EAU Guidelines On Non-Muscle-invasive Urothelial Carcinoma of The Bladder: Update 2013

EURURO-5156; No.
of Pages 15
EUROPEAN UROLOGY XXX (2013) XXX–XXX
available at www.sciencedirect.com
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Guidelines
EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma

of the Bladder: Update 2013
Marko Babjuk a,*, Maximilian Burger b, Richard Zigeuner c, Shahrokh F. Shariat d,

Bas W.G. van Rhijn e, Eva Compérat f, Richard J. Sylvester g, Eero Kaasinen h,
Andreas Böhle i, Joan Palou Redorta j, Morgan Rouprêt k,l
a
Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic; b Department of Urology and Paediatric
c
Urology, Julius-Maximilians-University Medical Centre, Würzburg, Germany; Department of Urology, Medical University of Graz, Graz, Austria;
d
Department of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria; e Department of Surgical Oncology (Urology), Netherlands
Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; f Department of Pathology, Hôpital de la Pitié-Salpêtrière, UPMC, Paris,
France; g Department of Biostatistics, EORTC Headquarters, Brussels, Belgium; h Department of Surgery, Hyvinkää Hospital, Hyvinkää, Finland; i Department
of Urology, HELIOS Agnes-Karll-Krankenhaus, Bad Schwartau, Germany; j Department of Urology, Fundació Puigvert, Universitat Autónoma de Barcelona,
k
Spain; AP-HP, Hôpital de la Pitié-Salpêtrière, Service d’Urologie, Paris, F-75013, France; l UPMC Université de Paris 06, GRC5, ONCOTYPE-Uro, Institut
Universitaire de Cancérologie, F-75005, Paris, France
Article info Abstract
Article history: Context: The first European Association of Urology (EAU) guidelines on bladder cancer were
published in 2002 [1]. Since then, the guidelines have been continuously updated.
Accepted June 3, 2013
Objective: To present the 2013 EAU guidelines on non–muscle-invasive bladder cancer (NMIBC).
Published online ahead of Evidence acquisition: Literature published between 2010 and 2012 on the diagnosis and treatment
print on June 12, 2013 of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence
and grades of recommendation were assigned.
Evidence synthesis: Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC.
Keywords: Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral
resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a
Bacillus Calmette-Guerin (BCG)
complete TUR is essential for the patient’s prognosis. Where the initial resection is incomplete, where
Bladder cancer there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should
Cystectomy be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for
individual patients using the EORTC scoring system and risk tables. The stratification of patients into
Cystoscopy low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients
Diagnosis with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an
EAU Guidelines intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr
of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or by further instillations of
Follow-up chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for
Intravesical chemotherapy 1–3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy
Prognosis should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the
guidelines is available from the EAU Web site: http://www.uroweb.org/guidelines/.
Transurethral resection (TUR) Conclusions: These abridged EAU guidelines present updated information on the diagnosis and
Urothelial carcinoma treatment of NMIBC for incorporation into clinical practice.
Patient summary: The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated
version of their guidelines. Current clinical studies support patient selection into different risk
groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development
of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more
aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide
chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystec-
tomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are
in the highest risk group for progression.
# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles
University, V Úvalu 84, Prague 5, 15006, Czech Republic. Tel. +420 224434801; Fax: +420 224434821.
E-mail address: marek.babjuk@lfmotol.cuni.cz (M. Babjuk).
0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2013.06.003
Please cite this article in press as: Babjuk M, et al. EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder:
Update 2013. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.003
EURURO-5156; No. of Pages 15
2 EUROPEAN UROLOGY XXX (2013) XXX–XXX
1. Introduction factors [6]. Tobacco smoking is the most important risk

factor for BCa, accounting for approximately 50% of cases
The first European Association of Urology (EAU) guidelines [6,7] (LE: 3).
on bladder cancer were published in 2002 [1]. Since then, Occupational exposure to aromatic amines, polycyclic
the guidelines have been continuously updated, and the aromatic hydrocarbons, and chlorinated hydrocarbons is
most recent version is available from the EAU Web site the second most important risk factor for BCa, accounting
(http://www.uroweb.org/guidelines/). An overview of the for about 10% of all cases. Such occupational exposure
updated 2013 EAU guidelines on non–muscle-invasive occurs mainly in the paint processing, dye, metal and
bladder cancer (NMIBC) (Ta, T1, and carcinoma in situ petroleum product industries [6,8] (LE: 3).
[CIS]) is provided in this paper. The information presented is The exposure to ionising radiation is connected with an
limited to urothelial carcinoma, if not specified otherwise. increased risk of BCa (LE: 3). Schistosomiasis is a cause of
The aim is to provide practical guidance on the clinical BCa, particularly squamous cell carcinoma [6] (LE: 3).
management of NMIBC with a focus on clinical presentation
and recommendations. 5. Classification
2. Evidence acquisition 5.1. TNM classification and definition of non–muscle-invasive

