60 years.
Consider germline testing in men with multiple family members diagnosed with PCa
at age < 60 years or a family member who died from PCa.
Consider germline testing in men with a family history of high-risk germline
mutations or a family history of multiple cancers on the same side of the family.
Strength rating
weak
weak
weak
weak
*Genetic counseling is required prior to germline testing.
5.2.7.3 Summary of evidence and recommendations for performing prostate biopsy
(in line with the Urological Infections Guidelines Panel)
Summary of evidence
A meta-analysis of seven studies including 1,330 patients showed significantly reduced
infectious complications in patients undergoing transperineal biopsy as compared to
transrectal biopsy.
Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal povidone-iodine
preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a
significantly lower rate of infectious complications.
A meta-analysis on eleven studies with 1,753 patients showed significantly reduced infections
after transrectal biopsy when using antimicrobial prophylaxis as compared to placebo/control.
Recommendations
Perform prostate biopsy using the transperineal approach due to the lower risk of
infectious complications.
Use routine surgical disinfection of the perineal skin for transperineal biopsy.
Use rectal cleansing with povidone-iodine in men prior to transrectal prostate biopsy.
Do not use fluoroquinolones for prostate biopsy in line with the European
Commission final decision on EMEA/H/A-31/1452.
Use either target prophylaxis based on rectal swab or stool culture; augmented
prophylaxis (two or more different classes of antibiotics); or alternative antibiotics
(e.g., fosfomycin trometamol, cephalosporin, aminoglycoside) for antibiotic
prophylaxis for transrectal biopsy.
Use a single oral dose of either cefuroxime or cephalexin or cephazolin as antibiotic
prophylaxis for transperineal biopsy. Patients with severe penicillin allergy may be
given sulphamethoxazole.
Ensure that prostate core biopsies from different sites are submitted separately for
processing and pathology reporting.
LE
1a
1a
1a
Strength rating*
Strong
Strong
Strong
Strong
Weak
Weak
Strong
*Note on strength ratings:
The above strength ratings are explained here due to the major clinical implications of these new recommendations.
Although data showing the lower risk of infection via the transperineal approach is low in certainty, its statistical and
clinical significance warrants its Strong rating. Strong ratings are also given for routine surgical disinfection of skin
in transperineal biopsy and povidone-iodine rectal cleansing in transrectal biopsy as, although quality of data is low,
the clinical benefit is high and practical application simple. A Strong rating is given for avoiding fluoroquinolones in
prostate biopsy due to its legal implications in Europe.
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Figure 5.1: Prostate biopsy workflow to reduce infectious complications*
Indication for prostate biopsy?
Transperineal biopsy feasible?
Yes
No
Transperineal biopsy - 1st choice (⊕⊕⊝⊝)
with:
• perineal cleansing
• antibiotic prophylaxis
Transrectal biopsy – 2nd choice (⊕⊕⊝⊝)
with:
• povidone-iodine rectal preparation
• antibiotic prophylaxis
Fluoroquinolones licensed?
Yes
No
1.
Targeted prophylaxis: based on rectal
swab or stool cultures
2.
Augmented prophylaxis: two or more
different classes of antibiotics
3.
Alternative antibiotics (⊕⊝⊝⊝):
• fosfomycin trometamol (e.g. 3 g before
and 3 g 24-48 hrs after biopsy)
• cephalosporin (e.g. ceftriaxone 1 g i.m.;
cefixime 400 mg p.o. for 3 days starting
24 hrs before biopsy)
• aminoglycoside (e.g. gentamicin 3 mg/kg
i.v.; amikacin 15 mg/kg i.m.)
Duration of antibiotic prophylaxis ≥ 24 hrs
(⊕⊕⊝⊝)
1.
Targeted prophylaxis (⊕⊕⊝⊝): based
on rectal swab or stool cultures
2.
Augmented prophylaxis (⊕⊝⊝⊝):
3.
• Fluoroquinolone plus aminoglycoside
• Fluoroquinolone plus cephalosporin
Fluoroquinolone prophylaxis
(range: ⊕⊝⊝⊝ - ⊕⊕⊝⊝)
6.1.6 General guidelines for the treatment of prostate cancer
Recommendations
Radiotherapeutic treatment
Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary
function and low- or good prognosis intermediate-risk localised disease.
Offer LDR or high-dose rate brachytherapy boost combined with IMRT including
IGRT to patients with good urinary function and intermediate-risk disease with
Strength rating
Strong
Strong
adverse features or high-risk disease.
6.2.1.3 Summary of evidence and guidelines for the treatment of low-risk disease
Summary of evidence
Systematic biopsies have been scheduled in AS protocols, the number and frequency of biopsies
varied, there is no approved standard.
Although per-protocol MR scans are increasingly used in AS follow-up no conclusive evidence exist in
terms of their benefit/and whether biopsy may be ommitted based on the imaging findings.
Personalised risk-based approaches will ultimately replace protocol-based management of patients on
AS.
Recommendations
Active surveillance (AS)
Selection of patients
Perform a mpMRI before a confirmatory biopsy if no MRI has been performed
before the initial biopsy.
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Strength rating
Strong
PROSTATE CANCER - LIMITED UPDATE 2021
Radiotherapeutic treatment
Offer low-dose rate brachytherapy to patients with low-risk PCa, without a recent
transurethral resection of the prostate and a good International Prostatic Symptom
Score.
Other therapeutic options
Do not offer ADT monotherapy to asymptomatic men not able to receive any local
treatment.
Strong
Strong
6.2.2.5 Guidelines for the treatment of intermediate-risk disease
Recommendations
Active surveillance (AS)
Offer AS to highly selected patients with ISUP grade group 2 disease (i.e. < 10%
pattern 4, PSA < 10 ng/mL, < cT2a, low disease extent on imaging and biopsy)
accepting the potential increased risk of metastatic progression.
Radiotherapeutic treatment
Offer low-dose rate brachytherapy to intermediate-risk patients with ISUP grade 2
with < 33% of biopsy cores involved, without a recent transurethral resection of the
prostate and with a good International Prostatic Symptom Score.
For intensity-modulated radiotherapy (IMRT) plus image-guided radiotherapy (IGRT),
use a total dose of 76–78 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks
or 70 Gy/28 fx in 6 weeks), in combination with short-term androgen deprivation
therapy (ADT) (4 to 6 months).
In patients not willing to undergo ADT, use a total dose of IMRT plus IGRT
(76–78 Gy) or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx
in 6 weeks) or a combination with brachytherapy.
Strength rating
Weak
Strong
Strong
Weak
6.2.3.4 Guidelines for radical treatment of high-risk localised disease
Recommendation
Therapeutic options outside surgery and radiotherapy
Only offer ADT monotherapy to those patients unwilling or unable to receive any
form of local treatment if they have a prostate-specific antigen (PSA)-doubling time
< 12 months, and either a PSA > 50 ng/mL or a poorly-differentiated tumour.
Strength rating
Strong
6.2.5.7 Guidelines for adjuvant treatment in pN0 and pN1 disease after radical prostatectomy
Recommendation
Offer adjuvant intensity-modulated radiation therapy (IMRT) plus image-guided
radiation therapy (IGRT) to high-risk patients (pN0) with ISUP grade group 4–5 and
pT3 ± positive margins.
Strength rating
Strong
6.2.6.5 Recommendations for the management of persistent PSA after radical prostatectomy
Recommendation
Offer a prostate-specific membrane antigen positron emission tomography (PSMA
PET) scan to men with a persistent PSA > 0.2 ng/mL if the results will influence
subsequent treatment decisions.
Strength rating
Weak
6.3.14 Guidelines for second-line therapy after treatment with curative intent
Local salvage treatment
Strength rating
Recommendations for biochemical recurrence (BCR) after radical prostatectomy
Offer monitoring, including prostate-specific antigen (PSA), to EAU BCR low-risk
Weak
patients.
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Offer early salvage intensity-modulated radiotherapy plus image-guided
radiotherapy to men with two consecutive PSA rises.
A negative PET/CT scan should not delay salvage radiotherapy (SRT), if otherwise
indicated.
Do not wait for a PSA threshold before starting treatment. Once the decision for
SRT has been made, SRT (at least 66 Gy) should be given as soon as possible.
Recommendations for BCR after radiotherapy
Offer monitoring, including prostate-specific antigen (PSA), to EAU Low-Risk BCR
patients.
Only offer salvage radical prostatectomy (RP), brachytherapy, high-intensity focused
ultrasound, or cryosurgical ablation to highly selected patients with biopsy proven
local recurrence within a clinical trial setting or well-designed prospective cohort
study undertaken in experienced centres.
Strong
Strong
Strong
Weak
Strong
6.4.9 Guidelines for the first-line treatment of metastatic disease
Recommendations
Discuss combination therapy including ADT plus systemic therapy with all M1 patients.
Do not offer ADT monotherapy to patients whose first presentation is M1 disease
if they have no contraindications for combination therapy and have a sufficient
life expectancy to benefit from combination therapy and are willing to accept the
increased risk of side effects.
Do not offer ADT combined with surgery to M1 patients outside of clinical trials.
Only offer metastasis-directed therapy to M1 patients within a clinical trial setting or
well-designed prospective cohort study.
Strength rating
Strong
Strong
Strong
Strong
6.5.14 Summary of evidence and guidelines for life-prolonging treatments of castrate-resistant disease
Recommendations
Treat patients with mCRPC with life-prolonging agents.
Offer mCRPC patients somatic and/or germline molecular testing as well as testing
for mismatch repair deficiencies or microsatellite instability.
Strength rating
Strong
Strong
6.5.15 Guidelines for systematic treatments of castrate-resistant disease
Recommendations
Base the choice of treatment on the performance status, symptoms, co-morbidities,
location and extent of disease, genomic profile, patient preference, and on the
previous treatment for hormone-sensitive metastatic PCa (mHSPC) (alphabetical
order: abiraterone, cabazitaxel, docetaxel, enzalutamide, olaparib, radium-223,
sipuleucel-T).
Offer patients with mCRPC who are candidates for cytotoxic therapy and are
chemotherapy naïve docetaxel with 75 mg/m2 every 3 weeks.
Offer patients with mCRPC and progression following docetaxel chemotherapy
further life-prolonging treatment options, which include abiraterone, cabazitaxel,
enzalutamide, radium-223 and olaparib in case of DNA homologous recombination
repair (HRR) alterations.
Base further treatment decisions of mCRPC on performance status, previous
treatments, symptoms, co-morbidities, genomic profile, extent of disease and
patient preference.
Offer abiraterone or enzalutamide to patients previously treated with one or two lines
of chemotherapy.
Avoid sequencing of androgen receptor targeted agents,
Offer chemotherapy to patients previously treated with abiraterone or enzalutamide.
Offer cabazitaxel to patients previously treated with docetaxel.
Recommendations for BCR after radiotherapy
Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pretreated mCRPC patients
with relevant DNA repair gene mutations.
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Strength rating
Strong
Strong
Strong
Strong
Strong
Weak
Strong
Strong
Strong
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7.2.6 Guidelines for follow-up during hormonal treatment
Recommendations
In M1 patients, schedule follow-up at least every 3 to 6 months.
In patients on long-term androgen deprivation therapy (ADT), measure initial bone
mineral density to assess fracture risk.
During follow-up of patients receiving ADT, check PSA and testosterone levels and
monitor patients for symptoms associated with metabolic syndrome as a side effect
of ADT. As a minimum requirement, include a disease-specific history, haemoglobin,
serum creatinine, alkaline phosphatase, lipid profiles and HbA1c level measurements.
When disease progression is suspected, restaging is needed and the subsequent
follow up adapted/individualised.
In M1 patients perform regular imaging (CT and bone scan) even without PSA
progression.
In patients with suspected progression, assess the testosterone level. By definition,
castration- resistant PCa requires a testosterone level < 50 ng/dL (< 1.7 nM/L).
Strength rating
Strong
Strong
Strong
Strong
Weak
Strong
8.3.2.5 Guidelines for quality of life in men undergoing systemic treatments
Recommendations
Strength rating
Advise men on ADT to maintain a healthy weight and diet, to stop smoking,
Strong
reduce alcohol to < 2 units daily and have yearly screening for diabetes and
hypercholesterolemia. Ensure that calcium and vitamin D meet recommended levels.
Offer anti-resorptive therapy to men on long term ADT with either a BMD T-score of Strong
<-2.5 or with an additional clinical risk factor for fracture or annual bone loss on ADT
is confirmed to exceed 5%.
2.
METHODS
2.1
Data identification
For the 2020 PCa Guidelines, new and relevant evidence has been identified, collated and appraised through a
comprehensive review of the GRADE forms [see definition below) and associated recommendation. Changes in
recommendations were only considered on the basis of high level evidence (i.e. systematic reviews with metaanalysis, randomised controlled trials [RCTs], and prospective comparative studies) published in the English
language. A total of 279 new references were added to the 2021 PCa Guidelines. Additional information can
be found in the general Methodology section of this print and online at the EAU website: https://uroweb.org/
guidelines/policies-and-methodological-documents/.
For each recommendation within the guidelines there is an accompanying online strength rating form, the basis
of which is a modified GRADE methodology [3, 4]. These forms address a number of key elements namely:
1.
the overall quality of the evidence which exists for the recommendation, references used in
this text are graded according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [5];
2.
the magnitude of the effect (individual or combined effects);
3.
the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
4.
the balance between desirable and undesirable outcomes;
5.
the impact of patient values and preferences on the intervention;
6.
the certainty of those patient values and preferences.
These key elements are the basis which panels use to define the strength rating of each recommendation.
The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [6]. The strength of each
recommendation is determined by the balance between desirable and undesirable consequences of alternative
management strategies, the quality of the evidence (including certainty of estimates), and nature and variability
of patient values and preferences. The strength rating forms will be available online.
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A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address. In addition,
the International Society of Geriatric Oncology (SIOG), the European Society for Radiotherapy & Oncology
(ESTRO), the European Society for Urogenital Radiology (ESUR), the European Association of Nuclear Medicine
(EANM) and the International Society of Urological Pathology (ISUP) have endorsed the PCa Guidelines.
2.2
Review
All radiotherapy sections from the 2021 print were peer-reviewed prior to publication, as were Sections 5.4
(Evaluating life expectancy and health status) and Chapter 8 (Quality of life). Publications ensuing from systematic
reviews have all been peer-reviewed.
2.3
Future goals
Results of ongoing and new systematic reviews will be included in the 2022 update of the PCa Guidelines:
•
•
•
•
•
•
A systematic review on the deferred treatment with curative intent for localised PCa, explore
heterogeneity of definitions, thresholds and criteria [7];
A systematic review on progression criteria and quality of life (QoL) of patients diagnosed with PCa;
A systematic review on the impact of surgeon and hospital caseload volume on oncological and nononcological outcomes after radical prostatectomy for non-metastatic prostate cancer [8];
Evaluation of oncological outcomes and data quality in studies assessing nerve sparing versus non-nerve
sparing radiccal prostatectomy in non-metastatic prostate cancer: a systematic review [9];
Patient- and tumor-related prognostic factors for post-operative incontinence after radical prostatectomy
for non-metastatic prostate cancer: A systematic review and meta-analysis [10];
Care pathways for the various stages of PCa management are being developed. These pathways will, in
due time, inform treatment flowcharts and an interactive app.
3.
EPIDEMIOLOGY AND AETIOLOGY
3.1
Epidemiology
Prostate cancer is the second most commonly diagnosed cancer in men, with an estimated 1.1 million
diagnoses worldwide in 2012, accounting for 15% of all cancers diagnosed [11]. The frequency of autopsydetected PCa is roughly the same worldwide [12]. A systematic review of autopsy studies reported a
prevalence of PCa at age < 30 years of 5% (95% confidence interval [CI]: 3–8%), increasing by an odds ratio
(OR) of 1.7 (1.6–1.8) per decade, to a prevalence of 59% (48–71%) by age > 79 years [13].
The incidence of PCa diagnosis varies widely between different geographical areas, being highest
in Australia/New Zealand and Northern America (age-standardised rates [ASR] per 100,000 of 111.6 and 97.2,
respectively), and in Western and Northern Europe (ASRs of 94.9 and 85, respectively), largely due to the
use of prostate-specific antigen (PSA) testing and the aging population. The incidence is low in Eastern and
South-Central Asia (ASRs of 10.5 and 4.5, respectively). Rates in Eastern and Southern Europe were low but
have shown a steady increase [11, 12]. Incidence and disease stage distibution patters follow (inter)national
organisations‘ recommendations (see Section 5.1) [14].
There is relatively less variation in mortality rates worldwide, although rates are generally high in
populations of African descent (Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 19 and
14), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [11].
3.2
Aetiology
3.2.1
Family history/hereditary prostate cancer
Family history and ethnic background are associated with an increased PCa incidence suggesting a genetic
predisposition [15, 16]. Only a small subpopulation of men with PCa have true hereditary disease. Hereditary
PCa (HPCa) is associated with a six to seven year earlier disease onset but the disease aggressiveness and
clinical course does not seem to differ in other ways [15, 17].
In a large USA population database, HPCa (in 2.18% of participants) showed a relative risk (RR) of 2.30 for
diagnosis of any PCa, 3.93 for early-onset PCa, 2.21 for lethal PCa, and 2.32 for clinically significant PCa
(csPCa) [18]. These increased risks of HPCa were higher than for familial PCa (> 2 first- or second-degree
relatives with PCa on the same side of the pedigree), or familial syndromes such as hereditary breast and
ovarian cancer and Lynch syndrome. The probability of high-risk PCa at age 65 was 11.4% (vs. a population
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risk of 1.4%) in a Swedish population-based study [19].
3.2.1.1
Germline mutations and prostate cancer
Genome-wide association studies have identified more than 100 common susceptibility loci contributing to
the risk for PCa [20-22]. Clinical cohort studies have reported rates of 15% to 17% of germline mutations
independent of stage [23, 24]. Giri et al. studied clinical genetic data from men with PCa unselected for
metastatic disease undergoing multigene testing across the US [23]. The authors found that 15.6% of men
with PCa have pathogenic variants identified in genes tested (BRCA1, BRCA2, HOXB13, MLH1, MSH2, PMS2,
MSH6, EPCAM, ATM, CHEK2, NBN, and TP53), and 10.9% of men have germline pathogenic variants in DNA
repair genes (see Table 5.2). Pathogenic variants were most commonly identified in BRCA2 (4.5%), CHEK2
(2.2%), ATM (1.8%), and BRCA1 (1.1%) [23]. Presence of Gleason 8 or higher was significantly associated with
DNA repair pathogenic variants (OR 1.85 [95% CI: 1.22–2.80], p = 0.004) [23].
Nicolosi and colleagues reported frequency and distribution of positive germline variants in 3,607 unselected
PCa patients and found that 620 (17.2%) had a pathogenic germline variant [24]. The percentage of BRCA1/2
mutations in this study was 6%. Among unselected men with metastatic PCa, an incidence of 11.8% was
found for germline mutations in genes mediating DNA-repair processes [25]. Most mutations were seen in
BRCA2 (5.35%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), and PALB2 (0.4%).
Targeted genomic analysis of genes associated with an increased risk of PCa could offer options to
identify families at high risk [26, 27].
Nyberg et al. presented results of a prospective cohort study of male BRCA1 and BRCA2 carriers and their
PCa risk confirming BRCA2 association with aggressive PCa [28]. Mutations in the PCa cluster region of the
BRCA2 gene may increase the PCa risk in particular. Castro and colleagues analysed the outcomes of 2,019
patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 non-carriers). Prostate cancers with
germline BRCA1/2 mutations were more frequently associated with ISUP > 4, T3/T4 stage, nodal involvement,
and metastases at diagnosis than PCa in non-carriers [29]. BReast-CAncer susceptibility gene mutation
carriers were reported to have worse outcome when compared to non-carriers after local therapy [30].
In a retrospective study of 313 patients who died of PCa and 486 patients with low-risk localised
PCa, the combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients
(6.07%) than in localised PCa patients (1.44%) [31].
