E U R O P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Review – Urothelial Cancer

Editorial by Ashish M. Kamat on pp. 105–106 of this issue

European Association of Urology Guidelines on Muscle-invasive

and Metastatic Bladder Cancer: Summary of the 2020 Guidelines

J. Alfred Witjes a,*, Harman Max Bruins b, Richard Cathomas c, Eva M. Compérat d,
Nigel C. Cowan e, Georgios Gakis f, Virginia Hernández g, Estefania Linares Espinós h,
Anja Lorch i, Yann Neuzillet j, Mathieu Rouanne j, George N. Thalmann k, Erik Veskimäe l,
Maria J. Ribal m, Antoine G. van der Heijden a
a
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; b Department of Urology, Zuyderland Medical Center,
c d
Sittard-Geleen-Heerlen, The Netherlands; Department of Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland; Department of Pathology,
e
Sorbonne University, Assistance Publique-Hôpitaux de Paris, Hopital Tenon, Paris, France; Department of Radiology, The Queen Alexandra Hospital,
f g
Portsmouth, UK; Department of Urology and Pediatric Urology, University of Würzburg, Würzburg, Germany; Department of Urology, Hospital
Universitario Fundación Alcorcón, Madrid, Spain; Department of Urology, Hospital Universitario La Paz, Madrid, Spain; i Department of Medical Oncology
h

and Hematology, University Hospital Zürich, Zürich, Switzerland; j Department of Urology, Foch Hospital, University of Versailles-Saint-Quentin-en-Yvelines,
Suresnes, France; k Department of Urology, Inselspital, University Hospital Bern, Switzerland; l Department of Urology, Tampere University Hospital, Tampere,
m
Finland; Department of Urology, Hospital Clinic, University of Barcelona, Barcelona, Spain

Article info Abstract

Article history: Context: This overview presents the updated European Association of Urology (EAU)
Accepted March 31, 2020 guidelines for muscle-invasive and metastatic bladder cancer (MMIBC).
Objective: To provide practical evidence-based recommendations and consensus state-
Associate Editor: ments on the clinical management of MMIBC with a focus on diagnosis and treatment.
Evidence acquisition: A broad and comprehensive scoping exercise covering all areas of
James Catto
the MMIBC guideline has been performed annually since its 2017 publication (based on
the 2016 guideline). Databases covered by the search included Medline, EMBASE, and
Keywords: the Cochrane Libraries, resulting in yearly guideline updates. A level of evidence and a
Bladder cancer grade of recommendation were assigned. Additionally, the results of a collaborative
multistakeholder consensus project on advanced bladder cancer (BC) have been incor-
Muscle invasive
porated in the 2020 guidelines, addressing those areas where it is unlikely that
Metastatic prospective comparative studies will be conducted.
Diagnosis Evidence synthesis: Variant histologies are increasingly reported in invasive BC and are
Management relevant for treatment and prognosis. Staging is preferably done with (enhanced)
Cystectomy computerised tomography scanning. Treatment decisions are still largely based on
clinical factors. Radical cystectomy (RC) with lymph node dissection remains the
Multimodality recommended treatment in highest-risk non–muscle-invasive and muscle-invasive
Quality of life nonmetastatic BC, preceded by cisplatin-based neoadjuvant chemotherapy (NAC) for
Follow-up invasive tumours in “fit” patients. Selected men and women benefit from sexuality
Guidelines sparing RC, although this is not recommended as standard therapy. Open and robotic RC
show comparable outcomes, provided the procedure is performed in experienced
European Association of Urology
centres. For open RC 10, the minimum selected case load is 10 procedures per year.
* Corresponding author. Department of Urology, Intern Mail 659, Radboud University Nijmegen
Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31 24 36 13 735; Fax: +31 24
35 41 031.
E-mail address: Fred.Witjes@radboudumc.nl (J.A. Witjes).

https://doi.org/10.1016/j.eururo.2020.03.055
0302-2838/© 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 83

If bladder preservation is considered, chemoradiation is an alternative in well-selected

patients without carcinoma in situ and after maximal resection. Adjuvant chemothera-
py should be considered if no NAC was given. Perioperative immunotherapy can be
offered in clinical trial setting. For fit metastatic patients, cisplatin-based chemotherapy
remains the first choice. In cisplatin-ineligible patients, immunotherapy in Programmed
Death Ligand 1 (PD-L1)-positive patients or carboplatin in PD-L1–negative patients is
recommended. For second-line treatment in metastatic disease, pembrolizumab is
recommended. Postchemotherapy surgery may prolong survival in responders. Quality
of life should be monitored in all phases of treatment and follow-up. The extended
version of the guidelines is available at the EAU website: https://uroweb.org/guideline/
bladder-cancer-muscle-invasive-and-metastatic/.
Conclusions: This summary of the 2020 EAU MMIBC guideline provides updated infor-
mation on the diagnosis and treatment of MMIBC for incorporation into clinical practice.
Patient summary: The European Association of Urology Muscle-invasive and Metastatic
Bladder Cancer (MMIBC) Panel has released an updated version of their guideline, which
contains information on histology, staging, prognostic factors, and treatment of MMIBC.
The recommendations are based on the current literature (until the end of 2019), with
emphasis on high-level data from randomised clinical trials and meta-analyses and on
the findings of an international consensus meeting. Surgical removal of the bladder and
bladder preservation are discussed, as well as the use of chemotherapy and immuno-
therapy in localised and metastatic disease.
© 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