bladder cancer
A systematic literature search was performed by the panel
members. For identification of original and review articles The Tumour, Node, Metastasis (TNM) classification system
published between 2010 and 2012, Medline, Web of approved by the Union International Contre le Cancer
Science, and Embase databases were used. Focus of the (UICC), which was updated in 2009, is used in these
searches was identification of all level 1 scientific data (ie, guidelines (Table 1) [9]. Papillary tumours confined to the
randomised controlled trials [RCTs], systematic reviews, mucosa and those which have invaded the lamina propria
and meta-analyses of RCTs). are classified as stage Ta and stage T1, respectively. Ta and
Panel members selected records with the highest level of T1 tumours can be removed by transurethral resection
evidence (LE) according to a modified classification system (TUR), and therefore they are grouped under the heading of
from the Oxford Centre for Evidence-based Medicine Levels NMIBC for therapeutic purposes. Also included under this
of Evidence [2]. Recommendations were graded to provide heading are flat, high-grade [HG] tumours that are confined
transparency regarding the underlying LE for each recom- to the mucosa, and classified as CIS (Tis). However, the term
mendation given. NMIBC is a suboptimal description. Whenever the termi-
nology NMIBC is used in individual cases, the tumour stage
3. Epidemiology and grade should be mentioned.
Bladder cancer (BCa) is the most common malignancy of the 5.2. Grading
urinary tract and the 7th most common cancer in men and
the 17th in women. In the European Union, the age- The new classification for grading noninvasive urothelial
standardised incidence rate is 27 per 100 000 in men and six bladder carcinomas proposed by the World Health Organi-
per 100 000 in women [3]. sation (WHO) and the International Society of Urological
Incidence varies between regions and countries; in Pathology was published in 2004 (Table 2) [10]. It provides
Europe, the highest age-standardised incidence rate has some changes compared with the original 1973 classifica-
been reported in Spain (41.5 in men and 4.8 in women [per tion. Among papillary lesions the classification defines
100 000 inhabitants]) and the lowest in Finland (18.1 in papillary urothelial neoplasms of low malignant potential
men and 4.3 in women) [3]. (PUNLMP), and low-grade (LG) and HG urothelial carcino-
In the European Union, age-standardised mortality rate mas. PUNLMP are lesions that do not have cytologic features
per 100 000 is 8 in men and 3 in women [3]. In 2008, BCa of malignancy but show normal urothelial cells in a
was the eighth most common cause of cancer-specific papillary configuration. They have a negligible risk for
mortality in Europe [3]. progression but have a tendency to recur. The intermediate
The incidence of BCa has decreased in some registries grade (grade 2), which was the subject of controversy in the
possibly reflecting the decreased impact of causative agents 1973 WHO classification, was removed from the 2004
[4]. The mortality of BCa has also decreased, possibly version (Table 2).
reflecting an increased standard of care [5]. The published comparisons, however, have not clearly
Approximately 75% of patients with BCa present with a confirmed that the WHO 2004 classification has better
NMIBC that is either confined to the mucosa (stage Ta, CIS) reproducibility than the 1973 classification [11,12].
or to the submucosa (stage T1). The prognostic value of both grading systems (WHO
1973 and 2004) has been confirmed. Attempts to demon-
4. Risk factors strate better prognostic value of one of them, however, have
yielded controversial results [11,13–16]. Most of the clinical
Genetic predisposition has a significant influence on BCa, trials published to date on Ta, T1 bladder tumours have
especially via its impact on susceptibility to other risk been performed using the 1973 WHO classification, and
EUROPEAN UROLOGY XXX (2013) XXX–XXX 3
Table 1 – 2009 TNM classification of urinary bladder cancer 5.4. Specific characteristics of carcinoma in situ and its clinical
classification
T: Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour CIS is a flat HG noninvasive urothelial carcinoma. It can
Ta Noninvasive papillary carcinoma occur in the whole urothelium (ie, the bladder, in the upper
Tis Carcinoma in situ: ‘‘flat tumour’’
T1 Tumour invades subepithelial connective tissue
urinary tract, and in the prostatic ducts and urethra).
T2 Tumour invades muscle Bladder CIS is classified into one of four different clinical
T2a Tumour invades superficial muscle (inner half) types [19]:
T2b Tumour invades deep muscle (outer half)
T3 Tumour invades perivesical tissue
T3a Microscopically Primary: Isolated CIS with no previous or concurrent
T3b Macroscopically (extravesical mass) papillary tumours and no previous CIS
T4 Tumour invades any of the following: prostate, Secondary: CIS detected during follow-up of patients with
uterus, vagina, pelvic wall, abdominal wall
a previous tumour that was not CIS
T4a Tumour invades prostate, uterus, or vagina
T4b Tumour invades pelvic wall or abdominal wall Concurrent: CIS in the presence of any other urothelial
N: Lymph nodes tumour in the bladder
NX Regional lymph nodes cannot be assessed Recurrent: Repeat occurrence of isolated CIS after initial
N0 No regional lymph node metastasis
successful response to intravesical treatment.
N1 Metastasis in a single lymph node in the true pelvis
(hypogastric, obturator, external iliac, or presacral)
N2 Metastasis in multiple lymph nodes in the true pelvis 6. Diagnosis
(hypogastric, obturator, external iliac, or presacral)
N3 Metastasis in a common iliac lymph node(s)
6.1. Symptoms
M: Distant metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis Patient history should be taken and recorded for all
M1 Distant metastasis important information with any possible connection to
BCa. Haematuria is the most common finding in NMIBC.
Lower urinary tract symptoms may reveal a CIS.
therefore, the following guidelines are based on this 6.2. Imaging

version. Until the WHO 2004 system is validated by more
prospective trials and incorporated into prognostic models, Intravenous urography (IVU) is used to detect filling defects
both classifications should be used. in the calyces, renal pelvis and ureters, and hydronephrosis,
which can indicate the presence of a ureteral tumour. Large
5.3. Variability among pathologists exophytic tumours may be seen as filling defects in the
bladder. The necessity to perform routine IVU once a
Despite well-defined criteria, there is significant variability bladder tumour has been detected is questioned because of
among pathologists for the diagnosis of CIS, in the the low incidence of significant findings [20,21] (LE: 2a).
classification of stage T1 versus Ta tumours, and tumour The incidence of upper urinary tract tumours (UTUCs) is low
grading in both the 1973 and 2004 classifications. The (1.8%) but increases to 7.5% in tumours located in the
general conformity in staging and grading is between 50% trigone [21] (LE: 2b). The risk of tumour recurrence as a
and 60% [11,16–18] (LE: 2a). UTUC during follow-up increases in multiple and high-risk
tumours [22] (LE: 2b).
Computed tomography (CT) urography is used as an
Table 2 – World Health Organisation grading in 1973 and in 2004 alternative to conventional IVU. Especially in muscle-
invasive tumours of the bladder and UTUCs, CT urography
1973 WHO grading
gives more information than IVU.
Urothelial papilloma
Grade 1: (G1) Well differentiated
Transabdominal ultrasound (US) permits characterisa-
Grade 2: (G2) Moderately differentiated tion of renal masses, detection of hydronephrosis, and
Grade 3: (G3) Poorly differentiated visualisation of intraluminal masses in the bladder. It can be
2004 WHO grading
as accurate as IVU for the diagnosis of upper urinary tract
Flat lesions
Hyperplasia (flat lesion without atypia or papillary) obstruction [20] (LE: 3). US is therefore a useful tool for the
Reactive atypia (flat lesion with atypia) detection of obstruction in patients with haematuria;
Atypia of unknown significance however, it cannot exclude the presence of upper tract
Urothelial dysplasia
tumours.
Urothelial carcinoma in situ
Papillary lesions CIS cannot be diagnosed with imaging methods.
Urothelial papilloma (which is a completely benign lesion)
Papillary urothelial neoplasm of low malignant potential 6.3. Urinary cytology
Low-grade papillary urothelial carcinoma
High-grade papillary urothelial carcinoma
Examination of voided urine or bladder-washing specimens
WHO = World Health Organisation. for exfoliated cancer cells has high sensitivity in HG/G3
tumours but low sensitivity in LG/G1 tumours. The 6.6. Cystoscopy