The Identification of Men With a Genetic Predisposition to ProstAte Cancer (IMPACT) study, which evaluates
targeted PCa screening (annually, biopsy recommended if PSA > 3.0 ng/mL) using PSA in men aged 40–69
years with germline BRCA1/2 mutations, has recently reported interim results [32]. The authors found that after
3 years of screening, BRCA2 mutation carriers were associated with a higher incidence of PCa, a younger
age of diagnosis, and more clinically significant tumours compared with non-carriers. The influence of BRCA1
mutations on PCa remained unclear. No differences in age or tumour characteristics were detected between
BRCA1 carriers and BRCA1 non-carriers. Limitations of the IMPACT study include the lack of multiparametric
magnetic resonance imaging (mpMRI) data and targeted biopsies as it was initiated before that era.
Similarly, Mano et al. reported on an Israeli cohort in which men with BRCA1 and BRCA2 mutations had a
significantly higher incidence of malignant disease. In contrast to findings of the IMPACT study, the rate of PCa
among BRCA1 carriers was more than twice as high (8.6% vs. 3.8%) compared to the general population [33].
3.2.2
Risk factors
A wide variety of exogenous/environmental factors have been discussed as being associated with the risk
of developing PCa or as being aetiologically important for the progression from latent to clinical PCa [34].
Japanese men have a lower PCa risk compared to men from the Western world. However, as Japanese men
move from Japan to California, their risk of PCa increases, approaching that of American men, implying a role
of environmental or dietary factors [35]. However, currently there are no known effective preventative dietary or
pharmacological interventions.
3.2.2.1
Metabolic syndrome
The single components of metabolic syndrome (MetS) hypertension (p = 0.035) and waist circumference
> 102 cm (p = 0.007) have been associated with a significantly greater risk of PCa, but in contrast, having
> 3 components of MetS is associated with a reduced risk (OR: 0.70, 95% CI: 0.60–0.82) [36, 37].
3.2.2.1.1 Diabetes/metformin
On a population level, metformin users (but not other oral hypoglycaemic agents) were found to be at a
decreased risk of PCa diagnosis compared with never-users (adjusted OR: 0.84, 95% CI: 0.74–0.96) [38].
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In 540 diabetic participants of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study,
metformin use was not significantly associated with PCa and therefore not advised as a preventive measure
(OR: 1.19, p = 0.50) [39]. The ongoing Systemic Therapy in Advancing or Metastatic Prostate Cancer:
Evaluation of Drug Efficacy (STAMPEDE) trial assesses metformin use in advanced PCa (Arm K) [40].
3.2.2.1.2 Cholesterol/statins
A meta-analysis of 14 large prospective studies did not show an association between blood total cholesterol, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol levels and the risk of either overall PCa or highgrade PCa [36]. Results from the REDUCE study also did not show a preventive effect of statins on PCa risk [39].
3.2.2.1.3 Obesity
Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses
(OR: 0.79, p = 0.01), but increased risk of high-grade PCa (OR: 1.28, p = 0.042) [41]. This effect seems mainly
explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated
height or BMI [42].
3.2.2.2
Dietary factors
The association between a wide variety of dietary factors and PCa have been studied (Table 3.1).
Table 3.1: Dietary factors that have been associated with PCa
Alcohol
Dairy
Fat
Tomatoes
(lycopenes/
carotenes)
Meat
Phytoestrogens
Soy
(phytoestrogens
[isoflavones/
coumestans])
Vitamin D
High alcohol intake, but also total abstention from alcohol has been associated with
a higher risk of PCa and PCa-specific mortality [43]. A meta-analysis shows a doseresponse relationship with PCa [44].
A weak correlation between high intake of protein from dairy products and the risk of
PCa was found [45].
No association between intake of long-chain omega-3 poly-unsaturated fatty acids
and PCa was found [46]. A relation between intake of fried foods and risk of PCa may
exist [47].
A trend towards a favourable effect of tomato intake (mainly cooked) and lycopenes on
PCa incidence has been identified in meta-analyses [48, 49]. Randomised controlled
trials comparing lycopene with placebo did not identify a significant decrease in the
incidence of PCa [50].
A meta-analysis did not show an association between red meat or processed meat
consumption and PCa [51].
Phytoestrogen intake was significantly associated with a reduced risk of PCa in a
meta-analysis [52].
Total soy food intake has been associated with reduced risk of PCa, but also with
increased risk of advanced disease [53, 54].
A U-shaped association has been observed, with both low- and high vitamin-D
concentrations being associated with an increased risk of PCa, and more strongly for
high-grade disease [54, 55].
Vitamin E/Selenium An inverse association of blood, but mainly nail selenium levels (reflecting long-term
exposure) with aggressive PCa have been found [56, 57]. Selenium and Vitamin E
supplementation were, however, found not to affect PCa incidence [58].
3.2.2.3
Hormonally active medication
3.2.2.3.1 5-alpha-reductase inhibitors (5-ARIs)
Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (~25%, for
ISUP grade 1 cancer only), this must be weighed against treatment-related side effects as well as the potential
small increased risk of high-grade PCa [59-61]. None of the available 5-ARIs have been approved by the
European Medicines Agency (EMA) for chemoprevention.
3.2.2.3.2 Testosterone
Hypogonadal men receiving testosterone supplements do not have an increased risk of PCa [62]. A pooled
analysis showed that men with very low concentrations of free testosterone (lowest 10%) have a below average
risk (OR: 0.77) of PCa [63].
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3.2.2.4
Other potential risk factors
A significantly higher rate of ISUP > 2 PCas (hazard ratio [HR]: 4.04) was found in men with inflammatory
bowel disease when compared to the general population [64]. Balding was associated with a higher risk
of PCa death [65]. Gonorrhoea was significantly associated with an increased incidence of PCa (OR: 1.31,
95% CI: 1.14–1.52) [66]. Occupational exposure may also play a role, based on a meta-analysis which
revealed that night-shift work is associated with an increased risk (2.8%, p = 0.030) of PCa [67]. Current
cigarette smoking was associated with an increased risk of PCa death (RR: 1.24, 95% CI: 1.18–1.31) and with
aggressive tumour features and worse prognosis, even after cessation [68, 69]. A meta-analysis on Cadmium
(Cd) found a positive association (magnitude of risk unknown due to heterogeneity) between high Cd exposure
and risk of PCa for occupational exposure, but not for non-occupational exposure, potentially due to higher Cd
levels during occupational exposure [70]. Men positive for human papillomavirus-16 may be at increased risk
[71]. Plasma concentration of the estrogenic insecticide chlordecone is associated with an increase in the risk
of PCa (OR: 1.77 for highest tertile of values above the limit of detection) [72].
A number of other factors previously linked to an increased risk of PCa have been disproved
including vasectomy [73] and self-reported acne [74]. There are conflicting data about the use of aspirin or
nonsteroidal anti-inflammatory drugs and the risk of PCa and mortality [75, 76].
Ultraviolet radiation exposure decreased the risk of PCa (HR: 0.91, 95% CI: 0.88–0.95) [77]. A review
found a small but protective association of circumcision status with PCa [78]. Higher ejaculation frequency
(> 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [79].
The associations with PCa identified to date lack evidence for causality. As a consequence there is
no data to suggest effective preventative strategies.
3.2.3
Summary of evidence for epidemiology and aetiology
Summary of evidence
Prostate cancer is a major health concern in men, with incidence mainly dependent on age.
Genetic factors are associated with risk of (aggressive) PCa.
A variety of exogenous/environmental factors have been associated with PCa incidence and prognosis.
Selenium or vitamin-E supplements have no beneficial effect in preventing PCa.
In hypogonadal men, testosterone supplements do not increase the risk of PCa.
No specific preventive or dietary measures are recommended to reduce the risk of developing PCa.
4.
CLASSIFICATION AND STAGING SYSTEMS
4.1
Classification
LE
3
3
3
2a
2
1a
The objective of a tumour classification system is to combine patients with a similar clinical outcome. This
allows for the design of clinical trials on relatively homogeneous patient populations, the comparison of
clinical and pathological data obtained from different hospitals across the world, and the development of
recommendations for the treatment of these patient populations. Throughout these Guidelines the 2017
Tumour, Node, Metastasis (TNM) classification for staging of PCa (Table 4.1) [80] and the EAU risk group
classification, which is essentially based on D’Amico’s classification system for PCa, are used (Table 4.2) [81].
The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence (BCR)
after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Multiparametric resonance imaging and
targeted biopsy may cause a stage shift in risk classification systems [82].
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Table 4.1: Clinical Tumour Node Metastasis (TNM) classification of PCa [80]
T - Primary Tumour (stage based on digital rectal examination [DRE] only)
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
T1
Clinically inapparent tumour that is not palpable
T1a
Tumour incidental histological finding in 5% or less of tissue resected
T1b
Tumour incidental histological finding in more than 5% of tissue resected
T1c
Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA])
T2
Tumour that is palpable and confined within the prostate
T2a
Tumour involves one half of one lobe or less
T2b
Tumour involves more than half of one lobe, but not both lobes
T2c
Tumour involves both lobes
T3
Tumour extends through the prostatic capsule
T3a
Extracapsular extension (unilateral or bilateral)
T3b
Tumour invades seminal vesicle(s)
T4
Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum,
levator muscles, and/or pelvic wall
N - Regional (pelvic) Lymph Nodes1
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
M - Distant Metastasis2
M0
No distant metastasis
M1
Distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)
1
2
Metastasis no larger than 0.2 cm can be designated pNmi.
When more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most
advanced category.
Clinical T stage only refers to DRE findings; local imaging findings are not considered in the TNM classification.
Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the clinical
TNM, except for clinical stage T1 and the T2 substages. Pathological stages pT1a/b/c do not exist and
histopathologically confirmed organ-confined PCas after RP are pathological stage pT2. The current Union for
International Cancer Control (UICC) no longer recognises pT2 substages [80].
4.2
Gleason score and International Society of Urological Pathology 2014 grade
In the original Gleason grading system, 5 Gleason grades (ranging from 1–5) based on histological tumour
architecture were distinguished, but in the 2005 and subsequent 2014 International Society of Urological
Pathology (ISUP) Gleason score (GS) modifications Gleason grades 1 and 2 were eliminated [83, 84]. The
2005 ISUP modified GS of biopsy-detected PCa comprises the Gleason grade of the most extensive (primary)
pattern, plus the second most common (secondary) pattern, if two are present. If one pattern is present, it
needs to be doubled to yield the GS. For three grades, the biopsy GS comprises the most common grade plus
the highest grade, irrespective of its extent. The grade of intraductal carcinoma should also be incorporated in
the GS [85]. In addition to reporting of the carcinoma features for each biopsy, an overall (or global) GS based
on the carcinoma-positive biopsies can be provided. The global GS takes into account the extent of each
grade from all prostate biopsies. The 2014 ISUP endorsed grading system [84, 86] limits the number of PCa
grades, ranging them from 1 to 5 (see Table 4.2), in order to:
1.
align the PCa grading with the grading of other carcinomas;
2.
eliminate the anomaly that the most highly differentiated PCas have a GS 6;
3.
to further define the clinically highly significant distinction between GS 7(3+4) and 7(4+3) PCa [87].
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Table 4.2: EAU risk groups for biochemical recurrence of localised and locally advanced prostate cancer
Definition
Low-risk
PSA < 10 ng/mL
Intermediate-risk
PSA 10-20 ng/mL
High-risk
PSA > 20 ng/mL
any PSA
and GS < 7 (ISUP grade 1) or GS 7 (ISUP grade 2/3) or GS > 7 (ISUP grade 4/5) any GS (any ISUP grade)
and cT1-2a
or cT2b
or cT2c
Localised
cT3-4 or cN+
Locally advanced
GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.
Table 4.3: International Society of Urological Pathology 2014 grade (group) system
Gleason score
ISUP grade
2-6
1
7 (3+4)
2
7 (4+3)
3
8 (4+4 or 3+5 or 5+3)
4
9-10
5
4.3
Prognostic relevance of stratification
Comparison of various risk stratification tools using death of disease as outcome parameter revealed that
3-tiered systems, including the EAU and D’Amico risk classification, were inferior to the MSKCC nomograms,
the CAPRA score and the 5-tiered CPG system [88]. Similarly, using death of disease as outcome parameter a
9-tier risk clinical prognostic stage group system, based on age, cT, cN, ISUP grade, percentage positive cores and
PSA as input variables further improved risk stratification in patients treated by surgery or radiotherapy (RT) [89].
A more precise stratification of the clinically heterogeneous subset of intermediate-risk group
patients could provide a better framework for their management. The adoption of the current ISUP grading
system, defining the split-up of GS 7 cancers into ISUP grade 2 (primary Gleason grade 3) and ISUP grade
3 (primary Gleason grade 4) because of their distinct prognostic impact strengthens such a separation of the
intermediate-risk group into a low-intermediate (ISUP grade 2) and high-intermediate (ISUP grade 3) risk group
[86] (see Section 6.2.2).
Emerging clinical data support this distinction between favourable- and unfavourable-risk patient
categories within the intermediate-risk group [87, 90].
4.4
Guidelines for classification and staging systems
Recommendations
Strength rating
Use the Tumour, Node, Metastasis (TNM) classification for staging of PCa.
Strong
Use the International Society of Urological Pathology (ISUP) 2014 system for grading of PCa. Strong
5.
DIAGNOSTIC EVALUATION
5.1
Screening and early detection
5.1.1
Screening
Population or mass screening is defined as the ‘systematic examination of asymptomatic men (at risk)’ and is
usually initiated by health authorities. The co-primary objectives are:
•
reduction in mortality due to PCa;
•
a maintained QoL as expressed by QoL-adjusted gain in life years (QALYs).
Prostate cancer mortality trends range widely from country to country in the industrialised world [91]. Mortality
due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries.
Currently, screening for PCa still remains one of the most controversial topics in the urological literature [92].
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Initial widespread aggressive screening in USA was associated with a decrease in mortality [93].
In 2012 the US Preventive Services Task Force (USPSTF) released a recommendation against PSA-based
screening [94], which was adopted in the 2013 AUA Guidelines [95] and resulted in a reduction in the use
of PSA for early detection [96]. This reduction in the use of PSA testing was associated with higher rates of
advanced disease at diagnosis (e.g., a 6% increase in the number of patients with metastatic PCa [14, 97-100].
While PCa mortality had decreased for two decades since the introduction of PSA testing [101], the incidence
of advanced disease and, possibly, cancer-related mortality slowly increased from 2008 and accelerated
in 2012 [102]. Moreover, additional evidence suggests a long-term benefit of PSA population screening in
terms of reduction of cancer-specific mortality [103, 104]. However, the temporal relationship between PSA
testing and decreased mortality, as well as a rising mortality following immediately after the USPSTF and AUA
Guidelines recommendation against PSA testing questions the direct causative link between both points.
In 2017 the USPSTF issued an updated statement suggesting that men aged 55–69 should be informed about
the benefits and harms of PSA-based screening as this might be associated with a small survival benefit. The
USPSTF has now upgraded this recommendation to a grade C [105], from a previous grade ‘D’ [105-107]. They
highlighted the fact that the decision to be screened should be an individual one. The grade D recommendation
remains in place for men over 70 years old. This represents a major switch from discouraging PSA-based
screening (grade D) to offering early diagnosis to selected men depending on individual circumstances.
A comparison of systematic and opportunistic screening suggested over-diagnosis and mortality
reduction in the systematic screening group compared to a higher over-diagnosis with a marginal survival
benefit, at best, in the opportunistic screening regimen [108].
A Cochrane review published in 2013 [109], which has since been updated [110], presents the main overview
to date. The findings of the updated publication (based on a literature search until April 3, 2013) are almost
identical to the 2009 review:
•
Screening is associated with an increased diagnosis of PCa (RR: 1.3, 95% CI: 1.02–1.65).
•
Screening is associated with detection of more localised disease (RR: 1.79, 95% CI: 1.19–2.70) and less
advanced PCa (T3–4, N1, M1) (RR: 0.80, 95% CI: 0.73–0.87).
•
From the results of 5 RCTs, randomising more than 341,000 men, no PCa-specific survival benefit was
observed (RR: 1.00, 95% CI: 0.86–1.17). This was the main endpoint in all trials.
•
From the results of four available RCTs, no overall survival (OS) benefit was observed (RR: 1.00, 95% CI:
0.96–1.03).
The included studies applied a range of different screening measures and testing intervals in patients who had
ondergone prior PSA testing, to various degrees. None included the use of risk calculators, MRI prior to biopsy
(vs. a single PSA threshold) or AS (as an alternative to RP) which no longer reflects current standard practice.
The diagnostic tool (i.e. biopsy procedure) was not associated with increased mortality within 120 days after
biopsy in screened men as compared to controls in the two largest population-based screening populations
(ERSPC and PLCO), in contrast to a 120-day mortality rate of 1.3% in screened vs. 0.3% in controls,
respectively, in a Canadian population-based screening study [111]. Increased diagnosis has historically led
to over-treatment with associated side effects. However, despite this, the impact on the patient’s overall QoL
is still unclear. Population level screening has never been shown to be detrimental [112-114]. Nevertheless,
all these findings have led to strong advice against systematic population-based screening in most countries,
including those in Europe.
In case screening is considered, a single PSA test is not enough based on the Cluster Randomized Trial
of PSA Testing for Prostate Cancer (CAP) trial. The CAP trial evaluated a single PSA screening vs. controls
not undergoing PSA screening on PCa detection in men aged 50 to 69 years old. The single PSA screening
intervention detected more low-risk PCa cases but had no significant effect on PCa mortality after a median
follow-up of 10 years [115].
Since 2013, the European Randomized Study of Screening for Prostate Cancer (ERSPC) data have
been updated with 16 years of follow-up (see Table 5.1) [116]. The key message is that with extended followup, the mortality reduction remains unchanged (21%, and 29% after non-compliance adjustment). However
the number needed to screen (NNS) and to treat is decreasing, and is now below the NNS observed in breast
cancer trials [116, 117]. Long-term follow-up of the PLCO (Prostate, Lung, Colon, Ovarian cancer screening
trial) showed no survival benefit for screening at a median follow-up of 16.7 years but a significant 17%
increase in Gleason score 2–6 cancers and 11% decrease in Gleason score 8–10 cancers [118].
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Table 5.1: Follow-up data from the ERSPC study [116]
Years of follow-up
Number needed to screen
Number needed to treat
9
1,410
48
11
979
35
13
781
27
16
570
18
5.1.2
Early detection
An individualised risk-adapted strategy for early detection may still be associated with a substantial risk of
over-diagnosis. It is essential to remember that breaking the link between diagnosis and active treatment is the
only way to decrease over-treatment, while still maintaining the potential benefit of individual early diagnosis for
men requesting it [16, 119].
Men at elevated risk of having PCa are those > 50 years [120] or at age > 45 years with a family history of
PCa (either paternal or maternal) [121] or of African descent [122, 123]. Men of African descent are more likely
to be diagnosed with more advanced disease [124] and upgrade was more frequent after prostatectomy as
compared to Caucasian men (49% vs. 26%) [125].
Germline mutations are associated with an increased risk of the development of aggressive PCa, i.e.
BRCA2 [126, 127]. Prostate-specific antigen screening in male BRCA1 and 2 carriers detected more significant
cancers at a younger age compared to non-mutation carriers [32, 33].
Men with a baseline PSA < 1 ng/mL at 40 years and < 2 ng/mL at 60 years are at decreased risk of PCa
metastasis or death from PCa several decades later [128, 129].
The use of DRE alone in the primary care setting had a sensitivity and specificity below 60%, possibly due to
inexperience, and can therefore not be recommended to exclude PCa [130]. Informed men requesting an early
diagnosis should be given a PSA test and undergo a DRE [131]. Prostate-specific antigen measurement and
DRE need to be repeated [115], but the optimal intervals for PSA testing and DRE follow-up are unknown as
they varied between several prospective trials. A risk-adapted strategy might be a consideration, based on the
initial PSA level. This could be every 2 years for those initially at risk, or postponed up to 8 to 10 years in those
not at risk with an initial PSA < 1 ng/mL at 40 years and a PSA < 2 ng/mL at 60 years of age and a negative
family history [132]. An analysis of ERSPC data supports a recommendation for an 8-year screening interval in
men with an initial PSA concentration < 1 μg/L; fewer than 1% of men with an initial PSA concentration < 1 ng/mL
were found to have a concentration above the biopsy threshold of 3 μg/L at 4-year follow-up; the cancer
detection rate by 8 years was close to 1% [133]. The long-term survival and QoL benefits of extended PSA
re-testing (every 8 years) remain to be proven at a population level. Data from the Goteborg arm of the ERSPC
trial suggest that the age at which early diagnosis should be stopped remains controversial, but an individual’s
life expectancy must definitely be taken into account. Men who have less than a 15-year life expectancy are
unlikely to benefit, based on data from the Prostate Cancer Intervention Versus Observation Trial (PIVOT)
and the ERSPC trials. Furthermore, although there is no simple tool to evaluate individual life expectancy;
co-morbidity is at least as important as age. A detailed review can be found in Section 5.4 ‘Estimating life
expectancy and health status’ and in the SIOG Guidelines [134].