sensitivity of cytology for CIS detection is 28–100% [23]
(LE: 2b). Cytology is thus useful when a HG/G3 malignancy The diagnosis of papillary BCa depends on cystoscopic
or CIS is present. It is often negative, however, in the examination of the bladder and histologic evaluation of
presence of LG/G1 cancer. Positive voided urinary cytology the resected tissue. CIS is diagnosed by a combination of
can indicate a urothelial tumour anywhere in the urinary cystoscopy, urine cytology, and histologic evaluation
tract; however, negative cytology does not exclude the of multiple bladder biopsies. Cystoscopy is initially per-
presence of a tumour. formed in the office. The use of a flexible instrument with
Cytologic interpretation is user dependent [24]. Evalua- topical intraurethral anaesthetic lubricant instillation
tion can be hampered by low cellular yield, urinary tract results in better compliance, especially in men [34].
infections, stones, or intravesical instillations. In experi- Careful inspection of the whole urothelial lining in
enced hands, however, the specificity exceeds 90% [25] (LE: the bladder should be performed. A description should
2b). Cytology should be performed on fresh urine with include the site, size, number, and appearance (papillary
adequate fixation. Morning urine is not suitable because of or solid) of the tumours, as well as a description of
the frequent presence of cytolysis. mucosal abnormalities. Use of a bladder diagram is
recommended.
6.4. Urine molecular tests If a bladder tumour has been visualised in earlier
imaging studies, diagnostic cystoscopy can be omitted
Driven by the low sensitivity of urine cytology, extensive because the patient will undergo TUR.
laboratory research has developed numerous urinary tests
for BCa detection [25–27]. The tests have usually higher 6.7. Transurethral resection
sensitivity but lower specificity than urinary cytology
(LE:3). Benign conditions and bacillus Calmette-Guérin The goal of the TUR in Ta, T1 BCa is to make the correct
(BCG) influence many urinary marker tests [25–27] (LE: 3). diagnosis and remove all visible lesions. TUR should be
performed systematically as follows:
6.5. Practical application of urinary cytology and markers
Bimanual palpation under anaesthesia.
The following applications of urinary cytology or molecular Insertion of the resectoscope, in men under visual
tests must be considered: guidance, with inspection of the whole urethra.
Inspection of the whole urothelial lining of the bladder.
Screening of the population at risk of BCa. The application Cold-cup bladder biopsies and biopsy from prostatic
of haematuria dipstick, NMP22, or UroVysion in BCa urethra if indicated (see section 6.9).
screening in high-risk populations has been reported Resection of the tumour. The strategy of resection
[28,29]. However, routine application of screening is depends on the size of the lesion. Small tumours
currently not recommended. (<1 cm) can be resected en bloc, which includes the
Exploration of patients after haematuria or other entire tumour and part of the underlying bladder wall.
symptoms suggestive of BCa (primary detection). None Larger tumours should be resected separately in frac-
of the tests can replace cystoscopy. However, urinary tions including the exophytic part of the tumour, the
cytology or markers can be used as an adjunct to underlying bladder wall with the detrusor muscle, and
cystoscopy to detect invisible tumours, particularly CIS. the edges of the resection area. This approach provides
In this setting, sensitivity for HG/G3 tumours and good information about the vertical and horizontal
specificity are particularly important. Urinary cytology extent of the tumour and helps to improve resection
is highly specific, but urinary markers lack this high completeness [35] (LE: 3). Deep resection is not
specificity and are not recommended for primary necessary in small, apparently LG/G1 lesions with a
detection. previous history of Ta (LG/G1) tumour. Cauterisation
Facilitating surveillance of NMIBC [30–32]. (1) Follow-up should be avoided as much as possible during TUR to
of high-risk NMIBC: High-risk tumours should be prevent tissue destruction.
detected early in follow-up. Therefore, the best surveil- In patients with palpable lesions before TUR, bimanual
lance strategy for these patients includes frequent palpation should be repeated after resection.
cystoscopy and cytology. (2) Follow-up in low/interme- The protocol is formulated, which must describe all steps
diate-risk NMIBC: To reduce the number of cystoscopy of the procedure, as well as the extent and completeness
procedures, urinary markers should be able to detect of resection.
recurrence before the tumours are large and numerous. An order form for pathologic evaluation is prepared.
According to current knowledge, no urinary marker can
replace cystoscopy during follow-up or help to lower The specimens from different biopsies and resection
cystoscopic frequency routinely. One prospective ran- fractions must be referred to the pathologist in separate
domised study confirmed that knowledge of positive test containers.
results (microsatellite analysis) can improve the quality Complete and correct TUR is essential to achieve a good
of follow-up cystoscopy [33] (LE: 1b). prognosis [36]. Absence of detrusor muscle in the specimen
is associated with a significantly higher risk of residual HAL fluorescence-guided TUR with standard TUR reported
disease and early recurrence [37] (LE: 2b). an absolute reduction of no more than 9% in the recurrence
Training in the methods of TUR should be included in rate within 9 mo in the HAL arm. Median time to recurrence
teaching programmes because it can improve results [38]. improved from 9.4 mo in the white light arm to 16.4 mo in
the HAL arm [50] (LE: 1b).
6.8. Office-based fulguration The value of fluorescence cystoscopy for improvement of
the outcome in relation to progression rate or survival
In patients with a history of small LG/G1 Ta tumours, remains to be demonstrated.
fulguration of small papillary recurrences on an outpatient PDD is recommended in patients who are suspected of
basis can reduce the therapeutic burden and can be a harbouring a HG/G3 tumour (eg, for biopsy guidance in
treatment option [39] (LE: 3). patients with positive cytology, or with a history of HG/G3
tumour).
6.9. Bladder and prostatic urethra biopsies
6.11. Second resection
CIS can present as a velvet-like reddish area that is
indistinguishable from inflammation, or it might not be The significant risk of residual tumour after initial TUR of Ta,
visible at all. T1 lesions has been demonstrated [36,51] (LE: 2a). The
When abnormal areas of urothelium are seen, it is tumour is often understaged by initial resection. It has been
advised to take cold-cup biopsies or biopsies with a demonstrated that a second TUR can increase the recur-
resection loop. rence-free survival [52] (LE: 2a).
Biopsies from normal-looking mucosa, so-called random A second TUR of the bladder is recommended in the
(mapping) biopsies, are not routinely recommended following situations:
because the likelihood of detecting CIS, especially in low-
risk tumours, is extremely low (<2%) [40] (LE: 2a). They After incomplete initial TUR
should be performed, however, in patients with positive If there was no muscle in the specimen after initial
urinary cytology and the absence of visible bladder tumour, resection, with exception of Ta, LG/G1 tumours and
in addition to upper tract diagnostics. It is recommended to primary CIS
take biopsies from the trigone, bladder dome, and from the In all T1 tumours
right, left, anterior, and posterior bladder walls. In all HG/G3 tumours, except primary CIS.
Involvement of the prostatic urethra and ducts in men
with NMIBC has been reported. The incidence of CIS in The second resection should be performed 2–6 wk after
prostatic urethra was 11.7% in one report (LE: 2b) [41]. The initial TUR, and it should include resection of the primary
risk of prostatic urethra or duct involvement is higher if the tumour site.
tumour is located on the trigone or bladder neck, in the
presence of bladder CIS, and in multiple tumours [42] (LE: 6.12. Pathologic report
3). Thus, when bladder CIS is suspected, cytology is positive
with no evidence of bladder tumour, or abnormalities of The pathologic report should specify [53] the following:
prostatic urethra are visible, prostatic urethral biopsies are
recommended [41]. The biopsy is taken from abnormal Location of the evaluated sample (mapping)
areas and from the precollicular area (between 5 and 7 Grade of each tumour
o’clock positions) using a resection loop. In primary NMIBC Depth of tumour invasion
when stromal invasion is not suspected, a cold-cup biopsy CIS
with forceps can be performed [43]. Detrusor muscle in the specimen
Lymphovascular invasion
6.10. Photodynamic diagnosis (fluorescence cystoscopy) Aberrant histology.
Photodynamic diagnosis (PDD) is performed using violet Close cooperation between urologists and pathologists is
light after intravesical instillation of 5-aminolaevulinic acid recommended.
(ALA) or hexaminolaevulinic acid (HAL). Fluorescence- Table 3 summarises the recommendations for the
guided biopsy and resection are more sensitive than diagnosis of NMIBC.
conventional procedures for the detection of malignant
tumours, particularly for CIS [44,45] (LE: 2a). PDD had lower 7. Predicting recurrence and progression
specificity than white light endoscopy [45]. False positivity
can be induced by inflammation or recent TUR, and during 7.1. Prognosis of Ta, T1 tumours
the first 3 mo after BCG instillation [46,47] (LE: 3).
Prospective randomised studies evaluating the impact of Patients with Ta, T1 tumours can be divided into risk groups
ALA fluorescence-guided TUR on disease recurrence rate based on prognostic factors. To predict separately the short-
have shown controversial results [44,45,48,49]. A large and long-term risks of both recurrence and progression in
multicentre prospective randomised trial that compared individual patients, a scoring system and risk tables were
Table 3 – Recommendations for the diagnosis of non–muscle-invasive bladder cancer
Initial diagnosis GR
Patient history should be taken and recorded regarding all important information with possible connection to bladder cancer including risk factors A
and history of suspect symptoms.
Renal and bladder US may be used during initial work-up in patients with haematuria. C
At the time of initial diagnosis of bladder cancer, CT urography or IVU should be performed only in selected cases (eg, tumours located in the trigone). B
Cystoscopy is recommended in all patients with symptoms suggestive of bladder cancer. It cannot be replaced by cytology or by any other A
noninvasive test.
Cystoscopy should describe all macroscopic features of the tumour (site, size, number, and appearance) and mucosal abnormalities. A bladder C
diagram is recommended.
Voided urine cytology is advocated to predict HG/G3 tumour before TUR. C
Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable because of the frequent presence of cytolysis. C
TUR of the bladder
TUR should be performed systematically in individual steps: bimanual palpation under anaesthesia; insertion of the resectoscope, under visual C
control with inspection of the whole urethra; inspection of the whole urothelial lining of the bladder; biopsy from prostatic urethra (if indicated);
cold-cup bladder biopsies (if indicated); resection of the tumour; bimanual palpation after resection; protocol formulation; formulation of order
form for pathologic evaluation.
Perform resection in one piece for small papillary tumours (<1 cm), including part from the underlying bladder wall. B
Perform resection in fractions (including muscle tissue) for tumours >1 cm in diameter. B
Biopsies should be taken from abnormal-looking urothelium. Biopsies from normal-looking mucosa (trigone, bladder dome, and right, left, anterior, C
and posterior bladder walls) are recommended only when cytology is positive or when exophytic tumour has a nonpapillary appearance.
Biopsy of the prostatic urethra is recommended for cases of bladder neck tumour, when bladder CIS is present or suspected, when there is positive C
cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible. If biopsy is not performed during
the initial procedure, it should be completed at the time of the second resection.
Biopsy of the prostatic urethra should be taken from abnormal areas and from the precollicular area (between 5 and 7 o’clock position) using a C
resection loop. In primary non–muscle-invasive tumours when stromal invasion is not suspected, the cold-cup biopsy with forceps can be used.
If equipment is available, fluorescence-guided (PDD) biopsy should be performed instead of random biopsies when bladder CIS or HG/G3 tumour B
is suspected (eg, positive cytology, recurrent tumour with previous history of a HG/G3 lesion).
The specimens from different biopsies and resection fractions must be referred to the pathologist in separate containers and labelled separately. C
TUR protocol must describe all steps of the procedure, as well as the extent and completeness of resection. C
A second TUR is recommended in the following situations: A
- After incomplete initial TUR
- If there is no muscle in the specimen after initial resection, with exception of Ta G1 tumours and primary CIS
- In all T1 tumours
- In all G3 tumours, except primary CIS
A second TUR should be performed 2–6 wk after initial resection. C
Classification and pathologic report
Depth of tumour invasion is classified according to the TNM system. A
For histologic classification, 1973 and 2004 WHO grading systems are used. Until the WHO 2004 system is validated by more prospective trials A
and incorporated into prognostic models, both classifications should be used.
Whenever the terminology NMIBC is used in individual cases, the tumour stage and grade should be mentioned. A
The pathologic report should specify tumour location, tumour grade, depth of tumour invasion, presence of CIS, and whether the detrusor A
muscle is present in the specimen.
The pathologic report should specify the presence of LVI or aberrant histology. C
CIS = carcinoma in situ; CT = computed tomography; GR = grade of recommendation; HG = high-grade; IVU = intravenous urography; LVI = lymphovascular
invasion; NMIBC = non–muscle-invasive bladder cancer; PDD = photodynamic diagnosis; TUR = transurethral resection; US = ultrasonography; WHO = World
Health Organisation.
developed by the EORTC [54]. The EORTC database provided the EORTC tables. For progression probabilities, it is lower
individual data for 2596 patients who did not have a second only in high-risk patients [55]. The lower risks in the CUETO
TUR or receive maintenance BCG therapy. The EORTC tables may be attributable to using BCG, which is a more
scoring system is based on the six most significant clinical effective instillation therapy.
and pathologic factors: Further prognostic factors have been described in
selected patient populations. Female sex and CIS in the
Number of tumours prostatic urethra are important prognostic factors in T1, G3
Tumour size patients treated with TUR and an induction course of BCG
Prior recurrence rate [41] (LE: 2b). Recurrence at 3 mo was the most important
T category predictor of progression in T1, G2 tumours treated with TUR
Presence of concurrent CIS [56] (LE: 2b).
Tumour grade (WHO 1973).
7.2. Prognosis of carcinoma in situ
A scoring model for BCG-treated patients that predicts
the short- and long-term risks of recurrence and progres- Without any treatment, approximately 54% of patients with
sion was developed by the Club Urológico Español de CIS progress to muscle-invasive disease [57]. There are no
Tratamiento Oncológico (CUETO). Using these tables, the reliable prognostic factors that can be used to predict the
calculated risk of recurrence is lower than that obtained by course of CIS. Some studies have reported a worse prognosis
Table 4 – Risk group stratification In a meta-analysis of 1476 patients, one immediate