Multiple tools are now available to determine the need for a biopsy to establish the diagnosis of a
PCa, including imaging by MRI, if available (see Section 5.2.4).
Urine and serum biomarkers as well as tissue-based biomarkers have been proposed for improving detection
and risk stratification of PCa patients, potentially avoiding unnecessary biopsies. However, further studies are
necessary to validate their efficacy [135]. At present there is too limited data to implement these markers into
routine screening programmes (see Section 5.2.3).
Risk calculators may be useful in helping to determine (on an individual basis) what the potential risk of cancer
may be, thereby reducing the number of unnecessary biopsies. Several tools developed from cohort studies
are available including:
•
the PCPT cohort: PCPTRC 2.0 http://myprostatecancerrisk.com/;
•
the ERSPC cohort: http://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators;
An updated version was presented in 2017 including prediction of low and high risk now also based on
the ISUP grading system and presence of cribriform growth in histology [136].
•
a local Canadian cohort: https://sunnybrook.ca/content/?page=asure-calc (among others).
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Since none of these risk calculators has clearly shown superiority, it remains a personal decision as to which
one to use [137]. A comparative analysis showed risk calculators containing MRI to be most predictive,
however, regional modifications may be required before implementation [138].
5.1.3
Genetic testing for inherited prostate cancer
Increasing evidence supports the implementation of genetic counselling and germline testing in early detection
and PCa management. Several commercial screening panels are now available to assess main PCa risk genes
[139]. However, it remains unclear when germline testing should be considered and how this may impact
localised and metastatic disease management. Germline BRCA1 and BRCA2 mutations occur in approximately
0.2% to 0.3% of the general population [140]. It is important to understand the difference between somatic
testing, which is performed on the tumour, and germline testing, which is performed on blood or saliva and
identifies inherited mutations. Genetic counselling is required prior to and after undergoing germline testing.
Germline mutations can drive the development of aggressive PCa. Therefore, the following men with a personal
or family history of PCa or other cancer types arising from DNA repair gene mutations should be considered for
germline testing:
•
Men with metastatic PCa;
•
Men with high-risk PCa and a family member diagnosed with PCa at age < 60 years;
•
Men with multiple family members diagnosed with csPCa at age < 60 years or a family member who died
from PCa cancer;
•
Men with a family history of high-risk germline mutations or a family history of multiple cancers on the
same side of the family.
Further research in this field (including not so well-known germline mutations) is needed to develop screening,
early detection and treatment paradigms for mutation carriers and family members.
Table 5.2: Germline mutations in DNA repair genes associated with increased risk of prostate cancer
Gene
BRCA2
Location Prostate Cancer risk Findings
13q12.3 - 2.5 to 4.6 [141, 142] • up to 12 % of men with metastatic PCa harbour
germline mutations in 16 genes (including BRCA2
-P
Ca at 55 years or
[5.3%]) [25]
under: RR: 8–23
• 2% of men with early-onset PCa harbour germline
[141, 143]
mutations in the BRCA2 gene [141]
• BRCA2 germline alteration is an independent
predictor of metastases and worse PCa-specific
survival [29, 144]
ATM
11q22.3 RR: 6.3 for metastatic • higher rates of lethal PCa among mutation carriers [31]
prostate [25]
• up to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including ATM [1.6%]) [25]
CHEK2
22q12.1 OR 3.3 [145, 146]
• up to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including CHEK2 [1.9%]) [25]
BRCA1
17q21
RR: 1.8–3.8 at 65
• higher rates of lethal PCa among mutation carriers [31]
years or under
• up to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including BRCA1 [0.9%]) [25]
[147, 148]
HOXB13
17q21.2 OR 3.4–7.9 [26, 149] • significantly higher PSA at diagnosis, higher Gleason
score and higher incidence of positive surgical margins
in the radical prostatectomy specimen than non-carriers
[150]
RR: 3.7 [151]
• Mutations in MMR genes are responsible for Lynch
MMR genes 3p21.3
syndrome [146]
2p21
MLH1
• MSH2 mutation carriers are more likely to develop PCa
2p16
MSH2
than other MMR gene mutation carriers [152]
7p22.2
MSH6
PMS2
BRCA2 = breast cancer gene 2; ATM = ataxia telangiectasia mutated; CHEK2 = checkpoint kinase 2;
BRCA1 = breast cancer gene 1; HOXB13 = homeobox B13; MMR = mismatch repair; MLH1 = mutL homolog 1;
MSH2 = mutS homolog 2; MSH6 = mutS homolog 6; PMS2 = post-meiotic segregation increased 2;
PCa = prostate cancer; RR = relative risk; OR = odds ratio.
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5.1.4
Guidelines for germline testing*
Recommendations
Consider germline testing in men with metastatic PCa.
Consider germline testing in men with high-risk PCa who have a family member diagnosed
with PCa at age < 60 years.
Consider germline testing in men with multiple family members diagnosed with PCa at age
< 60 years or a family member who died from PCa.
Consider germline testing in men with a family history of high-risk germline mutations or a
family history of multiple cancers on the same side of the family.
Strength rating
weak
weak
weak
weak
*Genetic counseling is required prior to germline testing.
5.1.5
Guidelines for screening and early detection
Recommendations
Do not subject men to prostate-specific antigen (PSA) testing without counselling them on
the potential risks and benefits.
Offer an individualised risk-adapted strategy for early detection to a well-informed man and
a life-expectancy of at least 10 to 15 years.
Offer early PSA testing to well-informed men at elevated risk of having PCa:
• men from 50 years of age;
• men from 45 years of age and a family history of PCa;
• men of African descent from 45 years of age;
• men carrying BRCA2 mutations from 40 years of age.
Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of 2 years
for those initially at risk:
• men with a PSA level of > 1 ng/mL at 40 years of age;
• men with a PSA level of > 2 ng/mL at 60 years of age;
Postpone follow-up to 8 years in those not at risk.
Stop early diagnosis of PCa based on life expectancy and performance status; men who
have a life-expectancy of < 15 years are unlikely to benefit.
5.2
Strength rating
Strong
Weak
Strong
Weak
Strong
Clinical diagnosis
Prostate cancer is usually suspected on the basis of DRE and/or PSA levels. Definitive diagnosis depends on
histopathological verification of adenocarcinoma in prostate biopsy cores.
5.2.1
Digital rectal examination
Most PCas are located in the peripheral zone and may be detected by DRE when the volume is > 0.2 mL.
In ~18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level [153]. A suspect DRE in
patients with a PSA level < 2 ng/mL has a positive predictive value (PPV) of 5–30% [154]. An abnormal DRE is
associated with an increased risk of a higher ISUP grade and is an indication for biopsy [155, 156].
5.2.2
Prostate-specific antigen
The use of PSA as a serum marker has revolutionised PCa diagnosis [157]. Prostate-specific antigen is organ
but not cancer specific; therefore, it may be elevated in benign prostatic hypertrophy (BPH), prostatitis and
other non-malignant conditions. As an independent variable, PSA is a better predictor of cancer than either
DRE or transrectal ultrasound (TRUS) [158].
There are no agreed standards defined for measuring PSA [159]. It is a continuous parameter, with higher
levels indicating greater likelihood of PCa. Many men may harbour PCa despite having low serum PSA [160].
Table 5.3 demonstrates the occurrence of ISUP > grade 2 PCa at low PSA levels, precluding an optimal PSA
threshold for detecting non-palpable but csPCa. The use of nomograms may help in predicting indolent PCa
[161].
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Table 5.3: Risk of PCa identified by systemic PCa biopsy in relation to low PSA values [160]
PSA level (ng/mL)
0.0–0.5
0.6–1.0
1.1–2.0
2.1–3.0
3.1–4.0
Risk of PCa (%)
6.6
10.1
17.0
23.9
26.9
Risk of ISUP grade > 2 PCa (%)
0.8
1.0
2.0
4.6
6.7
5.2.2.1
PSA density
Prostate-specific antigen density is the level of serum PSA divided by the prostate volume. The higher the PSA
density, the more likely it is that the PCa is clinically significant (see Section 6.2.1 - Treatment of low-risk disease).
5.2.2.2
PSA velocity and doubling time
There are two methods of measuring PSA kinetics:
•
PSA velocity (PSAV): absolute annual increase in serum PSA (ng/mL/year) [162];
•
PSA doubling time (PSA-DT): which measures the exponential increase in serum PSA over time [163].
Prostate-specific antigen velocity and PSA-DT may have a prognostic role in treating PCa but have limited
diagnostic use because of background noise (total prostate volume, and BPH), different intervals between PSA
determinations, and acceleration/deceleration of PSAV and PSA-DT over time [164]. These measurements do
not provide additional information compared with PSA alone [165-168].
Prostate-specific antigen kinetics is mainly exponential, especially during relapse. Two methods have been
described to calculate PSA-DT: the 2 -points and the log-slope method using more PSA measurements
[169]. The latter is considered more accurate as it eliminates inter- and intra-essay variations as well as any
physiological variations and potential imprecise measurements of low values [170, 171]. To obtain a reliable
evaluation, at least 3 PSA measurements must be available, collected four weeks apart as a minimum from the
same clinical laboratory [164]. A minimum increase of between 0.2 and 0.4 ng/mL is required [172].
As PSA-DT values may fluctuate over time in some men, only values obtained over the past 12 months should
be considered to assess disease course [164]. The Memorial Sloan Kettering Cancer Center PSA Doubling
Time calculator is one of the most widely used tools: https://www.mskcc.org/nomograms/prostate/psa_
doubling_time.
5.2.2.3
Free/total PSA ratio
Free/total (f/t) PSA must be used cautiously because it may be adversely affected by several pre-analytical and
clinical factors (e.g., instability of free PSA at 4°C and room temperature, variable assay characteristics, and
concomitant BPH in large prostates) [173]. Prostate cancer was detected in men with a PSA 4–10 ng/mL by
biopsy in 56% of men with f/t PSA < 0.10, but in only 8% with f/t PSA > 0.25 ng/mL [174]. A systematic review
including 14 studies found a pooled sensitivity of 70% in men with a PSA of 4–10 ng/mL [175]. Free/total PSA
is of no clinical use if the total serum PSA is > 10 ng/mL or during follow-up of known PCa. The clinical value of
f/t PSA is limited in light of the new diagnostic pathways incorporating MRI (see Section 5.2.4.2).
5.2.3
Biomarkers in prostate cancer
5.2.3.1
Blood based biomarkers: PHI/4K score/IsoPSA
Several assays measuring a panel of kallikreins in serum or plasma are now commercially available, including
the U.S. Food and Drug Administration (FDA) approved Prostate Health Index (PHI) test (combining free and
total PSA and the [-2]pro-PSA isoform [p2PSA]), and the four kallikrein (4K) score test (measuring free, intact
and total PSA and kallikrein-like peptidase 2 [hK2] in addition to age, DRE and prior biopsy status). Both tests
are intended to reduce the number of unnecessary prostate biopsies in PSA-tested men. A few prospective
multi-centre studies demonstrated that both the PHI and 4K score test out-performed f/t PSA PCa detection,
with an improved prediction of csPCa in men with a PSA between 2–10 ng/mL [176-179]. In a head-to-head
comparison both tests performed equally [180].
In contrast to the 4K score and PHI, which focus on the concentration of PSA isoforms, IsoPSA
utilises a novel technology which focuses on the structure of PSA [181]. Using an aqueous two-phase
solution, it partitions the isoforms of PSA and assesses for structural changes in PSA. In a recent multi-centre
prospective validation in 271 men the assay AUC was 0.784 for high-grade vs. low-grade cancer/benign
histology, which was superior to the AUCs of total PSA and percent free PSA [182].
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5.2.3.2
Urine biomarkers: PCA3/SelectMDX/Mi Prostate score (MiPS)/ExoDX
Prostate cancer gene 3 (PCA3) is a prostate-specific, non-coding microRNA (mRNA) biomarker that is
detectable in urine sediments obtained after three strokes of prostatic massage during DRE. The commercially
available Progensa urine test for PCA3 is superior to total and percent-free PSA for the detection of PCa in
men with elevated PSA as it shows significant increases in the area under the receiver-operator characteristic
curve (AUC) for positive biopsies [183-186]. PCA3 score increases with PCa volume, but there are conflicting
data about whether it independently predicts the ISUP grade [187]. Currently, the main indication for the
Progensa test is to determine whether repeat biopsy is needed after an initially negative biopsy, but its clinical
effectiveness for this purpose is uncertain [188]. Wei et al. showed 42% sensitivity at a cut-off of 60 in the
primary biopsy setting with a high specificity (91%) and a PPV of 80% suggesting that the assay may be used
in the primary setting [189].
The SelectMDX test is similarly based on mRNA biomarker isolation from urine. The presence of
HOXC6 and DLX1 mRNA levels is assessed to provide an estimate of the risk of both presence of PCa on
biopsy as well as presence of high-risk cancer [190].
TMPRSS2-ERG fusion, a fusion of the trans-membrane protease serine 2 (TMPRSS2) and the ERG
gene can be detected in 50% of PCas [191]. When detection of TMPRSS2-ERG in urine was added to PCA3
expression and serum PSA (Mi(chigan)Prostate Score [MiPS]), cancer prediction improved [192]. Exosomes
secreted by cancer cells may contain mRNA diagnostic for high-grade PCa [193, 194]. Use of the ExoDx
Prostate IntelliScore urine exosome assay resulted in avoiding 27% of unnecessary biopsies when compared
to standard of care. However, currently, both the MiPS-score and ExoDx assay are considered investigational.
In 6 head-to-head comparison studies of PCA3 and PHI, only Seisen et al. found a significant difference;
PCA3 detected more cancers, but for the detection of significant disease, defined as ISUP grade > 2, more
than three positive cores, or > 50% cancer involvement in any core, PHI proved superior [195]. Russo et al.
suggested in their systematic review that, based on moderate quality data, PHI and the 4K panel had a high
diagnostic accuracy and showed similar performance in predicting the detection of significant disease with a
AUC of 0.82 and 0.81, respectively [196]. However, in the screening population of the ERSPC study the use
of both PCA3 and 4K panel when added to the risk calculator led to an improvement in AUC of less than 0.03
[197]. Based on the available evidence, some biomarkers could help in discriminating between aggressive and
non-aggressive tumours with an additional value compared to the prognostic parameters currently used by
clinicians [198]. However, upfront multiparametric magnetic resonance imaging (mpMRI) is also likely to affect
the utility of above-mentioned biomarkers (see Section 5.2.4).
5.2.3.3
Tests to select men for a repeat biopsy
In men with an elevated risk of PCa with a prior negative biopsy, additional information may be gained by
the Progensa-PCA3 and SelectMDX DRE urine tests, the serum 4Kscore and PHI tests or a tissue-based
epigenetic test (ConfirmMDx). The role of PHI, Progensa PCA3, and SelectMDX in deciding whether to take a
repeat biopsy in men who had a previous negative biopsy is uncertain and probably not cost-effective [188].
The ConfirmMDx test is based on the concept that benign prostatic tissue in the vicinity of a PCa focus shows
distinct epigenetic alterations. In case PCa is missed at biopsy, demonstration of epigenetic changes in the
benign tissue would indicate the presence of carcinoma. The ConfirmMDX test quantifies the methylation
level of promoter regions of three genes (Methylated APC, RASSF1 and GSTP1) in benign prostatic tissue.
A multi-centre study found a NPV of 88% when methylation was absent in all three markers, implying that a
repeat biopsy could be avoided in these men [199]. Given the limited available data and the fact that the role
of mpMRI in tumour detection was not accounted for, no recommendation can be made regarding the routine
application of ConfirmMDX, in particular in the light of current use of mpMRI before biopsy. Table 5.4 presents
an overview of the most commonly available commercial tests.
Table 5.4: Description of additional investigational tests after a negative prostate biopsy*
Name of test
Progensa
SelectMDX
PHI
4Kscore Test
ConfirmMDX
Test substrate
DRE urine
DRE urine
Serum
Serum/plasma
Benign prostate biopsy
Molecular
lncRNA PCA3
mRNA HOXC6, DLX1
Total, free and p2PSA
Total, free, intact PSA, hK2
Methylated APC, RASSF1 and GSTP1
FDA approved
Yes
No
Yes
No
No
*Isolated high-grade prostatic intraepithelial neoplasia (PIN) in one or two biopsy sites is no longer an indication
for repeat biopsy [200].
PROSTATE CANCER - LIMITED UPDATE 2021
27
5.2.3.4
Guidelines for risk-assessment of asymptomatic men
Recommendations
In asymptomatic men with a prostate-specific antigen level between 2–10 ng/mL and a
normal digital rectal examination, use one oft the following tools for biopsy indication:
• risk-calculator;
• imaging;
• an additional serum, urine or tissue-based test.
Strength rating
Strong
Weak
5.2.4
The role of imaging in clinical diagnosis
5.2.4.1
Transrectal ultrasound and ultrasound-based techniques
Standard TRUS is not reliable at detecting PCa [201] and the diagnostic yield of additional biopsies performed
on hypoechoic lesions is negligible [202]. Prostate HistoScanningTM provided inconsistent results across
studies [203]. New sonographic modalities such as micro-Doppler, sonoelastography contrast-enhanced US
or high-resolution micro-ultrasound provided promising preliminary findings, either alone, or combined with
so-called ‘multiparametric US’. However, these techniques still have limited clinical appllicability due to lack of
standardisation, lack of large-scale evaluation of inter-reader variability and unclear results in transition zones
[204-206].
5.2.4.2
Multiparametric magnetic resonance imaging
5.2.4.2.1 Multiparametric magnetic resonance imaging performance in detecting PCa
Correlation with RP specimens shows that MRI has good sensitivity for the detection and localisation of ISUP
grade > 2 cancers, especially when their diameter is larger than 10 mm [207-209]. This good sensitivity was
further confirmed in patients who underwent template biopsies. In a recent Cochrane meta-analysis which
compared MRI to template biopsies (> 20 cores) in biopsy-naïve and repeat-biopsy settings, MRI had a pooled
sensitivity of 0.91 (95% CI: 0.83–0.95) and a pooled specificity of 0.37 (95% CI: 0.29–0.46) for ISUP grade > 2
cancers [210]. For ISUP grade > 3 cancers, MRI pooled sensitivity and specificity were 0.95 (95% CI: 0.87–
0.99) and 0.35 (95% CI: 0.26–0.46), respectively.
MRI is less sensitive in identifying ISUP grade 1 PCa. It identifies less than 30% of ISUP grade 1
cancers smaller than 0.5 cc identified on RP specimens by histopathology analysis [207]. In series using
template biopsy findings as the reference standard, MRI has a pooled sensitivity of 0.70 (95% CI: 0.59–0.80)
and a pooled specificity of 0.27 (95% CI: 0.19–0.37) for identifying ISUP grade 1 cancers [210].
The probability of detecting malignancy by MRI-identified lesions was standardised first by the
use of a 5-grade Likert score [211], and then by the Prostate Imaging – Reporting and Data System (PI-RADS)
score which has been updated several times since its introduction [212, 213]. In a meta-analysis of 13 studies
involving men with suspected or biopsy-proven PCa, the average PPVs for ISUP grade > 2 cancers of lesions
with a PI-RADSv2 score of 3, 4 and 5 were 12%, 48% and 72% respectively, but with significant heterogeneity
among studies (Table 5.5) [214]. Another retrospective study of 3,449 men with suspected or biopsy-proven
untreated PCa imaged across 26 academic centres found similar results with lesions of PI-RADS v2 scores of
3, 4 and 5 having a PPV for ISUP grade > 2 cancers of 15% (95% CI: 11–19), 39% (95% CI: 34–45) and 72%
(95% CI: 61–82), respectively [215].
Table 5.5: Proportion of malignant MRI lesions by ISUP grade groups and PI-RADS v2 scores [214]
PI-RADS v2
3
4
5
Total number
of lesions
707
886
495
ISUP 1
ISUP 2
ISUP 3
14% (9.4–18.7)
21% (13.0–28.9
12% (5.3–18.7)
9.3% (4.3–14.1)
1.5% (0.05–3)
29.7% (13.9–45.5) 7.7% (3.4–12)
33.5% (8.0–59.0) 15.7% (6.4–25.1)
ISUP > 4
0.7% (0–1.6)
10.8% (5.7–15.9)
23% (8.2–37.9)
Intervals in parenthesis are 95% CIs.
argeted biopsy improves the detection of ISUP grade > 2 cancer as compared to systematic
T
biopsy.
In pooled data of 25 reports on agreement analysis (head-to-head comparisons) between systematic biopsy
(median number of cores, 8–15) and MRI-targeted biopsies (MRI-TBx; median number of cores, 2–7), the
detection ratio (i.e. the ratio of the detection rates obtained by MRI-TBx alone and by systematic biopsy alone)
was 1.12 (95% CI: 1.02–1.23) for ISUP grade > 2 cancers and 1.20 (95% CI: 1.06–1.36) for ISUP grade > 3
cancers, and therefore in favour of MRI-TBx.
5.2.4.2.2
28
PROSTATE CANCER - LIMITED UPDATE 2021
However, the pooled detection ratios for ISUP grade > 2 cancers and ISUP grade > 3 cancers
were 1.44 (95% CI: 1.19–1.75) and 1.64 (95% CI: 1.27–2.11), respectively, in patients with prior negative
systematic biopsies, and only 1.05 (95% CI: 0.95–1.16) and 1.09 (95% CI: 0.94–1.26) in biopsy-naïve patients
[210]. Another meta-analysis of RCTs limited to biopsy-naïve patients with a positive MRI found that MRI-TBx
detected significantly more ISUP grade > 2 cancers than systematic biopsy (risk difference, -0.11 (95% CI: -0.2
to 0.0); p = 0.05), in prospective cohort studies (risk difference, -0.18 (95% CI: -0.24 to -0.11); p < 0.00001),
and in retrospective cohort studies (risk difference, -0.07 (95% CI: -0.12 to -0.02); p = 0.004). There was no
significant increase in the detection rate when systematic biopsies were combined to MRI-TBx [216].
Three prospective multi-centre trials evaluated MRI-TBx in biopsy-naïve patients. In the PRostate
Evaluation for Clinically Important Disease: Sampling Using Image-guidance Or Not? (PRECISION) trial, 500
biopsy-naïve patients were randomised to either MRI-TBx only or TRUS-guided systematic biopsy only. The
detection rate of ISUP grade > 2 cancers was significantly higher in men assigned to MRI-TBx (38%) than in
those assigned to SBx (26%, p = 0.005, detection ratio 1.46) [217]. In the Assessment of Prostate MRI Before
Prostate Biopsies (MRI-FIRST) trial, 251 biopsy-naïve patients underwent TRUS-guided systematic biopsy by
an operator who was blinded to MRI findings, and MRI-TBx by another operator. Magnetic resonance ImagingTBx detected ISUP grade > 2 cancers in a higher percentage of patients but the difference was not significant
(32.3% vs. 29.9%, p = 0.38; detection ratio: 1.08) [202]. However, MRI-TBx detected significantly more ISUP
grade > 3 cancers than systematic biopsy (19.9% vs. 15.1%, p = 0.0095; detection ratio: 1.32). A similar
trend for improved detection of ISUP grade > 3 cancers by MRI-TBx was observed in the Cochrane analysis;
however, it was not statistically significant (detection ratio 1.11 [0.88–1.40]) [210]. The Met Prostaat MRI Meer
Mans (4M) study included 626 biopsy-naïve patients; all patients underwent systematic biopsy, and those with
a positive MRI (PI-RADSv2 score of 3–5, 51%) underwent additional in-bore MRI-TBx. The results were close
to those of the MRI-FIRST trial with a detection ratio for ISUP grade > 2 cancers of 1.09 (detection rate: 25%
for MRI-TBx vs. 23% for systematic biopsy) [218]. However, in this study, MRI-TBx and systematic biopsy
detected an equal number of ISUP grade > 3 cancers (11% vs. 12%; detection ratio: 0.92).
The Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate
Cancer in Patients with Prior Negative Biopsies (FUTURE) randomised trial compared three techniques of
MRI-TBx in the repeat-biopsy setting [219]. In the subgroup of 152 patients who underwent both MRI-TBx and
systematic biopsy, MRI-TBx detected significantly more ISUP grade > 2 cancers than systematic biopsy (34%
vs. 16%; p < 0.001, detection ratio of 2.1), which is a finding consistent with the Cochrane agreement analysis
(detection ratio: 1.44). An ISUP grade > 2 cancer would have been missed in only 1.3% (2/152) of patients,
had systematic biopsy been omitted [220]. These findings support that MRI-TBx significantly out-performs
systematic biopsy for the detection of ISUP grade > 2 in the repeat-biopsy setting. In biopsy-naïve patients, the
difference appears to be less marked but remains in favour of MRI-TBx.
5.2.4.2.3
RI-TBx without systematic biopsy reduces the detection of ISUP grade 1 PCa as compared to
M
systematic biopsy.
In pooled data of 25 head-to-head comparisons between systematic biopsy and MRI-TBx, the detection ratio
for ISUP grade 1 cancers was 0.62 (95% CI: 0.44–0.88) in patients with prior negative biopsy and 0.63 (95%
CI: 0.54–0.74) in biopsy-naïve patients [210]. In the PRECISION and 4M trials, the detection rate of ISUP grade 1
patients was significantly lower in the MRI-TBx group as compared to systematic biopsy (9% vs. 22%,
p < 0.001, detection ratio of 0.41 for PRECISION; 14% vs. 25%, p < 0.001, detection ratio of 0.56 for 4M) [217,
218]. In the MRI-FIRST trial, MRI-TBx detected significantly fewer patients with clinically insignificant PCa
(defined as ISUP grade 1 and maximum cancer core length < 6 mm) than systematic biopsy (5.6% vs. 19.5%,
p < 0.0001, detection ratio of 0.29) [202]. Consequently, MRI-TBx without systematic biopsy significantly
reduces over-diagnosis of low-risk disease, as compared to systematic biopsy.
5.2.4.2.4 The added value of systematic and targeted biopsy
Magnetic resonance imaging-targeted biopsies can be used in two different diagnostic pathways: 1) the
‘combined pathway’, in which patients with a positive MRI undergo combined systematic and targeted biopsy,
and patients with a negative MRI undergo systematic biopsy; 2) the ‘MRI pathway’, in which patients with a
positive MRI undergo only MRI-TBx, and patients with a negative MRI who are not biopsied at all.
Choosing between these pathways depends not only on the detection rates obtained by the
two biopsy techniques, but also on whether or not they detect the same patients. Many studies evaluated
combined systematic and targeted biopsy in the same patients and could therefore assess the absolute added
value of each technique (i.e. the percentage of patients diagnosed by only one biopsy technique). Data from
the Cochrane meta-analysis of these studies and from the MRI-FIRST and 4M trials suggest that the absolute
added value of MRI-TBx for detecting ISUP grade > 2 cancers is higher than that of systematic biopsy (see
Table 5.6).
PROSTATE CANCER - LIMITED UPDATE 2021
29
Table 5.6: A
bsolute added values of targeted and systematic biopsies for ISUP grade > 2 and > 3 cancer
detection
ISUP grade
Biopsy-naïve
Prior negative
biopsy
Added value of
MRI-TBx
Added value
of systematic
biopsy
Overall
prevalence
Added value of
MRI-TBx
Added value
of systematic
biopsy
Overall
prevalence
ISUP > 2
Cochrane
metaanalysis*
[210]
6.3%
(4.8-8.2)
4.3%
(2.6-6.9)
MRI-FIRST 4M trial
trial* [202] [218]
7.6%
(4.6-11.6)
5.2%
(2.8-8.7)
6.0%
(3.4-9.7)
1.2%
(0.2-3.5)
27.7%
37.5%
(23.7-32.6) (31.4-43.8)
9.6%
(7.7-11.8)
2.3%
(1.2-4.5)
22.8%
(20.0-26.2)
ISUP > 3
Cochrane
metaanalysis*
[210]
7.0% (ND) 4.7%
(3.5-6.3)
5.0% (ND) 2.8%
(1.7-4.8)
MRI-FIRST 4M trial
trial* [202] [218]
-
30% (ND) 15.5%
21.1%
(12.6-19.5) (16.2-26.7)
6.3%
(5.2-7.7)
1.1%
(0.5-2.6)
-
12.6%
(10.5-15.6)
-
3.2% (ND)
4.1% (ND)
15% (ND)
-
-
*Intervals in parenthesis are 95% CI.
The absolute added value of a given biopsy technique is defined by the percentage of patients of the entire
cohort diagnosed only by this biopsy technique.
ISUP = International Society for Urological Pathology (grade); MRI-TBx = magnetic resonance imaging-targeted
biopsies; ND = not defined.
In Table 5.6, the absolute added values refer to the percentage of patients in the entire cohort; if the cancer
prevalence is taken into account, the ‘relative’ percentage of additional detected PCa can be computed.
Adding MRI-TBx to systematic biopsy in biopsy-naïve patients increases the number of ISUP grade > 2 and
grade > 3 PCa by approximately 20% and 30%, respectively. In the repeat-biopsy setting, adding MRI-TBx
increases detection of ISUP grade > 2 and grade > 3 PCa by approximately 40% and 50%, respectively.
Omitting systematic biopsy in biopsy-naïve patients would miss approximately 16% of ISUP grade > 2 PCa
and 18% of ISUP grade > 3 PCa. In the repeat-biopsy setting, it would miss approximately 10% of ISUP grade
> 2 PCa and 9% of ISUP grade > 3 PCa.
5.2.4.2.5 Number of biopsy procedures potentially avoided in the ‘MR pathway’
The diagnostic yield and number of biopsy procedures potentially avoided by the ‘MR pathway’ depends on
the Likert/PI-RADS threshold used to define positive MRI. In pooled studies on biopsy-naïve patients and
patients with prior negative biopsies, a Likert/PI-RADS threshold of > 3 would have avoided 30% (95% CI:
23–38) of all biopsy procedures while missing 11% (95% CI: 6–18) of all detected ISUP grade > 2 cancers
(relative percentage) [210]. Increasing the threshold to > 4 would have avoided 59% (95% CI: 43–78) of all
biopsy procedures while missing 28% (95% CI: 14–48) of all detected ISUP grade > 2 cancers [210]. Of note,
the percentages of negative MRI (Likert/PI-RADS score < 2) in the MRI-FIRST, PRECISION and 4M trials were
21.1%, 28.9% and 49%, respectively [202, 217, 218].
5.2.4.2.6 Other considerations
5.2.4.2.6.1 Multiparametric magnetic resonance imaging reproducibility
Despite the use of the PI-RADSv2 scoring system [212], MRI inter-reader reproducibility remains moderate at
best which currently limits its broad use by non-dedicated radiologists [221]. However, significant improvement
in the accuracy of MRI and MRI-TBx can be observed over time, both in academic and community hospitals,
especially after implementation of PI-RADSv2 scoring and multidisciplinary meetings using pathological
correlation and feedback [222-225]. An updated version of the PI-RADS score (PI-RADSv2.1) has been
recently published to improve reader reproducibility but it has not yet been fully evaluated [213]. It is still too
early to predict whether quantitative approaches and computer-aided diagnostic systems will improve the
characterisation of lesions seen at MRI [226-228].
30
PROSTATE CANCER - LIMITED UPDATE 2021
5.2.4.2.6.2 Targeted biopsy accuracy and reproducibility
Clinically significant PCa not detected by the ‘MRI pathway’ can be missed because of MRI failure (invisible
cancer or reader’s misinterpretation) or because of targeting failure (target missed or undersampled by MRITBx). In two retrospective studies of 211 and 116 patients with a unilateral MRI lesion, targeted biopsy alone
detected 73.5–85.5% of all csPCa (ISUP grade > 2); combining MRI-TBx with systematic biopsy of the lobe
with the MRI lesion detected 96–96.4% of all csPCas and combined targeted and systematic biopsy of
the contralateral lobe only identified 81.6–92.7% of csPCas [229, 230]. The difference may reflect targeting
errors leading to undersampling of the tumour. The accuracy of MRI-TBx is indeed substantially impacted
by the experience of the biopsy operator [221]. Increasing the number of cores taken per target may partially
compensate for guiding imprecision. In a retrospective study of 479 patients who underwent MRI-TBx with 4
cores per target that were sequentially labelled, the first 3 cores detected 95.1% of the csPCas detected by
the 4-core strategy [231]. In two other retrospective studies of 330 and 744 patients who underwent MRI-TBx
with up to 5 cores per target, the one-core and 3-core sampling strategies detected respectively 63–75% and
90–93% of the ISUP grade > 2 PCa detected by the 5-core strategy [232, 233]. These percentages are likely to
be influenced by the lesion size and location, the prostate volume or the operator’s experience, but no study
has quantified the impact of these factors yet.
5.2.4.2.6.3 Role of risk-stratification
Using risk-stratification to avoid biopsy procedures
Prostate-specific antigen density (PSAD) may help refine the risk of csPCa in patients undergoing MRI as
PSAD and the PI-RADS score are significant independent predictors of csPCa at biopsy [234, 235]. In a
meta-analysis of 8 studies, pooled MRI NPV for ISUP grade > 2 cancer was 84.4% (95% CI: 81.3–87.2) in the
wole cohort, 82.7% (95% CI: 80.5–84.7) in biopsy-naïve men and 88.2% (95% CI: 85–91.1) in men with prior
negative biopsies. In the subgroup of patients with PSAD < 0.15 ng/ml, NPV increased to respectively 90.4%
(95% CI: 86.8–93.4), 88.7% (95% CI: 83.1–93.3) and 94.1% (95% CI: 90.9–96.6) [236]. In contrast, the risk of
csPCa is as high as 27–40% in patients with negative MRI and PSAD > 0.15–0.20 ng/mL/cc [218, 235, 237240] (Table 5.7).
Combining MRI findings with the PCA3 score may also improve risk stratification [241]. Several
groups have developed comprehensive risk calculators which combine MRI findings with simple clinical data
as a tool to predict subsequent biopsy results [242]. At external validation, they tended to outperform risk
calculators not incorporating MRI findings (ERSPC and PBCG) with good discriminative power (as measured
by the AUC). However, they also tended to be miscalibrated with under- or over-prediction of the risk of ISUP
grade > 2 cancer [243, 244]. In one study that externally assessed four risk calculators combining MRI findings
and clinical data, only two demonstrated a distinct net benefit when a risk of false-negative prediction of 15%
was accepted. The others were harmful for this risk level, as compared to the ‘biopsy all’ strategy [243]. This
illustrates the prevalence-dependence of risk models. Recalibrations taking into account the local prevalence
are possible, but this approach is difficult in routine clinical practice as the local prevalence is difficult to
estimate and may change over time.
Using risk-stratification to avoid MRI and biopsy procedures
A retrospective analysis including 200 men from a prospective database of patients who underwent MRI and
combined systematic and targeted biopsy showed that upfront use of the Rotterdam Prostate Cancer Risk
Calculator (RPCRC) would have avoided MRI and biopsy in 73 men (37%). Of these 73 men, 10 had ISUP
grade 1 cancer and 4 had ISUP grade > 2 cancer [245]. A prospective multi-centre study evaluated several
diagnostic pathways in 545 biopsy-naïve men who underwent MRI and systematic and targeted biopsy. Using
a PHI threshold of > 30 to perform MRI and biopsy would have avoided MRI and biopsy in 25% of men at the
cost of missing 8% of the ISUP grade > 2 cancers [246]. Another prospective multi-centre trial including 532
men (with or without history of prostate biopsy) showed that using a threshold of > 10% for the Stockholm3
test to perform MRI and biopsy would have avoided MRI and biopsy in 38% of men at the cost of missing 8%
of ISUP grade > 2 cancers [247].
PROSTATE CANCER - LIMITED UPDATE 2021
31
Table 5.7: Impact of the PSA density on csPCa detection rates in patients with negative MRI findings
Study
Study design
Population
Washino,
et al. 2017
[235]
Retrosp.
Single-centre
n = 288
Biopsy naive
Distler,
et al. 2017
[234]
Hansen,
et al. 2017
[237]
Hansen,
et al. 2018
[238]
Oishi,
et al. 2019
[239]
Boesen,
et al. 2019
[240]
32
Retrosp.
analysis of
prospective
database
Single-centre
Retrosp.
Single-centre
Retrosp.
Multi-centre
n = 1,040
Biopsy
naive + prior
negative
biopsy
Biopsy protocol csPCa
csPCa detection rate
definition
SBx (14 cores) + ISUP > 2 or
Whole cohort (prevalence):
cognitive TBx
MCCL > 4 mm 49%
TTP (24 cores) + ISUP > 2
fusion TBx
PI-RADS 1-2 / Whole
cohort: 11% if PSAD < 0.15,
33% if PSAD > 0.15
TTP (24 cores) + ISUP > 2
n = 514
Prior negative fusion TBx
biopsy or AS
for ISUP 1
PCa
n = 807
Biopsy naive
PI-RADS 1-2:
0% if PSAD < 0.15,
20% if PSAD = 0.15-0.29,
30% if PSAD > 0.3
Whole cohort (prevalence):
43%
TTP + cognitive
or fusion TBx
Retrosp.
analysis of
prospective
database
Single-centre
SBx (12 cores)
n = 135
Biopsy
naive + prior
negative
biopsy + AS
+ Restaging
Only pts with
negative MRI
(PI-RADS < 2)
Retrosp.
analysis of
prospective
database
Single-centre
n = 808
Biopsy-naive
ISUP > 2
ISUP > 2
SBx (10 cores) + ISUP > 2
fusion TBx
PI-RADS 1-2 / prior
negative biopsy:
7% if PSAD < 0.15,
27% if PSAD > 0.15
Whole cohort (prevalence):
31%
Likert 1-2:
9% if PSAD < 0.10,
9% if PSAD < 0.2,
29% if PSAD > 0.2
Whole cohort (prevalence):
49%
PI-RADS 1-2:
10% if PSAD < 0.10,
21% if PSAD = 0.1-0.2,
33% if PSAD > 0.2
Whole cohort (prevalence):
18%
PSAD < 0.10: 6% (overall
pop), 15% (biopsy naïve),
0% (prior negative biopsy)
PSAD < 0.15: 10% (overall
pop), 20% (biopsy naïve),
0% (prior negative biopsy)
PSAD > 0.15: 40% (overall
pop), 29% (biopsy naïve),
29% (prior negative biopsy)
Whole cohort (prevalence):
35%
PI-RADS 1-2:
3% if PSAD < 0.10,
5% < 0.15,
5% if PSAD < 0.2,
32% if PSAD > 0.2
PROSTATE CANCER - LIMITED UPDATE 2021
Van der
Leest, et al.
2019 [218]
Prospective
Multi-centre
n = 626
Biopsy naive
TTP Bx (median
24 cores) +
fusion TBx
ISUP > 2
Whole cohort (prevalence):
30%
PI-RADS 1-2:
1.3% if PSAD < 0.10,
2% if PSAD < 0.15
csPCa = clinically significant prostate cancer; Retrosp. = retrospective; n = number of patients;
SBx = systematic transrectal biopsy; TBx = targeted biopsy; TTP = transperineal template biopsy;
PSAD = PSA density; ISUP = international Society of Urological Pathology; MCCL = maximum cancer core length.