Risk group Definition instillation of chemotherapy after TUR significantly reduced
recurrence rate by 11.7% compared with TUR alone [62] (LE:
Low-risk tumours Primary, solitary, Ta, LG/G1, <3 cm, no CIS
1a). A similar efficacy was reported in two more recent
Intermediate-risk All tumours not defined in the two adjacent
tumours categories (between the category of low and studies [63,64], with subgroup analyses suggesting that
high risk) immediate instillation is the most effective in tumour types
High-risk tumours Any of the following: with the lowest tendency towards recurrence, that is, in
T1 tumour
single primary or small tumours. Mitomycin C (MMC),
HG/G3 tumour
CIS epirubicin, and doxorubicin have all shown a beneficial
Multiple and recurrent and large (>3 cm) Ta, effect, with no efficacy comparisons made between the
G1, G2 tumours (all conditions must be presented drugs [62] (LE: 1a).
in this point)
There is evidence that immediate instillation might have
CIS = carcinoma in situ; LG = low grade, HG = high.grade. an impact on recurrence even when further adjuvant
instillations are given [65,66] (LE: 2a). In contrast, a
sufficient number of delayed repeat chemotherapy instilla-
Table 5 – Recommendations for stratification of NMIBC tions can also reduce recurrence stemming from tumour
Recommendation GR implantation [60,65,66]. Nevertheless, it is likely that
immediate instillation is more effective in preventing
Stratify patients into three risk groups according to Table 4. B
recurrence than any of the individual instillations that
Use EORTC risk tables and calculator for individual prediction B
of the risk of tumour recurrence and progression in different follow the immediate instillation [60,67] (LE: 3).
intervals after TUR. Prevention of tumour cell implantation should be
GR = grade of recommendation; EORTC = European Organisation for initiated within the first hours after cell seeding [68] (LE:
Research and Treatment of Cancer; TUR = transurethral resection. 3). In all single instillation studies, the instillation was
administered within 24 h. To maximise the efficacy of
immediate instillation, flexible practices should be devised
in patients with concurrent CIS and T1 tumours compared that allow the instillation to be given as early as possible.
with primary CIS, extended CIS, and those who do not Immediate instillation of postoperative chemotherapy
respond to BCG treatment [57,58] (LE: 3). should be omitted in any case of intra- or extraperitoneal
perforation, which is most likely to appear in extensive TUR
7.3. Recommendation for patients’ stratification in risk groups procedures and in situations with bleeding that require
bladder irrigation. Clear instructions should be given to the
The guidelines panel recommends stratification of patients nursing staff to control the free flow of the bladder catheter
into three risk groups that will facilitate treatment at the end of the instillation. Severe complications have
recommendations. Their definition, which takes into been reported in patients with drug extravasation [69].
account the EORTC risk tables probabilities of recurrence
and especially progression, can be found in Table 4. The 8.2. Additional intravesical chemotherapy instillations
recommendation is similar to that provided by the
International Bladder Cancer Group [59]. The need for further adjuvant intravesical therapy depends
For individual prediction of the risk of tumour recurrence on prognosis. In patients with tumours at low risk (Table 4),
and progression at different intervals after TUR, the a single immediate instillation reduces the risk of recur-
application of EORTC risk tables and calculator is recom- rence and is considered as the standard and sufficient
mended (electronic calculator is available at http://www. treatment [62] (LE: 1a). For other patients, however, a single
eortc.be/tools/bladdercalculator/). immediate instillation remains an incomplete treatment
Recommendations for NMIBC patients’ stratification can because of the considerable likelihood of recurrence and/or
be found in Table 5. progression.
A meta-analysis of 3703 patients from 11 RCTs showed a
8. Adjuvant intravesical chemotherapy highly significant 44% reduction in the odds of recurrence
(corresponding to an absolute difference of 13–14%) at 1 yr
Ta, T1 tumours recur frequently and progress to muscle- in favour of chemotherapy instillations over TUR alone but
invasive disease in a limited number of cases. It is therefore no effect on tumour progression [70].
necessary to consider adjuvant therapy in all patients. It is still controversial for how long and how frequently
chemotherapy instillations should be given [71]. The
8.1. One immediate postoperative intravesical instillation available evidence does not support any treatment >1 yr
(LE: 3).
Early single instillation has been shown to function by the
destruction of circulating tumour cells resulting from TUR, 8.3. Optimising intravesical chemotherapy
and by an ablative effect on residual tumour cells at
the resection site and on small overlooked tumours [60,61] Some promising data have been presented about enhancing
(LE: 3). the efficacy of MMC using microwave-induced hyperthermia
(Synergo) or electromotive drug administration in patients meta-analysis, only patients who received maintenance
with high-risk tumours. The current evidence, however, is BCG benefited. The most effective BCG maintenance
limited [72,73] (LE: 2b). Both treatment modalities are schedule, however, cannot be determined [85]. In their
considered experimental. meta-analysis, Böhle et al. concluded that at least 1 yr of
Adapting urinary pH, decreasing urinary excretion, and maintenance BCG is required to obtain superiority of BCG
buffering the intravesical solution during chemotherapy over MMC for the prevention of recurrence or progression
instillation reduces the recurrence rate [74] (LE: 1b). [80,84] (LE: 1a).
Concentration is more important than treatment duration The optimal number of induction instillations and
[75] (LE: 1b). In view of these data, it seems advisable to optimal frequency and duration of maintenance instilla-
dissolve the drug in a buffered solution at optimal pH and to tions remain unknown. However, in an RCT of 1355
ask the patient not to drink on the morning before patients, the EORTC recently showed that when BCG is
instillation. given at full dose, 3 yr of maintenance reduces the
recurrence rate as compared with 1 yr in high-risk but
9. Adjuvant intravesical bacillus Calmette-Guérin not in intermediate-risk patients. There were no differences
immunotherapy in progression or overall survival [86] (LE: 1b).
9.1. Bacillus Calmette-Guérin efficacy 9.3. Bacillus Calmette-Guérin toxicity
Five meta-analyses have confirmed that BCG after TUR is BCG intravesical treatment is associated with more side
superior to TUR alone or TUR and chemotherapy for the effects compared with intravesical chemotherapy [87] (LE:
prevention of tumour recurrence [76–80] (LE: 1a). Three 1a). Serious side effects are encountered in <5% of patients
recent RCTs on patients with intermediate- and high-risk and can be treated effectively [88] (LE: 1b). It has been
tumours compared BCG with a combination of epirubicin shown that the maintenance schedule is not associated with
and interferon [81], MMC [82], or epirubicin alone [83]. All an increased risk of side effects compared with the
of these studies have confirmed the superiority of BCG for induction course [88].
the prevention of tumour recurrence (LE: 1a). It has been Major complications can appear after systemic absorp-
shown that the effect was long lasting [82,83], and it was tion of the drug. Thus contraindications of BCG intravesical
also observed in a separate analysis of patients with instillation should be respected.
intermediate-risk tumours [82,83]. BCG should not be administered when the following
One meta-analysis [76] evaluated the individual data absolute contraindications exist:
from 2820 patients enrolled in nine RCTs that compared
MMC versus BCG. In the trials with BCG maintenance, a 32% During the first 2 wk after TUR
reduction in the risk of recurrence for BCG compared with In patients with macroscopic haematuria
MMC was found, whereas there was a 28% increase in the After traumatic catheterisation
risk of recurrence for patients treated with BCG in the trials In patients with symptomatic urinary tract infection.
without BCG maintenance.
Two meta-analyses demonstrated that BCG therapy The presence of leukocyturia or asymptomatic bacteriuria
prevents, or at least delays, the risk of tumour progression is not a contraindication for BCG application, and antibiotic
[84,85] (LE: 1a). A recent RCT with long-term observation prophylaxis is not necessary in these cases [89] (LE: 3).
demonstrated significantly fewer distant metastases and BCG should be used with caution (relative contraindica-
better overall survival and disease-specific survival in tion) in immunocompromised patients (immunosuppres-
patients treated with BCG compared with epirubicin [83] sion, human immunodeficiency virus infection) [90] (LE: 3).
(LE: 1b). In contrast, a meta-analysis of individual patient The management of side effects after BCG should reflect
data was not able to confirm any statistically significant their type and grade [91].
difference between MMC and BCG for progression, survival,
and cause of death [76]. 9.4. Optimal dose of bacillus Calmette-Guérin and bacillus
The conflicting results in the progression outcomes of the Calmette-Guérin strain
studies can be explained by different patient characteristics,
duration of follow-up, methodology, and statistical power. To reduce BCG toxicity, instillation of a reduced dose
Most studies were, however, able to show a reduction in the was proposed. Comparing a one-third dose to full-dose
risk of progression in high- and intermediate-risk tumours if BCG, CUETO found no overall difference in efficacy. However,
BCG was applied including a maintenance schedule. it has been suggested that a full dose of BCG is more effective
in multifocal tumours [92,93] (LE: 1b). Although fewer
9.2. The optimal schedule of BCG instillations patients have reported toxicity with the reduced dose, the
incidence of severe systemic toxicity was similar. In another
Induction BCG instillations are classically given according trial, a further reduction to one-sixth dose resulted in a
to the empirical 6-weekly schedule. For optimal efficacy, decrease in efficacy with equal toxicity [94] (LE: 1b).
BCG must be given on a maintenance schedule [76,80, The EORTC did not find any difference in toxicity
84,85] (LE: 1a). In the EORTC Genito-Urinary (GU) group between one-third and full-dose BCG; however, the former
was associated with a higher recurrence rate, especially exists about whether conservative therapy (intravesical BCG
when it was given only for 1 yr [86] (LE: 1b). instillations) or aggressive therapy (cystectomy) should be
No robust evidence assessing a difference in clinical performed. Tumour-specific survival rates after early cystec-
efficacy between various BCG strains has been reported so tomy for CIS are excellent, but up to 40–50% of patients may