5.2.4.2.6.4 Pre-biopsy MRI and MRI-TBx may induce an ISUP prostate cancer grade shift, as a result of
improved diagnosis
Magnetic resonance imaging findings are significant predictors of adverse pathology features on prostatectomy
specimens, and of survival-free BCR after RP or RT [82, 248-250]. In addition, tumours visible on MRI are
enriched in molecular hallmarks of aggressivity, as compared to invisible lesions [251]. Thus, MRI does identify
aggressive tumours.
Nonetheless, improved targeting obtained by MRI-TBx can artificially inflate the ISUP grade of
the tumours by focusing at the areas of high-grade cancer. As a result, ISUP grade > 2 cancers detected by
MRI-TBx are, on average, of better prognosis than those detected by the classical diagnostic pathway. This
is illustrated in a retrospective series of 1,345 patients treated by RP which showed that, in all risk groups,
patients diagnosed by MRI-TBx had better BCR-free survival than those diagnosed by systematic biopsy
only [82]. To mitigate this grade shift, in case of targeted biopsies, the 2019 ISUP consensus conference
recommended using an aggregated ISUP grade summarizing the results of all biopsy cores from the same MR
lesion, rather than using the result from the core with the highest ISUP grade [85]. When long-term follow-up
of patients who underwent MRI-TBx is available, a revision of the risk-groups definition will become necessary.
In the meantime, results of MRI-TBx must be interpreted in the context of this potential grade shift as an
increasing proportion of patients diagnosed with ISUP grade 2 cancers by MRI-TBx might be eligible for AS
[252].
5.2.4.2.7 Summary of evidence and practical considerations on pre-biopsy MRI and MRI-TBx
Pre-biopsy MRI and MRI-TBx substantially improve the detection of ISUP grade > 2 PCa. This improvement is
most notable in the repeat-biopsy setting, with marginal added value for systematic biopsies. It is less marked
in biopsy-naïve patients in whom systematic biopsy retains a higher added value, at least for the detection of
ISUP grade 2 cancers. MRI-TBx also detects significantly less ISUP grade 1 cancers than systematic biopsies.
The ‘MRI pathway’ is appealing since it could decrease the number of biopsy procedures, reduce
the detection of low-grade PCa while maintaining (or even improving) the detection of csPCa, as compared
to systematic biopsy. However, some cavaets need pointing out. First, MRI findings must be interpreted in
the light of the a priori risk of csPCa. Risk stratification combining clinical data, MRI findings and (maybe)
other biomarkers will help, in the future, defining those patients that can safely avoid biopsy. Second, without
standardisation of MRI interpretation and of MRI-TBx technique the ‘MR pathway’ may lead to suboptimal
care outside large-volume (expert) centres. Indeed, the inter-reader reproducibility of MRI is moderate at
best. Current biopsy-targeting methods remain imprecise and their accuracy is substantially impacted by the
operator’s experience. As a result, 3 to 5 biopsy cores per target may be needed to reduce the risk of missing
or undersampling the lesion, even with US/MR fusion systems. Third, the use of pre-biopsy MRI may induce
grade shift, even with the use of an aggregated ISUP grade for each MR lesion targeted at biopsy. Clinicians
must interpret MRI-TBx results in the context of this potential grade shift. A revision of the definitions of the risk
groups will be needed in the future to take into account wider use of MRI and MRI-TBx.
Finally, it must be emphasised that the ‘MR pathway’ has only been evaluated in patients in whom
the risk of csPCa was judged high enough to deserve biopsy. Pre-biopsy MRI must not be used in patients
who do not have an indication for prostate biopsy based on their family history or clinical and biochemical data.
Because of its low specificity, MRI in very low-risk patients would result in an inflation of false-positive findings
and subsequent unnecessary biopsies.
5.2.4.3
Guidelines for imaging in PCa detection
Introductory statement
Systematic biopsy is an acceptable approach in case magnetic resonance imaging (MRI) is
unavailable.
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Recommendations for all patients
Strength rating
Do not use multiparametric magnetic resonance imaging (mpMRI) as an initial screening tool. Strong
Adhere to PI-RADS guidelines for mpMRI acquisition and interpretation and evaluate
Strong
mpMRI results in multidisciplinary meetings with pathological feedback.
Recommendations in biopsy naïve patients
Perform mpMRI before prostate biopsy.
When mpMRI is positive (i.e. PI-RADS > 3), combine targeted and systematic biopsy.
When mpMRI is negative (i.e., PI-RADS < 2), and clinical suspicion of PCa is low, omit
biopsy based on shared decision-making with the patient.
Strength rating
Strong
Strong
Weak
Recommendations in patients with prior negative biopsy
Perform mpMRI before prostate biopsy.
When mpMRI is positive (i.e. PI-RADS > 3), perform targeted biopsy only.
When mpMRI is negative (i.e., PI-RADS < 2), and clinical suspicion of PCa is high, perform
systematic biopsy based on shared share decision-making with the patient.
Strength rating
Strong
Weak
Strong
5.2.5
Baseline biopsy
The need for prostate biopsy is based on PSA level, other biomarkers and/or suspicious DRE and/or imaging
(see Section 5.2.4). Age, potential co-morbidity and therapeutic consequences should also be considered and
discussed beforehand [253]. Risk stratification is a potential tool for reducing unnecessary biopsies [253].
Limited PSA elevation alone should not prompt immediate biopsy. Prostate-specific antigen
level should be verified after a few weeks, in the same laboratory using the same assay under standardised
conditions (i.e. no ejaculation, manipulations, and urinary tract infections [UTIs]) [254, 255]. Empiric use of
antibiotics in an asymptomatic patient in order to lower the PSA should not be undertaken [256].
Ultrasound (US)-guided biopsy is now the standard of care. Prostate biopsy is performed by either
the transrectal or transperineal approach. Cancer detection rates, when performed without prior imaging with
MRI, are comparable between the two approaches [257], however, some evidence suggests reduced infection
risk with the transperineal route (see Section 5.2.6.4) [258, 259].
Transurethral resection of the prostate (TURP) should not be used as a tool for cancer detection [260].
5.2.6
Repeat biopsy
5.2.6.1
Repeat biopsy after previously negative biopsy
The indications for repeat biopsy are:
•
rising and/or persistently elevated PSA (see Table 5.3 for risk estimates);
•
suspicious DRE, 5–30% PCa risk [153, 154];
•
intraductal carcinoma as a solitary finding, > 90% risk of associated high-grade PCa [261];
•
positive mpMRI findings (see Section 5.2.4.2).
The recommendation to perform a repeat biopsy after a diagnosis of atypical small acinar proliferation and
extensive high-grade PIN is based on earlier studies on systematic biopsies using a 6–10 core biopsy protocol.
In a contemporary series of biopsies the likelihood of finding a csPCa after follow-up biopsy after a diagnosis
of atypical small acinar proliferation was only 6% [262].
The added value of other biomarkers remains unclear (see Sections 5.2.3.1 and 5.2.3.2).
5.2.6.2
Saturation biopsy
The incidence of PCa detected by saturation repeat biopsy (> 20 cores) is 30–43% and depends on the
number of cores sampled during earlier biopsies [263]. Saturation biopsy may be performed with the
transperineal technique, which detects an additional 38% of PCa. The rate of urinary retention varies
substantially from 1.2% to 10% [264-267].
5.2.7
Prostate biopsy procedure
5.2.7.1
Sampling sites and number of cores
On baseline biopsies, where no prior imaging with mpMRI has been performed, or where mpMRI has not
shown any suspicious lesion, the sample sites should be bilateral from apex to base, as far posterior and lateral
as possible in the peripheral gland. Additional cores should be obtained from suspect areas identified by DRE;
suspect areas on TRUS might be consideration for additional biopsies. Sextant biopsy is no longer considered
adequate. At least 8 systematic biopsies are recommended in prostates with a size of about 30 cc [268]. Ten to
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12 core biopsies are recommended in larger prostates, with > 12 cores not being significantly more conclusive
[269, 270].
Eighteen to 24 template cores may be taken in transperineal biopsy with acceptable morbidity, but it
is unknown whether this number improves detection of significant cancer [271-273]. As per transrectal biopsy,
for maximal detection of significant cancer, cores should be directed towards the peripheral zone posteriorly
and laterally, but in transperineal biopsy can also more easily be directed to the anterior horns of the peripheral
zone as well. In the setting of a positive MRI with targeted biopsy cores being taken, the addition of template
cores may increase the detection of significant cancer slightly, but also increases the detection of insignificant
cancer [274, 275]. The optimal number of template cores in this setting is unknown.
Where mpMRI has shown a suspicious lesion MR-TBx can be obtained through cognitive guidance, US/MR
fusion software or direct in-bore guidance. Current literature, including systematic reviews and meta-analyses,
does not show a clear superiority of one image-guided technique over another [219, 276-279]. However,
regarding approach, the only systematic review and meta-analysis comparing MRI-targeted transrectal biopsy
to MRI-targeted transperineal biopsy, analysing 8 studies, showed a higher sensitivity for detection of csPCa
when the transperineal approach was used (86% vs. 73%) [280]. This benefit was especially pronounced for
anterior tumours. Multiple (3–5) cores should be taken from each lesion (see Section 5.2.4.2.7.2).
5.2.7.2
Antibiotics prior to biopsy
5.2.7.2.1 Transperineal prostate biopsy
A total of seven randomised studies including 1,330 patients compared the impact of biopsy route on
infectious complications. Infectious complications were significantly higher following transrectal biopsy (37
events among 657 men) compared to transperineal biopsy (22 events among 673 men) (RR: 1.81 [range
1.09–3.00], 95% CI) [281-288]. In addition, a systematic review including 165 studies with 162,577 patients
described sepsis rates of 0.1% and 0.9% for transperineal and transrectal biopsies, respectively [289]. Finally,
a population-based study from the UK (n = 73,630) showed lower re-admission rates for sepsis in patients
who had transperineal vs. transrectal biopsies (1.0% vs. 1.4%, respectively) [290]. The available evidence
demonstrates that the transrectal approach should be abandoned in favour of the transperineal approach
despite any possible logistical challenges.
To date, no RCT has been published investigating different antibiotic prophylaxis regimens for transperineal
prostate biopsy. However, as it is a clean procedure that avoids rectal flora, quinolones or other antibiotics
to cover rectal flora may not be necessary. A single dose of cephalosporin only to cover skin commensals
has been shown to be sufficient in multiple single cohort series [267, 291]. Prior negative mid-stream urine
(MSU) test and routine surgical disinfecting preparation of the perineal skin are mandatory. In one of the
largest studies to date, 1,287 patients underwent transperineal biopsy under local anaesthesia only [292].
Antibiotic prophylaxis consisted of a single oral dose of either cefuroxime or cephalexin. Patients with cardiac
valve replacements received amoxycillin and gentamicin, and those with severe penicillin allergy received
sulphamethoxazole. No quinolones were used. Only one patient developed a UTI with positive urine culture and
there was no urosepsis requiring hospitalisation.
In another study of 577 consecutive patients undergoing transperineal biopsy using single dose IV
cephazolin prophylaxis, one patient (0.2%) suffered prostatitis not requiring hospitalisation [267]. There were
no incidences of sepsis. In a further study of 485 patients using only cephazolin, 4 patients (0.8%) suffered
infectious complications [293].
5.2.7.2.2 Transrectal prostate biopsy
Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal povidone-iodine preparation
before biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly lower rate of infectious
complications (RR [95% CIs] 0.55 [0.41–0.72]) [288, 294-299]. Single RCTs showed no evidence of benefit for
perineal skin disinfection [300], but reported an advantage for rectal povidone-iodine preparation before biopsy
compared to after biopsy [301].
A meta-analysis of four RCTs including 671 men evaluated the use of rectal preparation by enema
before transrectal biopsy. No significant advantage was found regarding infectious complications (RR [95%
CIs] 0.96 [0.64–1.54]) [288, 302-304].
A meta-analysis of 26 RCTs with 3,857 patients found no evidence that use of peri-prostatic
injection of local anaesthesia resulted in more infectious complications than no injection (RR [95% CIs]
1.07 [0.77-1.48]) [288]. A meta-analysis of 9 RCTs including 2,230 patients found that extended biopsy
templates showed comparable infectious complications to standard templates (RR [95% CIs] 0.80 [0.53-1.22])
[288]. Additional meta-analyses found no difference in infections complications regarding needle guide type
(disposable vs. reusable), needle type (coaxial vs. non-coaxial), needle size (large vs. small), and number of
injections for peri-prostatic nerve block (standard vs. extended) [288].
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A meta-analysis of eleven studies with 1,753 patients showed significantly reduced infections after transrectal
prostate biopsy when using antimicrobial prophylaxis as compared to placebo/control (RR [95% CI] 0.56 [0.40–
0.77]) [305].
Fluoroquinolones have been traditionally used for antibiotic prophylaxis in this setting; however,
overuse and misuse of fluoroquinolones has resulted in an increase in fluoroquinolone resistance. In
addition, the European Commission has implemented stringent regulatory conditions regarding the use of
fluoroquinolones resulting in the suspension of the indication for peri-operative antibiotic prophylaxis including
prostate biopsy [306].
A systematic review and meta-analysis on antibiotic prophylaxis for the prevention of infectious
complications following prostate biopsy concluded that in countries where fluoroquinolones are allowed
as antibiotic prophylaxis, a minimum of a full one-day administration, as well as targeted therapy in case
of fluoroquinolone resistance, or augmented prophylaxis (combination of two or more different classes of
antibiotics) is recommended [305]. In countries where use of fluoroquinolones are suspended, cephalosporins
or aminoglycosides can be used as individual agents with comparable infectious complications based on a
meta-analysis of two RCTs [305]. A meta-analysis of three RCTs reported that fosfomycin trometamol was
superior to fluoroquinolones (RR [95% CI] 0.49 [0.27–0.87]) [305], but routine general use should be critically
assessed due to the relevant infectious complications reported in non-randomised studies [307]. Another
possibility is the use of augmented prophylaxis without fluoroquinolones, although no standard combination
has been established to date. Finally, targeted prophylaxis based on rectal swap/stool culture is plausible, but
no RCTs are available on non-fluoroquinolones. See figure 5.1 for prostate biopsy workflow to reduce infections
complications.
Based on a meta-analysis, suggested antimicrobial prophylaxis before transrectal biopsy may consist of:
1.
Targeted prophylaxis - based on rectal swab or stool culture.
2.
Augmented prophylaxis - two or more different classes of antibiotics (of note: this option is against
antibiotic stewardship programmes).
3.
Alternative antibiotics:
•
fosfomycin trometamol (e.g., 3 g before and 3 g 24–48 hrs. after biopsy);
•
cephalosporin (e.g., ceftriaxone 1 g i.m; cefixime 400 mg p.o for 3 days starting 24 hrs. before biopsy)
aminoglycoside (e.g., gentamicin 3 mg/kg i.v.; amikacin 15 mg/kg i.m).
5.2.7.3
Summary of evidence and recommendations for performing prostate biopsy
(in line with the Urological Infections Guidelines Panel)
Summary of evidence
A meta-analysis of seven studies including 1,330 patients showed significantly reduced infectious
complications in patients undergoing transperineal biopsy as compared to transrectal biopsy.
Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal povidone-iodine
preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly
lower rate of infectious complications.
A meta-analysis on eleven studies with 1,753 patients showed significantly reduced infections after
transrectal biopsy when using antimicrobial prophylaxis as compared to placebo/control.
Recommendations
Perform prostate biopsy using the transperineal approach due to the lower risk of infectious
complications.
Use routine surgical disinfection of the perineal skin for transperineal biopsy.
Use rectal cleansing with povidone-iodine in men prior to transrectal prostate biopsy.
Do not use fluoroquinolones for prostate biopsy in line with the European Commission final
decision on EMEA/H/A-31/1452.
Use either target prophylaxis based on rectal swab or stool culture; augmented prophylaxis
(two or more different classes of antibiotics); or alternative antibiotics (e.g., fosfomycin
trometamol, cephalosporin, aminoglycoside) for antibiotic prophylaxis for transrectal biopsy.
Use a single oral dose of either cefuroxime or cephalexin or cephazolin as antibiotic
prophylaxis for transperineal biopsy. Patients with severe penicillin allergy may be given
sulphamethoxazole.
Ensure that prostate core biopsies from different sites are submitted separately for
processing and pathology reporting.
36
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1a
1a
1a
Strength rating*
Strong
Strong
Strong
Strong
Weak
Weak
Strong
PROSTATE CANCER - LIMITED UPDATE 2021
Figure 5.1: Prostate biopsy workflow to reduce infectious complications*
Indication for prostate biopsy?
Transperineal biopsy feasible?
Yes
No
Transperineal biopsy - 1st choice (⊕⊕⊝⊝)
with:
• perineal cleansing
• antibiotic prophylaxis
Transrectal biopsy – 2nd choice (⊕⊕⊝⊝)
with:
• povidone-iodine rectal preparation
• antibiotic prophylaxis
Fluoroquinolones licensed?
Yes
No
1.
Targeted prophylaxis: based on rectal
swab or stool cultures
2.
Augmented prophylaxis: two or more
different classes of antibiotics
3.
Alternative antibiotics (⊕⊝⊝⊝):
• fosfomycin trometamol (e.g. 3 g before
and 3 g 24-48 hrs after biopsy)
• cephalosporin (e.g. ceftriaxone 1 g i.m.;
cefixime 400 mg p.o. for 3 days starting
24 hrs before biopsy)
• aminoglycoside (e.g. gentamicin 3 mg/kg
i.v.; amikacin 15 mg/kg i.m.)
Duration of antibiotic prophylaxis ≥ 24 hrs
(⊕⊕⊝⊝)
1.
Targeted prophylaxis (⊕⊕⊝⊝): based
on rectal swab or stool cultures
2.
Augmented prophylaxis (⊕⊝⊝⊝):
3.
• Fluoroquinolone plus aminoglycoside
• Fluoroquinolone plus cephalosporin
Fluoroquinolone prophylaxis
(range: ⊕⊝⊝⊝ - ⊕⊕⊝⊝)
GRADE Working Group grades of evidence.
• High certainty: (⊕⊕⊕⊕) very confident that the true effect lies close to that of the estimate of the effect.
• M
oderate certainty: (⊕⊕⊕) moderately confident in the effect estimate: the true effect is likely to be close to
the estimate of the effect, but there is a possibility that it is substantially different.
• L
ow certainty: (⊕⊕) confidence in the effect estimate is limited: the true effect may be substantially
different from the estimate of the effect.
• V
ery low certainty: (⊕) very little confidence in the effect estimate: the true effect is likely to be
substantially different from the estimate of effect.
*Figure adapted from Pilatz et al., [308] with permission from Elsevier.
*Note on strength ratings:
The above strength ratings are explained here due to the major clinical implications of these new
recommendations. Although data showing the lower risk of infection via the transperineal approach is low
in certainty, its statistical and clinical significance warrants its Strong rating. Strong ratings are also given for
routine surgical disinfection of skin in transperineal biopsy and povidone-iodine rectal cleansing in transrectal
biopsy as, although quality of data is low, the clinical benefit is high and practical application simple. A ‘Strong’
rating is given for avoiding fluoroquinolones in prostate biopsy due to its legal implications in Europe.
5.2.7.4
Local anaesthesia prior to biopsy
Ultrasound-guided peri-prostatic block is recommended [309]. It is not important whether the depot is apical or
basal. Intra-rectal instillation of local anaesthesia is inferior to peri-prostatic infiltration [310]. Local anaesthesia
can also be used effectively for mpMRI-targeted and systemic transperineal biopsy [311]. Patients are placed
in the lithotomy position. Bupivacaine is injected into the perineal skin and subcutaneous tissues, followed
two minutes later by a peri-prostatic block. A systematic review evaluating pain in 3 studies comparing
transperineal vs. transrectal biopsies found that the transperineal approach significantly increased patient pain
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(RR: 1.83 [1.27–2.65]) [312]. In a randomised comparison a combination of peri-prostatic and pudendal block
anaesthesia reduced pain during transperineal biopsies compared to peri-prostatic anaesthesia only [313].
Targeted biopsies can then be taken via a brachytherapy grid or a freehand needle-guiding device under local
infiltration anaesthesia [311, 314, 315].