far. be overtreated [57] (LE: 3).
9.5. Indications for bacillus Calmette-Guérin 10.1. Intravesical treatment of bladder carcinoma in situ
There is a consensus that not all patients with NMIBC A meta-analysis of clinical trials that has compared
should be treated with BCG due to the risk of toxicity. intravesical BCG with intravesical chemotherapy has shown
Ultimately, the choice of treatment depends on the a significantly increased response rate after BCG and a
patient’s risk (Table 4): reduction of 59% in the odds of treatment failure with BCG
[95] (LE: 1a).
BCG does not alter the natural course of low-risk tumours, In an EORTC-GU group meta-analysis, in a subgroup of
and it could be considered as overtreatment for this 403 patients with CIS, BCG reduced the risk of progression
category. by 35% as compared with intravesical chemotherapy or
In patients with high-risk tumours, for whom radical different immunotherapy [85] (LE: 1b).
cystectomy is not carried out, 1–3 yr of full-dose In summary, compared with chemotherapy, BCG treat-
maintenance BCG is indicated. The additional beneficial ment of CIS increases the complete response rate and the
effect of the second and third years of maintenance on overall percentage of patients who remain disease free, and
recurrence in high-risk tumours should be weighed it reduces the risk of tumour progression (LE: 1a).
against its added costs and inconveniences.
In intermediate-risk tumours, full-dose BCG with 1 yr of 10.2. Treatment of extravesical carcinoma in situ
maintenance is more effective than chemotherapy for
prevention of recurrence; however, it has more side Patients with CIS are at high risk of extravesical involve-
effects than chemotherapy. For this reason both BCG with ment in the upper urinary tract and in the prostatic urethra.
maintenance and intravesical chemotherapy remain an Patients with extravesical involvement had worse survival
option. The final choice should reflect the individual than those with bladder CIS alone [96] (LE: 3).
patient’s risk of recurrence and progression as well as the Patients with CIS in the epithelial lining of the prostatic
efficacy and side effects of each treatment modality. urethra can be treated by intravesical instillation of BCG.
TUR of the prostate can improve the contact of BCG with the
10. Specific aspects of treatment of carcinoma in prostatic urethra [97] (LE: 3).
situ In patients with prostatic duct involvement, radical
cystectomy should be considered [97] (LE: 3).
CIS cannot be resolved by TUR alone. Histologic diagnosis of Treatment of CIS that involves the upper urinary tract is
CIS must be followed by further treatment, either intravesical discussed in the guidelines on urothelial carcinomas of the
instillations or radical cystectomy (LE: 2). No consensus upper urinary tract.
Table 6 – Recommendations for adjuvant therapy in Ta, T1 tumours and for treatment of CIS
Recommendation GR
The type of intravesical therapy should be based on the risk groups shown in Tables 4 and 9. A
One immediate chemotherapy instillation is recommended in tumours presumed to be at low or intermediate risk. –
In patients with low-risk tumours, one immediate instillation of chemotherapy is recommended as the complete adjuvant treatment. A
In patients with intermediate-risk tumours, one immediate instillation of chemotherapy should be followed by 1 yr of full-dose BCG treatment A
or by further instillation of chemotherapy for a maximum of 1 yr.
In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. A
In patients with CIS in the epithelial lining of the prostatic urethra, TUR of the prostate followed by intravesical instillation of BCG is an option. C
In patients at highest risk of tumour progression (Table 9), immediate radical cystectomy should be considered. C
In BCG-refractory tumours, radical cystectomy is indicated. B
Intravesical chemotherapy
One immediate instillation of chemotherapy should be omitted in any case of overt or suspected intra- or extraperitoneal perforation (after extensive C
TUR or bleeding requiring bladder irrigation).
The optimal schedule of further intravesical chemotherapy instillations and its duration is not defined; it should not exceed 1 yr. C
If intravesical chemotherapy is given, it is advised to use the drug at its optimal pH and to maintain the concentration of the drug during instillation B
by reducing fluid intake.
The length of individual instillation should be 1–2 h. C
BCG intravesical immunotherapy
Absolute contraindications of BCG intravesical instillation are during the first 2 wk after TUR; in patients with macroscopic haematuria; after C
traumatic catheterization; and in patients with symptomatic urinary tract infection.
The management of side effects after BCG intravesical instillation should reflect their type and grade. C
BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ; GR = grade of recommendation; TUR = transurethral resection.
Table 6 summarises the recommendations for adjuvant Table 8 – Treatment recommendations for BCG failure and
recurrences after BCG
therapy in Ta, T1 tumours and for therapy of CIS.
Category Treatment recommendation GR
11. Treatment of failures of intravesical therapy
BCG-refractory tumour 1. Radical cystectomy B
2. Bladder-preserving strategies
11.1. Failure of intravesical chemotherapy in patients not suitable for
cystectomy
HG/G3 recurrence 1. Radical cystectomy C
Patients with recurrence of NMIBC after a chemotherapy
after BCG 2. Repeat BCG course
regimen can profit from BCG instillations. Prior intravesical 3. Bladder-preserving strategies
chemotherapy has no impact on the effect of BCG Non–HG/G3 recurrence 1. Repeat BCG or intravesical C
instillation [76] (LE: 1a). after BCG for primary chemotherapy
intermediate-risk tumour 2. Radical cystectomy
11.2. Recurrence and failure after intravesical bacillus BCG = bacillus Calmette-Guérin; GR = grade of recommendation.
Calmette-Guérin immunotherapy
Categories of unsuccessful treatment with intravesical BCG The potential benefit of radical cystectomy must be
are summarised in Table 7. weighed against the risk and impact on quality of life. It is
Patients with BCG failure are unlikely to respond to reasonable to propose immediate radical cystectomy to
further BCG therapy; therefore, radical cystectomy is the those patients with NMIBC who are at highest risk of
preferred option. progression. These are patients with the following char-
Several bladder preservation strategies are available acteristics [41,54,55] (LE: 3):
[98]. Changing from BCG to these options can yield
responses in selected cases with BCG failure [99–101] Multiple and/or large (>3 cm) T1, (HG/G3) tumours
(LE: 3). However, experience is limited, and treatments T1, (HG/G3) tumours with concurrent CIS
other than radical cystectomy must be considered oncolo- Recurrent T1, (HG/G3) tumours
gically inferior at the present time [102] (LE: 3). T1, G3 and CIS in prostatic urethra
The results of various studies suggest that repeat BCG Micropapillary variant of urothelial carcinoma.
therapy is appropriate for non–high-grade and even for
some HG/G3 recurrent tumours [103] (LE: 3). Treatment In these cases, discussing immediate radical cystectomy
recommendations are provided in Table 8. and conservative treatment with BCG instillation is
recommended.
12. Radical cystectomy for non–muscle-invasive Radical cystectomy is strongly recommended in patients
bladder cancer with BCG-refractory tumours, as mentioned earlier. Delay of
radical cystectomy might lead to decreased disease-specific
If radical cystectomy is indicated before pathologically survival [104] (LE: 3).
confirmed progression into muscle-invasive tumour, Table 9 summarises the treatment principles for NMIBC.
immediate (directly following NMIBC diagnosis) and early
(after BCG failure) radical cystectomy can be distinguished. 13. Follow-up of patients with non–muscle-
invasive bladder cancer
Table 7 – Categories of unsuccessful treatment with intravesical
BCG As a result of the risk of recurrence and progression, patients
with NMIBC need to be followed up; however, the
BCG failure
Whenever a muscle-invasive tumour is detected during follow-up.
frequency and duration of cystoscopy and imaging should
BCG-refractory tumour: reflect the individual patient’s degree of risk. Using risk
1. If HG/G3, non–muscle-invasive papillary tumour is present at tables, we are able to predict the short- and long-term risks
3 mo [102]. Further conservative treatment with BCG is connected
of recurrence and progression in individual patients, and
with increased risk of progression [103] (LE: 3).
2. If CIS (without concurrent papillary tumour) is present at both can adapt the follow-up schedule accordingly [54,55].
3 mo and 6 mo. In patients with CIS present at 3 mo, an additional When planning the follow-up schedule and methods, the
BCG course can achieve a complete response in >50% of cases [57] (LE: 3). following aspects should be considered:
3. If HG/G3 tumour appears during BCG therapy.*
HG/G3 recurrence after BCG. Recurrence of HG/G3 (WHO 2004/1973)
tumour after completion of BCG maintenance, despite an initial
The prompt detection of muscle-invasive and HG/G3
response (LE: 3).* NMIBC recurrence is crucial because a delay in diagnosis
BCG intolerance and therapy can be life threatening.
Severe side effects that prevent further BCG instillation before completing Tumour recurrence in the low-risk group is nearly always
induction [91].
low stage and LG/G1. Small non-invasive (Ta), LG/G1
BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ; LE = level of papillary recurrence does not present an immediate
evidence; WHO = World Health Organisation. danger to the patient, and early detection is not essential
*
Patients with LG recurrence during or after BCG treatment are not
for successful therapy [105] (LE: 2b). Fulguration of small
considered as BCG failure.
papillary recurrences on an outpatient basis could be a
Table 9 – Summary of treatment recommendations in Ta, T1 tumours according to risk stratification
Risk category Definition Treatment recommendation
Low-risk tumours Primary, solitary, Ta, LG/G1, <3 cm, no CIS One immediate instillation of chemotherapy
Intermediate-risk tumours All cases between categories of low and high risk One immediate instillation of chemotherapy followed
by further instillations, either chemotherapy for a
maximum of 1 yr or 1 yr of full-dose BCG
High-risk tumours Any of the following: Intravesical full-dose BCG instillations for 1–3 yr or
cystectomy (in highest risk tumours)
T1 tumours
HG/G3 tumours
CIS
Multiple and recurrent and large (>3 cm) Ta, G1, G2
tumours (all these conditions must be presented)
Subgroup of highest T1, HG/G3 associated with concurrent bladder CIS, multiple and/or Radical cystectomy should be considered
risk tumours large T1, HG/G3 and/or recurrent T1, HG/G3, T1, HG/G3 with CIS
in prostatic urethra, micropapillary variant of urothelial carcinoma
BCG failure Radical cystectomy is recommended
BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ.
Table 10 – Recommendations for follow-up of non–muscle-invasive bladder cancer in patients after TUR
Recommendation GR
The follow-up is based on regular cystoscopy. A