5.2.7.5
Complications
Complications of TRUS biopsy are listed in Table 5.8 [316]. Mortality after prostate biopsy is extremely rare and
most are consequences of sepsis [111]. Low-dose aspirin is no longer an absolute contraindication [317]. A
systematic review found favourable infection rates for transperineal compared to TRUS biopsies with similar
rates of haematuria, haematospermia and urinary retention [318]. A meta-analysis of 4,280 men randomised
between transperineal vs. TRUS biopsies in 13 studies found no significant differences in complication rates,
however, data on sepsis compared only 497 men undergoing TRUS biopsy to 474 having transperineal biopsy.
The transperineal approach required more (local) anaesthesia [257].
Table 5.8: Percentage of complications per TRUS biopsy session, irrespective of the number of cores
Complications
Haematospermia
Haematuria > 1 day
Rectal bleeding < 2 days
Prostatitis
Fever > 38.5°C
Epididymitis
Rectal bleeding > 2 days +/− surgical intervention
Urinary retention
Other complications requiring hospitalisation
Percentage of patients affected
37.4
14.5
2.2
1.0
0.8
0.7
0.7
0.2
0.3
5.2.7.6
Seminal vesicle biopsy
Indications for seminal vesicle (SV) (staging) biopsies are poorly defined. At a PSA of > 15 ng/mL, the odds
of tumour involvement are 20–25% [319]. A SV staging biopsy is only useful if it has a decisive impact
on treatment, such as ruling out radical tumour resection or for potential subsequent RT. Its added value
compared with mpMRI is questionable.
5.2.7.7
Transition zone biopsy
Transition zone sampling during baseline biopsies has a low detection rate and should be limited to MRIdetected lesions or repeat biopsies [320].
5.2.8
Pathology of prostate needle biopsies
5.2.8.1
Processing
Prostate core biopsies from different sites are processed separately. Before processing, the number and length
of the cores are recorded. The length of biopsy tissue significantly correlates with the PCa detection rate
[321]. To achieve optimal flattening and alignment, a maximum of three cores should be embedded per tissue
cassette, and sponges or paper used to keep the cores stretched and flat [322, 323]. To optimise detection of
small lesions, paraffin blocks should be cut at three levels and intervening unstained sections may be kept for
immunohistochemistry (IHC) [320].
5.2.8.2
Microscopy and reporting
Diagnosis of PCa is based on histology. The diagnostic criteria include features pathognomonic of cancer,
major and minor features favouring cancer and features against cancer. Ancillary staining and additional
(deeper) sections should be considered if a suspect lesion is identified [324-326]. Diagnostic uncertainty
is resolved by intradepartmental or external consultation [324]. Section 5.2.8.3 lists the recommended
terminology for reporting prostate biopsies [322]. Type and subtype of PCa should be reported such as for
instance acinar adenocarcinoma (> 95% of PCa), ductal adenocarcinoma (< 5%) and poorly differentiated
small or large cell neuroendocrine carcinoma (< 1%), even if representing a small proportion of the PCa. The
distinct aggressive nature of ductal adenocarcinoma and small/large cell neuroendocrine carcinoma should be
commented upon in the pathology report [322].
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5.2.8.2.1
Recommended terminology for reporting prostate biopsies [255]
Recommendations
Benign/negative for malignancy; if appropriate, include a description.
Active inflammation.
Granulomatous inflammation.
High-grade prostatic intraepithelial neoplasia (PIN).
High-grade PIN with atypical glands, suspicious for adenocarcinoma (PINATYP).
Focus of atypical glands/lesion suspicious for adenocarcinoma/atypical small acinar
proliferation, suspicious for cancer.
Adenocarcinoma, provide type and subtype.
Intraductal carcinoma.
Strength rating
Strong
Each biopsy site should be reported individually, including its location (in accordance with the sampling site)
and histopathological findings, which include the histological type and the ISUP 2014 grade [84]. For mpMRI
targeted biopsies consisting of multiple cores per target the aggregated ISUP grade and percentage of highgrade carcinoma should be reported per targeted lesion [85]. If the targeted biopsies are negative, presence
of specific benign pathology should be mentioned, such as dense inflammation, fibromuscular hyperplasia
or granulomatous inflammation [327]. A global ISUP grade comprising all systematic (non-targeted) biopsies
is also reported (see Section 4.2). The global ISUP grade takes into account all systemic biopsies positive for
carcinoma, by estimating the total extent of each Gleason grade present. For instance, if three biopsy sites
are entirely composed of Gleason grade 3 and one biopsy site of Gleason grade 4 only, the global ISUP grade
would be 2 (i.e. GS 7[3+4]) or 3 (i.e. GS 7[4+3]), dependent on whether the extent of Gleason grade 3 exceeds
that of Gleason grade 4, whereas the worse grade would be ISUP grade 4 (i.e. GS 8[4+4]). Recent publications
demonstrated that global ISUP grade is somewhat superior in predicting prostatectomy ISUP grade [328] and
BCR [329].
Lymphovascular invasion (LVI) and extraprostatic extension (EPE) must each be reported, if
identified. More recently, expansile cribriform pattern of PCa as well as intraductal carcinoma in biopsies were
identified as independent prognosticators of metastatic disease [330] and PCa-specific survival [331] and
presence of both adverse pathologies should be reported [85].
The proportion of systematic (non-targeted) carcinoma-positive cores as well as the extent of
tumour involvement per biopsy core correlate with the ISUP grade, tumour volume, surgical margins and
pathologic stage in RP specimens and predict BCR, post-prostatectomy progression and RT failure. These
parameters are included in nomograms created to predict pathologic stage and SV invasion after RP and RT
failure [332-334]. A pathology report should therefore provide both the proportion of carcinoma-positive cores
and the extent of cancer involvement for each core. The length in mm and percentage of carcinoma in the
biopsy have equal prognostic impact [335]. An extent of > 50% of adenocarcinoma in a single core is used in
some AS protocols as a cut off [336] triggering immediate treatment vs. AS in patients with ISUP grade 1.
A prostate biopsy that does not contain glandular tissue should be reported as diagnostically inadequate.
Mandatory elements to be reported for a carcinoma-positive prostate biopsy are:
•
type of carcinoma;
•
primary and secondary/worst Gleason grade (per biopsy site and global);
•
percentage high-grade carcinoma (global);
•
extent of carcinoma (in mm or percentage) (per biopsy site);
•
if present: EPE, SV invasion, LVI, intraductal carcinoma/cribriform pattern, peri-neural invasion;
•
ISUP grade (global);
•
In targeted biopsies aggregate ISUP grade and percentage high-grade carcinoma per targeted site;
•
In carcinoma-negative targeted biopsy report specific benign pathology, e.g., fibromuscular hyperplasia
or granulomatous inflammation, if present [85];
5.2.8.3
Tissue-based prognostic biomarker testing
After a comprehensive literature review and several panel discussions an ASCO-EAU-AUA multidisciplinary
expert panel made recommendations regarding the use of tissue-based PCa biomarkers. The
recommendations were limited to 5 commercially available tests (Oncotype Dx®, Prolaris®, Decipher®, Decipher
PORTOS and ProMark®) with extensive validation in large retrospective studies and evidence that their test
results might actually impact clinical decision-taking [337].
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The selected commercially available tests significantly improved the prognostic accuracy of clinical
multivariable models for identifying men who would benefit of AS and those with csPCa requiring curative
treatment, as well as for guidance of patient management after RP. In addition, a few studies showed that
tissue biomarker tests and MRI findings independently improved the detection of clinically significant cancer
in an AS setting, but it remains unclear which men would benefit of both tests. Since the long-term impact
of the use of these commercially available tests on oncological outcome remains unproven and prospective
trials are largely lacking, the Panel concluded that these tests should not be offered routinely but only in
subsets of patients where the test result provides clinically actionable information, such as for instance in men
with favourable intermediate-risk PCa who might opt for AS or men with unfavourable intermediate-risk PCa
scheduled for RT to decide on treatment intensification with hormonal therapy (HT).
5.2.8.4
Histopathology of radical prostatectomy specimens
5.2.8.4.1 Processing of radical prostatectomy specimens
Histopathological examination of RP specimens describes the pathological stage, histopathological type,
grade and surgical margins of PCa. It is recommended that RP specimens are totally embedded to enable
assessment of cancer location, multifocality and heterogeneity. For cost-effectiveness, partial embedding may
also be considered, particularly for prostates > 60 g. The most widely accepted method includes complete
embedding of the posterior prostate and a single mid-anterior left and right section. Compared with total
embedding, partial embedding detected 98% of PCa with an ISUP grade > 2 with accurate staging in 96% of
cases [338].
The entire RP specimen should be inked upon receipt in the laboratory to demonstrate the surgical margins.
Specimens are fixed by immersion in buffered formalin for at least 24 hours, preferably before slicing. Fixation
can be enhanced by injecting formalin which provides more homogeneous fixation and sectioning after
24 hours [339]. After fixation, the apex and the base (bladder neck) are removed and cut into (para)sagittal
or radial sections; the shave method is not recommended [83]. The remainder of the specimen is cut in
transverse, 3–4 mm sections, perpendicular to the long axis of the urethra. The resultant tissue slices can
be embedded and processed as whole-mounts or after quadrant sectioning. Whole-mounts provide better
topographic visualisation, faster histopathological examination and better correlation with pre-operative
imaging, although they are more time-consuming and require specialist handling. For routine sectioning, the
advantages of whole mounts do not outweigh their disadvantages.
5.2.8.4.1.1 Guidelines for processing prostatectomy specimens
Recommendations
Ensure total embedding, by conventional (quadrant) or whole-mount sectioning.
Ink the entire surface before cutting, to evaluate the surgical margin.
Examine the apex and base separately, using the cone method with sagittal or radial
sectioning.
Strength rating
Strong
Strong
Strong
5.2.8.4.2 Radical prostatectomy specimen report
The pathology report provides essential information on the prognostic characteristics relevant for clinical
decision-making (Table 5.9). As a result of the complex information to be provided for each RP specimen, the
use of synoptic(-like) or checklist reporting is recommended (Table 5.10). Synoptic reporting results in more
transparent and complete pathology reporting [340].
Table 5.9: Mandatory elements provided by the pathology report
Histopathological type: > 95% of PCa represents conventional (acinar) adenocarcinoma.
Grading according to ISUP grade (or not applicable if therapy-related changes).
Presence of intraductal and/or cribriform carcinoma.
Tumour (sub)staging and surgical margin status: location and extent of EPE, presence of bladder neck
invasion, laterality of EPE or SV invasion, location and extent of positive surgical margins.
Additional information may be provided on multifocality, and diameter/volume and zonal location of the
dominant tumour.
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Table 5.10: Example checklist: reporting of prostatectomy specimens
Histopathological type
Type of carcinoma, e.g. conventional acinar, or ductal
Histological grade
Primary (predominant) Gleason grade
Secondary Gleason grade
Tertiary Gleason grade (if applicable)
Global ISUP grade
Approximate percentage of Gleason grade 4 or 5
Tumour quantitation (optional)
Percentage of prostate involved
Size/volume of dominant tumour nodule
Pathological staging (pTNM)
If extraprostatic extension is present:
• indicate whether it is focal or extensive*;
• specify sites;
• indicate whether there is seminal vesicle invasion.
If applicable, regional lymph nodes:
• location;
• number of nodes retrieved;
• number of nodes involved.
Surgical margins
If carcinoma is present at the margin:
• specify sites.
Other
Presence of lymphovascular/angio-invasion
Location of dominant tumour
Presence of intraductal carcinoma/cribriform architecture
*Focal is defined as carcinoma glands extending less than 1 high-power field (HPF) in the extraprostatic fat in
1 or 2 sections and extensive is extension beyond or in more sections.
5.2.8.4.3 ISUP grade in prostatectomy specimens
Grading of conventional prostatic adenocarcinoma using the (ISUP 2014 modified) Gleason system is the
strongest prognostic factor for clinical behaviour and treatment response [84]. The ISUP grade is incorporated
in nomograms that predict disease-specific survival (DSS) after prostatectomy [341].
The ISUP grade is based on the sum of the most and second-most dominant (in terms of volume) Gleason
grade. ISUP grade 1 is GS 6. ISUP grades 2 and 3 represent carcinomas constituted of Gleason grade 3 and
4 components, with ISUP grade 2 when 50% of the carcinoma, or more, is Gleason grade 3 and ISUP grade 3
when the grade 4 component represents more than 50% of the carcinoma. In a carcinoma almost entirely
composed of Gleason grade 3 the presence of a minor (< 5%) Gleason pattern 4 component is not included in
the Gleason score (ISUP grade 1), but its presence is commented upon.
ISUP grade 4 is largely composed of Gleason grade 4 and ISUP grade 5 of a combination of
Gleason grade 4 and 5 or only Gleason grade 5. A global ISUP grade is given for multiple tumours, but a
separate tumour focus with a higher ISUP grade should also be mentioned. Tertiary Gleason grade 5, if > 5%
of the PCa volume, is an unfavourable prognostic indicator for BCR and should be incorporated in the ISUP
grade. If less than 5% its presence should be mentioned in the report [85, 342].
5.2.8.4.4 Definition of extraprostatic extension
Extraprostatic extension is defined as carcinoma mixed with peri-prostatic adipose tissue, or tissue that
extends beyond the prostate gland boundaries (e.g., neurovascular bundle, anterior prostate). Microscopic
bladder neck invasion is considered EPE. It is useful to report the location and extent of EPE because the latter
is related to recurrence risk [343].
There are no internationally accepted definitions of focal or microscopic, vs. non-focal or extensive
EPE. Some describe focal as a few glands [344] or < 1 HPF in one or at most two sections [345] whereas
others measure the depth of extent in millimetres [346].
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At the apex of the prostate, tumour mixed with skeletal muscle does not constitute EPE. In the
bladder neck, microscopic invasion of smooth muscle fibres is not equated to bladder wall invasion, i.e. not
as pT4, because it does not carry independent prognostic significance for PCa recurrence and should be
recorded as EPE (pT3a) [347, 348]. Stage pT4 is only assigned when the tumour invades the bladder muscle
wall as determined macroscopically [349].
5.2.8.4.5 PCa volume
The independent prognostic value of PCa volume in RP specimens has not been established [345, 350-353].
Nevertheless, a cut-off of 0.5 mL is traditionally used to distinguish insignificant from clinically relevant cancer
[350]. Improvement in prostatic radio-imaging allows more accurate pre-operative measurement of cancer
volume. It is recommended that at least the diameter/volume of the dominant tumour nodule should be
assessed, or a rough estimate of the percentage of cancer tissue provided [354].
5.2.8.4.6 Surgical margin status
Surgical margin is an independent risk factor for BCR. Margin status is positive if tumour cells are in contact
with the ink on the specimen surface. Margin status is negative if tumour cells are close to the inked surface
[351] or at the surface of the tissue lacking ink. In tissues that have severe crush artefacts, it may not be
possible to determine margin status [355].
Surgical margin is separate from pathological stage, and a positive margin is not evidence of EPE
[356]. There is insufficient evidence to prove a relationship between margin extent and recurrence risk [345].
However, some indication must be given of the multifocality and extent of margin positivity, such as the linear
extent in mm of involvement: focal, < 1 mm vs. extensive, > 1 mm [357], or number of blocks with positive
margin involvement. Gleason score at the positive margin was found to correlate with outcome, and should be
reported [313].
5.3
Diagnosis - Clinical Staging
5.3.1
T-staging
The cT category used in the risk table only refers to the DRE finding. The imaging parameters and biopsy
results for local staging are, so far, not part of the risk category stratification [358].
5.3.1.1
TRUS
Transrectal ultrasound is no more accurate at predicting organ-confined disease than DRE [359]. Some singlecentre studies reported good results in local staging using 3D TRUS or colour Doppler but these good results
were not confirmed by large-scale studies [360, 361].
5.3.1.2
MRI
T2-weighted imaging remains the most useful method for local staging on MRI. At 1.5 Tesla, MRI has good
specificity but low sensitivity for detecting T3 stages. Pooled data from a meta-analysis showed a sensitivity
and specificity of 0.57 (95% CI: 0.49–0.64) and 0.91 (95% CI: 0.88–0.93), 0.58 (95% CI: 0.47–0.68) and 0.96
(95% CI: 0.95–0.97), and 0.61 (95% CI: 0.54–0.67) and 0.88 (95% CI: 0.85–0.91), for EPE, SVI, and overall
stage T3 assessement, respectively [362]. Magnetic resonance imaging cannot detect microscopic EPE. Its
sensitivity increases with the radius of extension within peri-prostatic fat. In one study, the EPE detection rate
increased from 14 to 100% when the radius of extension increased from < 1 mm to > 3 mm [363]. In another
study, MRI sensitivity, specificity and accuracy for detecting pT3 stage were 40%, 95% and 76%, respectively,
for focal (i.e. microscopic) EPE, and 62%, 95% and 88% for extensive EPE [364].
The use of high field strength (3 Tesla) or functional imaging in addition to T2-weighted imaging
improves sensitivity for EPE or SVI detection [362] but the experience of the reader remains of paramount
importance [365] and the inter-reader agreement remains moderate with kappa values ranging from 0.41 to
0.68 [366].
Several series suggested that MRI findings could improve the prediction of the pathological stage
when combined with clinical and biopsy data [248]. However, all these studies were based on cohorts of men
diagnosed with systematic biopsy and their generalisability in the targeted biopsy setting is questionable. For
risk calculators predicting EPE and SVI based on MRI findings, clinical data and combined systematic and
targeted biopsy results have been recently reported [367], but they have not undergone external validation yet.
Given its low sensitivity for focal (microscopic) EPE, MRI is not recommended for local staging in
low-risk patients [368-370]. However, MRI can still be useful for treatment planning.
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5.3.2
N-staging
5.3.2.1
Computed tomography and magnetic resonance imaging
Abdominal CT and T1-T2-weighted MRI indirectly assess nodal invasion by using LN diameter and
morphology. However, the size of non-metastatic LNs varies widely and may overlap the size of LN metastases.
Usually, LNs with a short axis > 8 mm in the pelvis and > 10 mm outside the pelvis are considered malignant.
Decreasing these thresholds improves sensitivity but decreases specificity. As a result, the ideal size threshold
remains unclear [371, 372]. Computed tomography (CT) and MRI sensitivity is less than 40% [373, 374]. Among
4,264 patients, 654 (15.3%) of whom had positive LNs at LND, CT was positive in only 105 patients (2.5%)
[371]. In a multi-centre database of 1,091 patients who underwent pelvic LN dissection, CT sensitivity and
specificity were 8.8% and 98%, respectively [375]. Detection of microscopic LN invasion by CT is < 1% in
patients with ISUP grade < 4 cancer, PSA < 20 ng/mL, or localised disease [376-378].
Diffusion-weighted MRI (DW-MRI) may detect metastases in normal-sized nodes, but a negative
DW-MRI cannot rule out the presence of LN metastases [372, 379].
5.3.2.2
Risk calculators incorporating MRI findings
Because CT and MRI lack sensitivity for direct detection of positive LNs, nomograms combining clinical and
biopsy findings (such as the nomograms developed by the Memorial Sloan Cancer Center (MSKCC) [380],
by Briganti et al. or by Gandaglia et al. [381, 382] have been used to identify patients at higher risk of LN
invasion who should be considered for LN dissection. Although these nomograms are associated with good
performance, they have been developed using systematic biopsy findings and may therefore not be sensitive to
patients diagnosed with combined MRI-TBx and systematic biopsy.
Two models incorporating MRI-TBx biopsy findings and MRI-derived findings recently underwent
external validation [367, 383]. One model tested on an external cohort of 187 patients treated by RP and
extended LN dissection showed a prevalence of LN invasion of 13.9% (vs. 16.9% in the development cohort).
The C-index was 0.73 (vs. 0.81 in the development cohort); at calibration analysis, the model tended to
overpredict the actual risk [383]. Another model was validated in an external multi-centre cohort of 487 patients
with a prevalence of 8% of LN invasion (vs. 12.5% in the development cohort).The AUC was 0.79 (vs. 0.81
in the development cohort). Using a risk cut-off of 7% would have avoided LN dissection in 56% of patients,
while missing LN invasion in 13 (34%) of the 38 patients with LN invasion [367].