Patients with low-risk tumours should undergo cystoscopy at 3 mo. If negative, subsequent cystoscopy is advised 9 mo later, and then yearly C
for 5 yr.
Patients with high-risk tumours should undergo cystoscopy and urinary cytology at 3 mo. If negative, subsequent cystoscopy and cytology should C
be repeated every 3 mo for a period of 2 yr, and every 6 mo thereafter until 5 yr, and then yearly.
Patients with intermediate-risk tumours should have an in-between follow-up scheme using cystoscopy and cytology, which is adapted C
according to personal and subjective factors.
Regular (yearly) upper tract imaging (CT-IVU or IVU) is recommended for high-risk tumours. C
Endoscopy under anaesthesia and bladder biopsies should be performed when office cystoscopy shows suspicious findings or if urinary cytology B
is positive.
During follow-up in patients with positive cytology and no visible tumour in the bladder, R-biopsies or biopsies with PDD (if equipment is available), B
and investigation of extravesical locations (CT urography, prostatic urethra biopsy) are recommended.
CT = computed tomography; GR = grade of recommendation; IVU = intravenous urography; PDD = photodynamic diagnosis; R-biopsies = random biopsies.
safe option [39] (LE: 3). Some authors have even defended Study concept and design: Babjuk, Böhle, Burger, Compérat, Kaasinen,
temporary surveillance in selected cases [105] (LE: 3). Redorta, van Rhijn, Rouprêt, Shariat, Sylvester, Zigeuner.
The first cystoscopy after TUR at 3 mo is an important Acquisition of data: Babjuk, Böhle, Burger, Compérat, Kaasinen, Redorta,
van Rhijn, Rouprêt, Shariat, Sylvester, Zigeuner.
prognostic indicator [54,56,106,107] (LE: 1a). The first
Analysis and interpretation of data: Babjuk, Böhle, Burger, Compérat,
cystoscopy should thus always be performed 3 mo after
Kaasinen, Redorta, van Rhijn, Rouprêt, Shariat, Sylvester, Zigeuner.
TUR.
Drafting of the manuscript: Babjuk.
In tumours at low risk, the risk of recurrence after 5 Critical revision of the manuscript for important intellectual content:
recurrence-free years is low [106] (LE: 3). Discontinuation Babjuk, Böhle, Burger, Compérat, Kaasinen, Redorta, van Rhijn, Rouprêt,
of cystoscopy or its replacement with less invasive Shariat, Sylvester, Zigeuner.
methods can be considered [107]. Statistical analysis: Babjuk, Sylvester.
In tumours originally at intermediate or high risk, Obtaining funding: None.
recurrences after a 10-yr tumour-free interval are not Administrative, technical, or material support: None.
unusual [108] (LE: 3). Therefore, lifelong follow-up is Supervision: Babjuk.
recommended [107]. Other (specify): None.
The risk of upper urinary tract recurrence increases in