5.3.2.3
Choline PET/CT
In a meta-analysis of 609 patients, pooled sensitivity and specificity of choline PET/CT for pelvic LN
metastases were 62% (95% CI: 51–66%) and 92% (95% CI: 89–94%), respectively [384]. In a prospective
trial of 75 patients at intermediate risk of nodal involvement (10–35%), the sensitivity was only 8.2% at
region-based analysis and 18.9% at patient-based analysis, which is too low to be of clinical value [385]. The
sensitivity of choline PET/CT increases to 50% in patients at high risk and to 71% in patients at very high risk,
in both cases out-performing contrast-enhanced CT [386]. However, comparisons between choline PET/CT
and DW-MRI yielded contradictory results, with PET/CT sensitivity found to be superior [387], similar [388, 389]
or inferior [385] than that of DW-MRI.
Due of its low sensitivity, choline PET/CT does not reach clinically acceptable diagnostic accuracy
for detection of LN metastases, or to rule out a nodal dissection based on risk factors or nomograms (see
Section 6.3.4.1.2).
5.3.2.4
Prostate-specific membrane antigen-based PET/CT
Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/CT uses several different
radiopharmaceuticals; the majority of published studies used 68Ga-labelling for PSMA PET imaging, but some
used 18F-labelling. At present there are no conclusive data about comparison of such tracers, with additional
new radiotracers being developed. 68Ga-labelled or 18F-labelled radiotracers for PSMA PET/CT imaging provide
good contrast-to-noise ratio, thereby improving the detectability of lesions. Prostate-specific membrane
antigen is also an attractive target because of its specificity for prostate tissue, even if PSMA expression in
other non-prostatic malignancies or benign conditions may cause incidental false-positive findings [390-394].
A prospective, multi-centre study addressed the use of 68Ga-PSMA PET/CT in patients with newly diagnosed
PCa and negative bone scan findings. In 103 eligible patients at increased risk for metastatic LNs prior to
surgery, 97 extended pelvic lymph-node dissections (ePLND) were performed, resulting in the identification of
85 LN metastases in 41 patients (42.3%). Positron-emission tomography was positive in 17 patients, resulting
in a per-patient-based sensitivity and specificity of 41.5% (95% CI: 26.7–57.8) and 90.9% (95% CI: 79.3–96.6),
respectively. A treatment change occurred in 12.6% of patients [395]. Another prospective multi-centre trial
investigated the diagnostic accuracy of 18F-DCFPyL ([2-(3-(1-carboxy-5-[(6-18F-fluoropyridine-3-carbonyl)amino]-pentyl)-ureido)-pentanedioic acid] PET/CT for LN staging in 117 patients with primary PCa, prior to
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robot-assisted radical prostatectomy (RARP) with ePLND. 18F-DCFPyL PET/CT showed a high specificity
(94.0%; CI: 86.9–97.5%), and a limited sensitivity (41.2%,CI: 19.4–66.5%) for the detection of pelvic LN
metastases [396]. This suggests that current PSMA-based PET/CT imaging cannot yet replace diagnostic
ePLND.
Prostate-specific antigen may be a predictor of a positive PSMA PET/CT. In the primary staging
cohort from a meta-analysis [397], however, only 4 studies reported PSMA PET-positivity based on the PSA
value, offering no robust estimates of positivity. The tracer uptake is also influenced by the ISUP grade and the
PSA level. In a series of 90 patients with primary PCa, tumours with an ISUP grade between 1 and 3 showed
significantly lower tracer uptake than tumours with an ISUP grade > 4. Similarly, patients with PSA levels
> 10 ng/mL showed significantly higher uptake than those with PSA levels < 10 ng/mL [398].
Comparison between PSMA PET/CT and MRI was recently performed in a systematic review and metaanalysis including 13 studies (n = 1,597) [399]. 68Ga-PSMA was found to have a higher sensitivity and a
comparable specificity for staging pre-operative LN metastases in intermediate- and high-risk PCa. The pooled
sensitivity and specificity of 68Ga-PSMA PET were 0.65 (95% CI: 0.49–0.79) and 0.94 (95% CI: 0.88–0.97),
respectively, while the corresponding values of MRI were 0.41 (95% CI: 0.26–0.57) and 0.92 (95% CI:
0.86–0.95). 68Ga-PSMA PET was potentially a more effective and appropriate imaging modality to predict LN
metastasis prior to surgery as indicated by the area under the symmetric receiver-operating characteristic
(SROC) curve. Another prospective trial reported superior sensitivity of PSMA PET/CT as compared to MRI for
nodal staging of 36 high-risk PCa patients [400].
PSMA PET/CT has a good sensitivity and specificity for LN involvement, possibly impacting clinical decisionmaking. In a recent review and meta-analysis including 37 articles, a subgroup analysis was perfomed in
patients undergoing PSMA PET/CT for primary staging. On a per-patient-based analysis, the sensitivity and
specificity of 68Ga-PSMA PET were 77% and 97%, respectively, after eLND at the time of RP. On a per-lesionbased analysis, sensitivity and specificity were 75% and 99%, respectively [397].
In summary, PSMA PET/CT is more appropriate in N-staging as compared to MRI, abdominal contrastenhanced CT or choline PET/CT; however, small LN metastases, under the spatial resolution of PET (~5 mm),
may still be missed.
5.3.3
M-staging
5.3.3.1
Bone scan
99mTc-Bone scan has been the most widely used method for evaluating bone metastases of PCa. A metaanalysis showed combined sensitivity and specificity of 79% (95% CI: 73–83%) and 82% (95% CI: 78–85%)
at patient level and 59% (95% CI: 55–63%) and 75% (95% CI: 71–79%) at lesion level [401]. Bone scan
diagnostic yield is significantly influenced by the PSA level, the clinical stage and the tumour ISUP grade and
these three factors were the only independent predictors of bone scan positivity in a study of 853 patients [402].
The mean bone scan positivity rate in 23 different series was 2.3% in patients with PSA levels < 10 ng/ mL,
5.3% in patients with PSA levels between 10.1 and 19.9 ng/mL and 16.2% in patients with PSA levels of
20.0–49.9 ng/mL. It was 6.4% in men with organ-confined cancer and 49.5% in men with locally advanced
cancers. Detection rates were 5.6% and 29.9% for ISUP grade 2 and > 3, respectively [371]. In two studies,
a major Gleason pattern of 4 was found to be a significant predictor of positive bone scan [403, 404]. Bone
scanning should be performed in symptomatic patients, independent of PSA level, ISUP grade or clinical stage
[371].
5.3.3.2
Fluoride PET and PET/CT, choline PET/CT and MRI
18F-sodium fluoride (18F-NaF) PET or PET/CT was reported to have similar specificity and superior sensitivity
to bone scintigraphy for detecting bone metastases in patients with newly diagnosed high-risk PCa [405,
406]. However, in a prospective study 18F-NaF PET showed no added value over bone scintigraphy in patients
with newly diagnosed intermediate- or high-risk PCa and negative bone scintigraphy results [407]. Recently,
the interobserver agreement for the detection of bone metastases and the accuracy of 18F-NaF PET/CT in
the diagnosis of bone metastases were investigated. Bone metastases were identified in 211 out of 219
patients with an excellent interobserver agreement, demonstrating that 18F-NaF PET/CT is a robust tool for the
detection of osteoblastic lesions in patients with PCa [408].
It remains unclear whether choline PET/CT is more sensitive than bone scan but it has higher
specificity with fewer indeterminate bone lesions [384, 409, 410].
Diffusion-weighted whole-body and axial MRI are more sensitive than bone scan and targeted
conventional radiography in detecting bone metastases in high-risk PCa [411, 412]. Whole-body MRI is also
more sensitive and specific than combined bone scan, targeted radiography and abdominopelvic CT [413].
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A meta-analysis found that MRI is more sensitive than choline PET/CT and bone scan for detecting bone
metastases on a per-patient basis, although choline PET/CT had the highest specificity [401].
It is of note that choline PET/CT and DW-MRI can also detect visceral and nodal metastases. Bone
scan and 18F-NaF PET/CT only assess the presence of bone metastases.
5.3.3.3
Prostate-specific membrane antigen-based PET/CT
A systematic review including 12 studies (n = 322) reported high variation in 68Ga-PSMA PET/CT sensitivity
for initial staging (range 33–99% median sensitivity on per-lesion analysis 33–92%, and on per-patient
analysis 66–91%), with good specificity (per-lesion 82–100%, and per-patient 67–99%), with most studies
demonstrating increased detection rates with respect to conventional imaging modalities (bone scan and CT)
[414]. Table 5.11 reports the data of the 5 studies including histopathologic correlation.
Table 5.11: PSMA PET/CT results in primary staging alone [414]
Study
Budaus
Herlemann
Van Leeuwen
Maurer
Rahbar
Sensitivity
(per lesion)
33%
84%
58%
74%
92%
Specificity
(per lesion)
100%
82%
100%
99%
92%
PPV
(per lesion)
100%
84%
94%
95%
96%
NPV
(per lesion)
69%
82%
98%
94%
85%
NPV = negative predictive value; PPV = positive predictive value.
One prospective multi-centre study evaluated changes in planned management before and after PSMA PET/CT
in 108 intermediate- and high-risk patients referred for primary staging. As compared to conventional staging,
additional LNs and bone/visceral metastases were detected in 25% and 6% of patients, respectively [415];
management changes occurred in 21% of patients. A recent retrospective review investigated the risk of
metastases identified by 68Ga-PSMA at initial staging in 1,253 patients (high-risk disease in 49.7%) [416].
Metastatic disease was identified by PSMA PET/CT in 12.1% of men, including 8.2% with a PSA level of
< 10 ng/mL and 43% with a PSA level of > 20 ng/mL. Lymph node metastases were suspected in 107 men,
with 47.7% outside the boundaries of an ePLND. Bone metastases were identified in 4.7%. In men with
intermediate-risk PCa metastases were identified in 5.2%, compared to 19.9% with high-risk disease.
In the PSMA PET/CT prospective multi-centre study in patients with high-risk PCa before curativeintent surgery or RT (proPSMA), 302 patients were randomly assigned to conventional imaging with CT and
bone scintigraphy or 68Ga-PSMA-11 PET/CT. The primary outcome focused on the accuracy of first-line
imaging for the identification of pelvic LN or distant metastases, using a predefined reference standard
consisting of histopathology, imaging, and biochemistry at 6-month follow-up. Accuracy of 68Ga-PSMA PET/CT
was 27% (95% CI: 23–31) higher than that of CT and bone scintigraphy (92% [88–95] vs. 65% [60–69];
p < 0.0001). Conventional imaging had a lower sensitivity (38% [24–52] vs. 85% [74–96]) and specificity (91%
[85–97] vs. 98% [95–100]) than PSMA PET/CT. Furthermore, 68Ga-PSMA PET/CT scan prompted management
change more frequently as compared to conventional imaging (41 [28%] men [21–36] vs. 23 [15%] men [10–22],
p = 0.08), with less equivocal findings (7% [4–13] vs. 23% [17–31]) and lower radiation exposure (8.4 mSv vs.
19.2 mSv; p < 0.001) [417].
5.3.4
Summary of evidence and practical considerations on initial N/M staging
The field of non-invasive N- and M-staging of PCa patients is evolving very rapidly. Evidence shows that
choline PET/CT, PSMA PET/CT and MRI provide a more sensitive detection of LN- and bone metastases
than the classical work-up with bone scan and abdominopelvic CT. In view of the evidence offered by the
randomised, multi-centre proPSMA trial [417], replacing bone scan and abdominopelvic CT by more sensitive
imaging modalities may be a consideration in patients with high-risk PCa undergoing initial staging. However, in
absence of prospective studies demonstrating survival benefit, caution must be used when taking therapeutic
decisions [418]. The prognosis and ideal management of patients diagnosed as metastatic by these more
sensitive tests is unknown. In particular, it is unclear whether patients with metastases detectable only
with PET/CT or MRI should be managed using systemic therapies, or whether they should be subjected to
aggressive local and metastases-directed therapies [419].
Results from RCTs evaluating the management and outcome of patients with (and without)
metastases detected by choline PET/CT, PSMA PET/CT and MRI are awaited before a decision can be made to
treat patients based on the results of these tests [420].
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5.3.5
Summary of evidence and guidelines for staging of prostate cancer
Summary of evidence
LE
PSMA PET/CT is more accurate for staging than CT and bone scan but to date no outcome data exist 1b
to inform subsequent management.
Any risk group staging
Use pre-biopsy MRI for local staging information.
Low-risk localised disease
Do not use additional imaging for staging purposes.
Intermediate-risk disease
In ISUP grade > 3, include at least cross-sectional abdominopelvic imaging and a bonescan for metastatic screening.
High-risk localised disease/locally advanced disease
Perform metastatic screening including at least cross-sectional abdominopelvic imaging
and a bone-scan.
5.4
Strength rating
Weak
Strong
Weak
Strong
Estimating life expectancy and health status
5.4.1
Introduction
Evaluation of life expectancy and health status is important in clinical decision-making for screening, diagnosis,
and treatment of PCa. Prostate cancer is common in older men (median age 68) and diagnoses in men > 65 will
result in a 70% increase in annual diagnosis by 2030 in Europe and the USA [421, 422].
Active treatment mostly benefits patients with intermediate- or high-risk PCa and longest expected
survival. In localised disease, over 10 years life expectancy is considered mandatory for any benefit from local
treatment and an improvement in CSS may take longer to become apparent. Older age and worse baseline
health status have been associated with a smaller benefit in PCa-specific mortality (PCSM) and life expectancy
of surgery vs. active surveillance (AS) [423]. Although in a RCT the benefit of surgery with respect to death from
PCa was largest in men < 65 years of age (RR: 0.45), RP was associated with a reduced risk of metastases and
use of androgen deprivation therapy (ADT) among older men (RR: 0.68 and 0.60, respectively) [424]. External
beam radiotherapy shows similar cancer control regardless of age, assuming a dose of > 72 Gy when using
intensity-modulated or image-guided RT [425].
Older men have a higher incidence of PCa and may be under-treated despite the high overall
mortality rates [426, 427]. Of all PCa-related deaths 71% occur in men aged > 75 years [428], probably due
to the higher incidence of advanced disease and death from PCa despite higher death rates from competing
causes [429-431]. In the USA, only 41% of patients aged > 75 years with intermediate- and high-risk disease
received curative treatment compared to 88% aged 65–74 [432].
5.4.2
Life expectancy
Life expectancy tables for European men are available online: https://ec.europa.eu/eurostat/web/productsdatasets/-/tps00205. Survival may be variable and therefore estimates of survival must be individualised. Gait
speed is a good single predictive method of life expectancy (from a standing start, at usual pace, generally over
6 meters). For men at age 75, 10-year survival ranged from 19% < 0.4 m/s to 87%, for > 1.4 m/s [433].
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Figure 5.2: Predicted Median Life Expectancy by Age and Gait Speed for males* [433]
*Figure reproduced with permission of the publisher, from Studenski S, et al. JAMA 2011 305(1)50.
5.4.3
Health status screening
Heterogeneity increases with advancing age, so it is important to use measures other than just age or
performance status (PS) when considering treatment options. The International SIOG PCa Working Group
recommends that treatment for adults over 70 years of age should be based on a systematic evaluation of
health status using the G8 (Geriatric 8) screening tool (see Table 5.12) [134]. This tool helps to discriminate
between those who are fit and those with frailty, a syndrome of reduced ability to respond to stressors.
Patients with frailty have a higher risk of mortality and negative side effects of cancer treatment [434]. Healthy
patients with a G8 score > 14 or vulnerable patients with reversible impairment after resolution of their geriatric
problems should receive the same treatment as younger patients. Frail patients with irreversible impairment
should receive adapted treatment. Patients who are too ill should receive only palliative treatment (see Figure
5.3) [134]. Patients with a G8 score < 14 should undergo a comprehensive geriatric assessment (CGA) as this
score is associated with 3-year mortality. A CGA is a multi-domain assessment that includes co-morbidity,
nutritional status, cognitive and physical function, and social supports to determine if impairments are
reversible [435]. A systematic review of the effect of geriatric evaluation for older cancer patients showed
improved treatment tolerance and completion [436].
The Clinical Frailty Scale (CFS) is another screening tool for frailty (see Table 5.4.2) [437]. Although
not frequently used in the cancer setting, it is considered to be a common language for expressing degree of
frailty. The scale runs from 1 to 9, with higher scores indicating increasing frailty. Patients with a higher CFS
score have a higher 30-day mortality after surgery and are less likely to be discharged home [438].
It is important to use a validated tool to identify frailty, such as the G8 or CFS, as clinical judgement
has been shown to be poorly predictive of frailty in older patients with cancer [439].
5.4.3.1
Co-morbidity
Co-morbidity is a major predictor of non-cancer-specific death in localised PCa treated with RP and is more
important than age [440, 441]. Ten years after not receiving active treatment for PCa, most men with a high
co-morbidity score had died from competing causes, irrespective of age or tumour aggressiveness [440].
Measures for co-morbidity include: Cumulative Illness Score Rating-Geriatrics (CISR-G) [442, 443] (Table 5.13)
and Charlson Co-morbidity Index (CCI) [444].
5.4.3.2
Nutritional status
Malnutrition can be estimated from body weight during the previous 3 months (good nutritional status < 5%
weight loss; risk of malnutrition: 5–10% weight loss; severe malnutrition: > 10% weight loss) [445].
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5.4.3.3
Cognitive function
Cognitive impairment can be screened for using the mini-COG (https://mini-cog.com/) which consists of
three-word recall and a clock-drawing test and can be completed within 5 minutes. A score of < 3/5 indicates
the need to refer the patient for full cognitive assessment. Patients with any form of cognitive impairment
(e.g., Alzheimer’s or vascular dementia) may need a capacity assessment of their ability to make an informed
decision, which is an increasingly important factor in health status assessment [446-448]. Cognitive impairment
also predicts risk of delirium, which is important for patients undergoing surgery [449].
5.4.3.4
Physical function
Measures for overall physical functioning include: Karnofsky score and ECOG scores [450]. Measures for
dependence in daily activities include: Activities of Daily Living (ADL; basic activities) and Instrumental Activities
of Daily Living (IADL; activities requiring higher cognition and judgement) [451-453].
5.4.3.5
Shared decision-making
The patient’s own values and preferences should be taken into account as well as the above factors. A shared
decision-making process also involves anticipated changes to quality of life (QoL) functional ability, and a
patient’s hopes, worries and expectations about the future [454]. Particularly in older and frail patients, these
aspects should be given equal importance to disease characteristics during the decision-making process [455].
Older patients may also wish to involve family members, and this is particularly important where cognitive
impairment exists.
5.4.4
Conclusion
Individual life expectancy, health status, frailty, and co-morbidity, not only age, should be central in clinical
decisions on screening, diagnostics, and treatment for PCa. A life expectancy of 10 years is most commonly
used as a threshold for benefit of local treatment. Older men may be undertreated. Patients aged 70 years of
age or older who have frailty should receive a comprehensive geriatric assessment. Resolution of impairments
in vulnerable men allows a similar urological approach as in fit patients.
Table 5.12: G8 screening tool (adapted from [456])
A
B
C
D
E
F
G
H
48
Items
Has food intake declined over the past 3 months
due to loss of appetite, digestive problems,
chewing, or swallowing difficulties?
Possible responses (score)
0 = severe decrease in food intake
1 = moderate decrease in food intake
2 = no decrease in food intake
Weight loss during the last 3 months?
0 = weight loss > 3 kg
1 = does not know
2 = weight loss between 1 and 3 kg
3 = no weight loss
Mobility?
0 = bed or chair bound
1 = able to get out of bed/chair but does not go out
2 = goes out
Neuropsychological problems?
0 = severe dementia or depression
1 = mild dementia
2 = no psychological problems
0 = BMI < 19
BMI? (weight in kg)/(height in m2)
1 = BMI 19 to < 21
2 = BMI 21 to < 23
3 = BMI > 23
Takes more than three prescription drugs per
0 = yes
day?
1 = no
0.0 = not as good
In comparison with other people of the same
age, how does the patient consider his/her health 0.5 = does not know
status?
1.0 = as good
2.0 = better
Age
0 = > 85
1 = 80-85
2 = < 80
Total score
0-17
PROSTATE CANCER - LIMITED UPDATE 2021
Figure 5.3: Decision tree for health status screening (men > 70 years)** [134]
Screening by G8 and mini-COG
G8 score > 14/17
no geriatric
evaluation is
needed
TM*
G8 score ≤ 14/17
a full geriatric evaluation is
mandatory
- Abnormal ADL: 1 or 2
- Weight loss 5-10%
- Comorbidities CISR-G
grades 1-2
- Abnormal ADL: > 2
- Weight loss > 10%
- Comorbidities CISR-G
grades 3-4
Geriatric assessment
then geriatric intervention
Group 1
Fit
Group 2
Vulnerable
Group 3
Frail
Mini-COGTM = Mini-COGTM cognitive test; ADLs = activities of daily living; CIRS-G = Cumulative Illness
Rating Score - Geriatrics; CGA = comprehensive geriatric assessment.
*F
or Mini-COGTM, a cut-off point of < 3/5 indicates a need to refer the patient for full evaluation of potential
dementia.
**Reproduced with permission of Elsevier, from Boyle H.J., et al. Eur J Cancer 2019:116; 116 [134].
Figure 5.4: The Clinical Frailty Scale version 2.0 [437]*
CLINICAL FRAILTY SCALE
1
2
LIVING
WITH
MODERATE
FRAILTY
People who need help with all outside
activities and with keeping house.
Inside, they often have problems with
stairs and need help with bathing and
might need minimal assistance (cuing,
standby) with dressing.
7
LIVING
WITH
SEVERE
FRAILTY
Completely dependent for personal
care, from whatever cause (physical or
cognitive). Even so, they seem stable
and not at high risk of dying (within ~6
months).
8
LIVING
WITH VERY
SEVERE
FRAILTY
VERY People who are robust, active, energetic
FIT and motivated. They tend to exercise
regularly and are among the fittest for
their age.
FIT People who have no active disease
symptoms but are less fit than category
1. Often, they exercise or are very active
occasionally, e.g., seasonally.
3
MANAGING People whose medical problems are
WELL well controlled, even if occasionally
4
LIVING
WITH
VERY MILD
FRAILTY
5
6
symptomatic, but often are not
regularly active beyond routine walking.
LIVING
WITH
MILD
FRAILTY
Previously “vulnerable,” this category
marks early transition from complete
independence. While not dependent on
others for daily help, often symptoms
limit activities. A common complaint
is being “slowed up” and/or being tired
during the day.
People who often have more evident
slowing, and need help with high
order instrumental activities of daily
living (finances, transportation, heavy
housework). Typically, mild frailty
progressively impairs shopping and
walking outside alone, meal preparation,
medications and begins to restrict light
housework.
9
Completely dependent for personal care
and approaching end of life. Typically,
they could not recover even from a
minor illness.
TERMINALLY Approaching the end of life. This
ILL category applies to people with a life
expectancy <6 months, who are not
otherwise living with severe frailty.
(Many terminally ill people can still
exercise until very close to death.)
SCORING FRAILTY IN PEOPLE WITH DEMENTIA
The degree of frailty generally
corresponds to the degree of
dementia. Common symptoms in
mild dementia include forgetting
the details of a recent event, though
still remembering the event itself,
repeating the same question/story
and social withdrawal.
www.geriatricmedicineresearch.ca
In moderate dementia, recent memory is
very impaired, even though they seemingly
can remember their past life events well.
They can do personal care with prompting.
In severe dementia, they cannot do
personal care without help.
In very severe dementia they are often
bedfast. Many are virtually mute.
Clinical Frailty Scale ©2005–2020 Rockwood,
Version 2.0 (EN). All rights reserved. For permission:
www.geriatricmedicineresearch.ca
Rockwood K et al. A global clinical measure of fitness
and frailty in elderly people. CMAJ 2005;173:489–495.
*Permission to reproduce the CFS was granted by the copyright holder.
PROSTATE CANCER - LIMITED UPDATE 2021
49
Table 5.13: Cumulative Illness Score Rating-Geriatrics (CISR-G)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Cardiac (heart only)
Hypertension (rating is based on severity; affected systems are rated separately)
Vascular (blood, blood vessels and cells, marrow, spleen, lymphatics)
Respiratory (lungs, bronchi, trachea below the larynx)
ENT (eye, ear, nose, throat, larynx)
Upper GI (esophagus, stomach, duodenum. Biliar and parcreatic trees; do not include diabetes)
Lower GI (intestines, hernias)
Hepatic (liver only)
Renal (kidneys only)
Other GU (ureters, bladder, urethra, prostate, genitals)
Musculo-Skeletal-Integumentary (muscles, bone, skin)
Neurological (brain, spinal cord, nerves; do not include dementia)
Endocrine-Metabolic (includes diabetes, diffuse infections, infections, toxicity)
Psychiatric/Behavioural (includes dementia, depression, anxiety, agitation, psychosis)
All body systems are scores on a 0 - 4 scale.
- 0: No problem affecting that system.
- 1: Current mild problem or past significant problem.
- 2: Moderate disability or morbidity and/or requires first line therapy.
- 3: S
evere problem and/or constant and significant disability and/or hard to control chronic
problems.
- 4: E
xtremely severe problem and/or immediate treatment required and/or organ failure and/or
severe functional impairment.
Total score 0-56
5.4.5
Guidelines for evaluating health status and life expectancy
Recommendations
Use individual life expectancy, health status, and co-morbidity in PCa management.
Use the Geriatric-8, mini-COG and Clinical Frailty Scale tools for health status screening.
Perform a full specialist geriatric evaluation in patients with a G8 score < 14.
Consider standard treatment in vulnerable patients with reversible impairments (after
resolution of geriatric problems) similar to fit patients, if life expectancy is > 10 years.
Offer adapted treatment to patients with irreversible impairment.
Offer symptom-directed therapy alone to frail patients.
6.
Strength rating
Strong
Strong
Strong
Weak
Weak
Strong
TREATMENT
This chapter reviews the available treatment modalities, followed by separate sections addressing treatment
for the various disease stages.
6.1
Treatment modalities
6.1.1
Deferred treatment (active surveillance/watchful waiting)
In localised disease a life expectancy of at least 10 years is considered mandatory for any benefit from local
treatment. Data are available on patients who did not undergo local treatment with up to 25 years of followup, with endpoints of OS and CSS. Several series have shown a consistent CSS rate of 82–87% at 10 years
[457-462], and 80–95% for T1/T2 and ISUP grade < 2 PCas [463]. In three studies with data beyond 15 years,
the DSS was 80%, 79% and 58% [459, 461, 462], and two reported 20-year CSS rates of 57% and 32%,
respectively [459, 461]. In addition, many patients classified as ISUP grade 1 would now be classified as ISUP
grade 2–3 based on the 2005 Gleason classification, suggesting that the above-mentioned results should be
considered as minimal. Patients with well-, moderately- and poorly-differentiated tumours had 10-year CSS
rates of 91%, 90% and 74%, respectively, correlating with data from the pooled analysis [463]. Observation
was most effective in men aged 65–75 years with low-risk PCa [464].
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PROSTATE CANCER - LIMITED UPDATE 2021
Co-morbidity is more important than age in predicting life expectancy in men with PCa. Increasing co-morbidity
greatly increases the risk of dying from non-PCa-related causes and for those men with a short life expectancy.
In an analysis of 19,639 patients aged > 65 years who were not given curative treatment, most men with a CCI
score > 2 had died from competing causes at 10 years follow-up regardless of their age at time of diagnosis.
Tumour aggressiveness had little impact on OS suggesting that patients could have been spared biopsy
and diagnosis of cancer. Men with a CCI score < 1 had a low risk of death at 10 years, especially for wellor moderately-differentiated lesions [440]. This highlights the importance of assessing co-morbidity before
considering a biopsy.
In screening-detected localised PCa the lead-time bias is likely to be greater. Mortality from
untreated screen-detected PCa in patients with ISUP grade 1–2 might be as low as 7% at 15 years followup [465]. Consequently, approximately 45% of men with PSA-detected PCa are suitable for close follow-up
through a robust surveillance programme. There are two distinct strategies for conservative management that
aim to reduce over-treatment: AS and Watchful waiting (WW) (Table 6.1.1).
6.1.1.1
Definitions
Active surveillance aims to avoid unnecessary treatment in men with clinically localised PCa who do not require
immediate treatment, but at the same time achieve the correct timing for curative treatment in those who
eventually do [466]. Patients remain under close surveillance through structured surveillance programmes with
regular follow-up consisting of PSA testing, clinical examination, mpMRI imaging and repeat prostate biopsies,
with curative treatment being prompted by pre-defined thresholds indicative of potentially life-threatening
disease which is still potentially curable, while considering individual life expectancy.
Watchful waiting refers to conservative management for patients deemed unsuitable for curative treatment
from the outset, and patients are clinically ‘watched’ for the development of local or systemic progression
with (imminent) disease-related complaints, at which stage they are then treated palliatively according to their
symptoms in order to maintain QoL.
Table 6.1.1: Definitions of active surveillance and watchful waiting [465]
Treatment intent
Follow-up
Assessment/markers used
Life expectancy
Aim
Comments
Active surveillance
Curative
Pre-defined schedule
DRE, PSA, mpMRI, re-biopsy
> 10 years
Minimise treatment-related toxicity
without compromising survival
Low-risk patients
Watchful waiting
Palliative
Patient-specific
Not pre-defined, but dependent
on development of symptoms of
progression
< 10 years
Minimise treatment-related toxicity
Can apply to patients with all stages
DRE = digital rectal examination; PSA = prostate-specific antigen; mpMRI = multiparametric magnetic
resonance imaging.
6.1.1.2
Active surveillance
No formal RCT is available comparing this modality to standard treatment. The Prostate Testing for Cancer and
Treatment (ProtecT) trial is discussed later as it is not a formal AS strategy but rather active monitoring (AM),
which is a significantly less stringent surveillance strategy in terms of clinical follow-up, imaging and repeat
biopsies [467].
Several cohorts have investigated AS in organ-confined disease, the findings of which were summarised in a
systematic review [468]. More recently, the largest prospective series of men with low-risk PCa managed by AS
was published [469]. Table 6.1.2 summarises the results of selective AS cohorts. It is clear that the long-term
OS and CSS of patients on AS are extremely good. However, more than one-third of patients are ‘reclassified’
during follow-up, most of whom undergo curative treatment due to disease upgrading, increase in disease
extent, disease stage, progression or patient preference. There is considerable variation and heterogeneity
between studies regarding patient selection and eligibility, follow-up policies (including frequency and type
of imaging such as mpMRI imaging, type and frequency of repeat prostate biopsies, such as MRI-targeted
biopsies or transperineal template biopsies, use of PSA kinetics and density, and frequency of clinical followup), when active treatment should be instigated (i.e. reclassification criteria) and which outcome measures
should be prioritised [466]. These will be discussed further in section 6.2.1.
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51
Table 6.1.2: Active surveillance in screening-detected prostate cancer
Studies
N
Median FU (mo)
Van As, et al. 2008 [470]
Carter, et al. 2007 [471]
Adamy, et al. 2011 [472]
Soloway, et al. 2010 [473]
Roemeling, et al. 2007 [474]
Khatami, et al. 2007 [475]
Klotz, et al. 2015 [476]
Tosoian, et al. 2015 [469]
Total
326
407
533-1,000
99
278
270
993
1,818
4,724-5,191
22
41
48
45
41
63
77
60
46.5
pT3 in RP patients* 10-year
OS (%)
8/18 (44%)
98
10/49 (20%)
98
4/24 (17%)
90
0/2
100
89
n.r.
85
93
93
10-year
CSS (%)
100
100
99
100
100
100
98.1
99.9
99
* Patients receiving active therapy following initial active surveillance.
CSS = cancer-specific survival; FU = follow-up; mo = months; n = number of patients; n.r. = not reported;
OS = overall survival; RP = radical prostatectomy.
6.1.1.3
Watchful Waiting
6.1.1.3.1 Outcome of watchful waiting compared with active treatment
The SPCG-4 study was a RCT from the pre-PSA era, randomising patients to either WW or RP (Table 6.1.3)
[477]. The study found RP to provide superior CSS, OS and progression-free survival (PFS) compared to
WW at a median follow-up of 23.6 years (range 3 weeks–28 years). The PIVOT trial was a RCT conducted in
the early PSA era and made a similar comparison between RP vs. observation in 731 men (50% with nonpalpable disease) [478] but in contrast to the SPCG-4, it found little to no benefit of RP (cumulative incidence
of all-cause death, RP vs. observation: 68% vs. 73%; RR: 0.92, 95% CI: 0.84–1.01) within a median followup period of 18.6 years (interquartile range, 16.6 to 20 years). Exploratory subgroup analysis showed that
the borderline benefit from RP was most marked for intermediate-risk disease (RR: 0.84, 95% CI: 0.73–0.98)
but there was no benefit in patients with low- or high-risk disease. Overall, no adverse effects on HRQoL
and psychological well-being was apparent in the first years [479]. However, one of the criticisms of the
PIVOT trial is the relatively high overall mortality rate in the WW group (73% at a median follow-up period of
18.6 years (interquartile range, 16.6 to 20.0 years) compared with more contemporary series.
Table 6.1.3: Outcome of SPCG-4 at a median follow-up of 23.6 years [477]
RP (n = 348) (%)
Disease-specific mortality
Overall mortality
Metastatic progression
19.6
71.9
26.6
Watchful waiting
(n = 348) (%)
31.3
83.8
43.3
Relative risk
(95% CI)
0.55 (0.41–0.74)
0.74 (0.62–0.87)
0.54 (0.42–0.70)
p-value
< 0.001
< 0.001
< 0.001
CI = confidence interval; RP = radical prostatectomy.
6.1.1.4
The ProtecT study
The ProtecT trial randomised 1,643 patients into three arms: active treatment with either RP or EBRT, and
AM [467]. In this AM schedule patients with a PSA rise of more than 50% in 12 months underwent a repeat
biopsy, but none had systematic repeat biopsies. Fifty-six percent of patients had low-risk disease, with
90% having a PSA < 10 ng/mL, 77% ISUP grade 1 (20% ISUP grade 2–3), and 76% T1c, while the other
patients had mainly intermediate-risk disease. After 10 years of follow-up, CSS was the same between
those actively treated and those on AM (99% and 98.8%, respectively), as was the OS. Only metastatic
progression differed (6% in the AM group as compared to 2.6% in the treated group). The key finding was
that AM was as effective as active treatment at 10 years, at a cost of increased progression and double the
metastatic risk. Metastases remained rare (6%), but more frequent than seen with AS protocols; probably
driven by differences in intensity of monitoring and patient selection. It is important to note that the AM arm
in ProtecT represented an intermediate approach between contemporary AS protocols and WW in terms of
a monitoring strategy based almost entirely on PSA measurements alone; there was no use of mpMRI scan,
either at recruitment or during the monitoring period, nor was there any protocol-mandated repeat prostate
biopsies at regular intervals. In addition, approximately 40% of randomised patients had intermediate-risk
disease. Nevertheless, the ProtecT study has reinforced the role of deferred active treatment (i.e. either AS or
some form of initial AM) as a feasible alternative to active curative interventions in patients with low-grade and
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low-stage disease. Beyond 10 years, no data is available, as yet, although AS is likely to give more reassurance
especially in younger men, based on more accurate risk stratification at recruitment and more stringent criteria
regarding follow-up, imaging, repeat biopsy and reclassification. Individual life expectancy must be evaluated
before considering any active treatment in low-risk patients and in those with up to 10 years’ individual life
expectancy.
6.1.2
Radical prostatectomy
6.1.2.1
Introduction
The goal of RP by any approach is the eradication of cancer while, whenever possible, preserving pelvic
organ function [480]. The procedure involves removing the entire prostate with its capsule intact and SVs,
followed by vesico-urethral anastomosis. Surgical approaches have expanded from perineal and retropubic
open approaches to laparoscopic and robotic-assisted techniques; anastomoses have evolved from Vest
approximation sutures to continuous suture watertight anastomoses under direct vision and mapping of the
anatomy of the dorsal venous complex (DVC) and cavernous nerves has led to excellent visualisation and
potential for preservation of erectile function [481]. The main results from multi-centre RCTs involving RP are
summarised in Table 6.1.4.
Table 6.1.4: Oncological results of radical prostatectomy in organ-confined disease in RCTs
Study
Acronym
Population
Bill-Axelson, et al.
2018 [477]
Wilt, et al.
2017 [482]
SPCG-4
Pre-PSA era
PIVOT
ProtecT
Hamdy, et al.
2016 [467]
Treatment
period
1989-1999
Median
FU (mo)
283
Early years of
PSA testing
1994-2002
152
Screened
population
1999-2009
120
Risk category
CSS (%)
Low risk and
Intermediate risk
Low risk
Intermediate risk
80.4
(at 23 yr.)
95.9
91.5
(at 19.5 yr.)
99
(at 10 yr.)
Mainly low- and
intermediate risk
CSS = cancer-specific survival; FU = follow-up; mo = months; PSA = prostate-specific antigen; yr. = year.
6.1.2.2
Pre-operative preparation
6.1.2.2.1 Pre-operative patient education
As before any surgery appropriate education and patient consent is mandatory prior to RP. Peri-operative
education has been shown to improve long-term patient satisfaction following RP [483]. Augmentation of
standard verbal and written educational materials such as use of interactive multimedia tools [484, 485] and
pre-operative patient-specific 3D printed prostate models has been shown to improve patient understanding
and satisfaction and should be considered to optimise patient-centred care [486].
Pre-operative pelvic floor exercises
Although many patients who have undergone RP will experience a return to urinary continence [487], temporary
urinary incontinence is common early after surgery, reducing QoL. Pre-operative pelvic floor exercises (PFE)
with, or without, biofeedback have been used with the aim of reducing this early post-operative incontinence.
A systematic review and meta-analysis of the effect of pre-RP PFE on post-operative urinary incontinence
showed a significant improvement in incontinence rates at 3 months post-operatively with an OR of 0.64
(p = 0.005), but not at 1 month or 6 months [488]. Pre-operative PFE may therefore provide some benefit,
however the analysis was hampered by the variety of PFE regimens and a lack of consensus on the definition
of incontinence.
Prophylactic antibiotics
Prophylactic antibiotics should be used; however no high-level evidence is available to recommend specific
prophylactic antibiotics prior to RP (See EAU Urological Infections Guidelines). In addition, as the susceptibility
of bacterial pathogens and antibiotic availability varies worldwide, any use of prophylactic antibiotics should
adhere to local guidelines.
Neoadjuvant androgen deprivation therapy
Several RCTs have analysed the impact of neoadjuvant ADT before RP, most of these using a 3-month
period. The main findings were summarised in a Cochrane review [489]. Neoadjuvant ADT is associated with
a decreased rate of pT3 (downstaging), decreased positive margins, and a lower incidence of positive LNs.
These benefits are greater with increased treatment duration (up to 8 months). However, since neither the PSA
PROSTATE CANCER - LIMITED UPDATE 2021
53
relapse-free survival nor CSS were shown to improve, neoadjuvant ADT should not be considered as standard
clinical practice. One recent RCT compared neoadjuvant luteinising hormone-releasing hormone (LHRH) alone
vs. LHRH plus abiraterone plus prednisone prior to RP in 65 localised high-risk PCa patients [490]. Patients in
the combination arm were found to have both significantly lower tumour volume and significantly lower BCR at
> 4 years follow-up (p = 0.0014). Further supportive evidence is required before recommending combination
neoadjuvant therapy including abiraterone prior to RP.
6.1.2.3
Surgical techniques
Prostatectomy can be performed by open-, laparoscopic- or robot-assisted (RARP) approaches. The initial
open technique of RP described by Young in 1904 was via the perineum [481] but suffered from a lack of
access to pelvic LNs. If lymphadenectomy is required during perineal RP it must be done via a separate
open retropubic (RRP) or laparoscopic approach. The open retropubic approach was popularised by Walsh
in 1982 following his anatomical description of the DVC, enabling its early control and of the cavernous
nerves, permitting a bilateral nerve-sparing procedure [491]. This led to the demise in popularity of perineal
RP and eventually to the f