patients with multiple and high-risk tumours [22] (LE: 3). Financial disclosures: Marko Babjuk certifies that all conflicts of interest,
Knowledge of positive test results (microsatellite analy- including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
sis) can improve the quality of follow-up cystoscopy [33]
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
(LE: 1b).
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: Marko Babjuk receives company
Recommendations for the follow-up schedule of NMIBC speaker honoraria from GE Healthcare and GSK. Maximilian Burger is a
are presented in Table 10. company consultant for Photocure ASA, Astellas, and Ipsen Pharma. He
receives company speaker honoraria from Ipsen Pharma, Astellas,
Author contributions: Marko Babjuk had full access to all the data in the Springer, and Novartis. He participates in trials for Photocure SA and
study and takes responsibility for the integrity of the data and the Ipsen Pharma. Richard Zigeuner receives company speaker honoraria
accuracy of the data analysis. from Pfizer, Bayer Healthcare, Roche, Novartis, GSK, and Amgen. He
receives fellowships and travel grants from Bayer Healthcare, Pfizer, [11] May M, Brookman-Amissah S, Roigas J, et al. Prognostic accuracy
Roche, Novartis, GSK, and Astellas. He receives research grants from of individual uropathologists in non-invasive urinary bladder
Bayer Healthcare. Shahrokh F. Shariat is a company consultant for carcinoma: a multicentre study comparing the 1973 and 2004
Ferring Pharmaceuticals and participates in trials for Alere Inc. on World Health Organisation Classifications. Eur Urol 2010;57:
NMP22. He is the inventor or co-inventor of the following patents: 850–8.
Shariat S, Slawin K, inventors. Methods to determine prognosis after [12] van Rhijn BW, van Leenders GJ, Ooms BC, et al. The pathologist’s
therapy for prostate cancer. US patent application serial number: Docket mean grade is constant and individualizes the prognostic value of
#60/266,976. Filed May 31, 2001; Shariat S, Lerner S, Slawin K, inventors. bladder cancer grading. Eur Urol 2010;57:1052–7.
Methods to determine prognosis after therapy for bladder cancer. US [13] Pan CC, Chang YH, Chen KK, et al. Prognostic significance of the
patent application serial number: Docket #675.003 US1. Filed June 1, 2004 WHO/ISUP classification for prediction of recurrence, pro-
2001; Shariat S, Slawin K, Kattan M, Scardino P, inventors. Pre- and gression, and cancer-specific mortality of non-muscle-invasive
posttreatment nomograms for predicting recurrence in patients with urothelial tumors of the urinary bladder: a clinicopathologic study
clinically localized prostate cancer that includes the blood markers of 1,515 cases. Am J Clin Pathol 2010;133:788–95.
interlukin-6 soluble receptor and transforming growth. Slawin K, [14] Otto W, Denzinger S, Fritsche HM, et al. The WHO classification of
Kattan M, Shariat S, Stephenson A, Scardino P, inventors. Nomogram 1973 is more suitable than the WHO classification of 2004 for
for predicting outcome of salvage radiotherapy for suspected local predicting survival in pT1 urothelial bladder cancer. BJU Int 2011;
recurrence of prostate cancer after radical prostatectomy. US patent 107:404–8.
applcation serial number: Docket #. Fi; Shariat S, inventor. Solube Fas: a [15] Pellucchi F, Freschi M, Ibrahim B, et al. Clinical reliability of the 2004
promising novel urinary marker for the detection of bladder transitional WHO histological classification system compared with the 1973
cell carcinoma (UTSD: 1666). US patent application serial in process. Bas WHO system for Ta primary bladder tumors. J Urol 2011;186:
W.G. van Rhijn and Eva Compérat have nothing to disclose. Richard J. 2194–9.
Sylvester is a company consultant for Spectrum and Allergan. Eero [16] Witjes JA, Moonen PMJ, van der Heijden AG. Review pathology in a
Kaasinen receives research grants from Pfizer Foundation and Pfizer (for diagnostic bladder cancer trial. Urology 2006;67:751–5.
a research group). Andreas Böhle receives company speaker honoraria [17] Van der Meijden A, Sylvester R, Collette L, et al. The role and impact
from Sanofi-Aventis, Medac, Bard, and Fresenius. Joan Palou Redorta is a of pathology review on stage and grade assessment on stages
company consultant for Sanofi-Pasteur and Allergan, receives company Ta and T1 bladder tumors: a combined analysis of 5 European
speaker honoraria from Sanofi-Pasteur and General Electric, and Organization for Research and Treatment of Cancer trials. J Urol
participates in trials for General Electric. Morgan Rouprêt is a company 2000;164:1533–7.
consultant for Lilly and GSK; he participates in trials for Takeda. [18] Van Rhijn BWG, van der Kwast TH, Kakiashvili DM, et al. Patho-
logical stage review is indicated in primary pT1 bladder cancer.
Funding/Support and role of the sponsor: None.
BJU Int 2010;106:206–11.
[19] Lamm DL, Herr HW, Jakse G, et al. Updated concepts and treatment
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EAU Guidelines On Non-Muscle-invasive Urothelial Carcinoma of The Bladder: Update 2013

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EURURO-5156; No.

EUROPEAN UROLOGY XXX (2013) XXX–XXX

EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma

Marko Babjuk a,*, Maximilian Burger b, Richard Zigeuner c, Shahrokh F. Shariat d,

Article info Abstract

2 EUROPEAN UROLOGY XXX (2013) XXX–XXX

1. Introduction factors [6]. Tobacco smoking is the most important risk

2. Evidence acquisition 5.1. TNM classification and definition of non–muscle-invasive

EUROPEAN UROLOGY XXX (2013) XXX–XXX 3

therefore, the following guidelines are based on this 6.2. Imaging

4 EUROPEAN UROLOGY XXX (2013) XXX–XXX

tumours but low sensitivity in LG/G1 tumours. The 6.6. Cystoscopy

EUROPEAN UROLOGY XXX (2013) XXX–XXX 5

6 EUROPEAN UROLOGY XXX (2013) XXX–XXX

Table 3 – Recommendations for the diagnosis of non–muscle-invasive bladder cancer

EUROPEAN UROLOGY XXX (2013) XXX–XXX 7

Table 4 – Risk group stratification In a meta-analysis of 1476 patients, one immediate

8 EUROPEAN UROLOGY XXX (2013) XXX–XXX

9.1. Bacillus Calmette-Guérin efficacy 9.3. Bacillus Calmette-Guérin toxicity

EUROPEAN UROLOGY XXX (2013) XXX–XXX 9

10 EUROPEAN UROLOGY XXX (2013) XXX–XXX

EUROPEAN UROLOGY XXX (2013) XXX–XXX 11

Table 9 – Summary of treatment recommendations in Ta, T1 tumours according to risk stratification

Risk category Deﬁnition Treatment recommendation

BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ.

The follow-up is based on regular cystoscopy. A

 The risk of upper urinary tract recurrence increases in

12 EUROPEAN UROLOGY XXX (2013) XXX–XXX

EUROPEAN UROLOGY XXX (2013) XXX–XXX 13

14 EUROPEAN UROLOGY XXX (2013) XXX–XXX

EUROPEAN UROLOGY XXX (2013) XXX–XXX 15

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