1. Introduction the management of advanced and variant bladder cancer

The current summary of the 2020 European Association of
Urology (EAU) Muscle-invasive and Metastatic Bladder Cancer
(MMIBC) guideline aims at helping urologists to assess the
evidence-based management of muscle-invasive bladder
cancer (MIBC) and to incorporate guideline recommendations
into their clinical practice. Guidelines, however, can never
replace clinical expertise when making treatment decisions
for individual patients in a specific context. The guideline
panel consists of an international multidisciplinary group of
experts from the fields of urology, pathology, radiology, and
oncology, whose conflicts of interest can be found online
(https://uroweb.org/guideline/bladder-cancer-muscle-
invasive-and-metastatic/).
A broad and comprehensive literature search, limited to
English-language publications, covering all sections of the
MIBC guideline, is performed on a yearly basis. Databases
searched included Medline, EMBASE, and the Cochrane
Libraries. For the 2020 update, for example, 1899 unique
records were identified and screened for relevance, result-
ing in the inclusion of 62 new publications. A detailed
search strategy is available online: http://uroweb.org/
guideline/bladdercancer-muscle-invasive-andmetastatic/?
type=appendices-publications.
Search results are discussed by the panel members, and
selected publications are assigned a level of evidence based
on a modified Oxford Centre for Evidence-Based Medicine
Levels of Evidence classification [1]. Recommendations are
graded, either “strong” or “weak”, determined by the
balance between desirable and undesirable consequences
of alternative management strategies, the quality of the
evidence, and nature and variability of patient values and
preferences according to a modified Grades of Recommen-
dation, Assessment, Development and Evaluation (GRADE)
approach [2,3].
The 2020 MIBC guidelines update includes the findings
of a collaborative multistakeholder consensus project on
(BC) addressing areas in which it is unlikely that clinical
trials and prospective comparative studies will be con-
ducted [4,5]. The methodology used is presented in detail in
the scientific publications.
After publication, the 2018 MIBC guidelines were shared
with seven patients treated for MIBC. Although they found
the text in general to be informative and instructive, some
parts were more difficult to understand, amongst others,
due to many abbreviations and methodological elements.
Sections with less clear evidence were also less compre-
hensible (eg, “recurrent disease” and “markers”). There was
an interest in whether screening for BC is a consideration. In
“follow-up”, “quality of life (QoL)”, and “survivorship
aspects”, information should be presented on what patients
and families might expect after treatment. Finally, lifestyle
elements would be of relevance, for which patient
involvement was considered missing.
Compared with the 2017 manuscript [6], essential new
passages are presented in the sections on variant histology,
function sparing cystectomy, node dissection, multimodal
therapy, surgical volume, chemo- and immunotherapy, and
QoL.
Finally, in some tables, recommendations are presented
that are not supported by text in this summary due to word
count limitations. For the background of these recommen-
dations, the reader is referred to the full guideline text.
2. Epidemiology
BC epidemiology still shows a clear male predominance,
and incidence and mortality rates differ per European
country, probably due to differences in risk factors,
detection, and availability of treatments (Table 1).
Tobacco smoking intensity is the most well-established
risk factor for and directly related to BC, causing 50–65% of
male cases and 20–30% of female cases [7]. An immediate
decrease in the risk of BC was observed in those who
84 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4
Table 1 – Summary of evidence and recommendations for
epidemiology and risk factors.
Summary of evidence
Worldwide, BC is the 11th most commonly diagnosed
cancer.
Several risk factors associated with BC diagnosis have
been identified.
Active and passive tobacco smoking continues to be the
main risk factor, while the exposure-related incidence is
decreasing.
The increased risk of developing BC in patients
undergoing EBRT, brachytherapy, or a combination of
EBRT and brachytherapy must be considered during
patient follow-up. As BC 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 smoking 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 BC
or a history of BC.
BC = bladder cancer; EBRT = external beam radiation therapy; LE = level of
evidence.
stopped smoking. The reduction was about 40% within 1–
4 yr of quitting smoking and 60% after 25 yr of cessation
[8]. Occupational exposure to carcinogenic aromatic amines
is the second most important risk factor, accounting for 20–
25% of BC (dyes, rubbers, textiles, paints, and leathers) with
a latency period of several decades. Older studies have
reported an increased rate of BC after external beam
radiotherapy (EBRT) for gynaecological malignancies and
prostate cancer (PCa). More recently, it was proposed that
modern EBRT modalities for PCa, such as intensity-
modulated radiotherapy (IMRT), may have lower rates of
in-field bladder and rectal secondary malignancies
[9]. However, considering the long latency time, an
increased risk should be considered during follow-up.
The link between dietary factors and BC remains
unproven in an on-going European prospective study,
although recently an inverse association between flavo-
noids and lignans, and the risk of aggressive BC tumours has
been described [10].
Elevated blood pressure and triglycerides are associated
with increased risks of BC among men, whereas high body
mass index was associated with decreased BC risk [11]. The
association with diabetes mellitus is inconsistent, but
recently a dose-dependent association with BC was found
for the oral hypoglycaemic drug pioglitazone [12], which
caused the US Food and Drug Administration (FDA) to
recommend not prescribing pioglitazone in patients with
active BC.
There is a well-established relationship between schis-
tosomiasis and urothelial carcinoma (UC) and squamous
cell carcinoma of the bladder, but schistosomiasis control is
improving. Recent meta-analyses suggested BC to have a
relation with urinary calculi and [13], but not with chronic
LE urinary tract infection (UTI) [14].
Several studies have shown that women present with
2a
more advanced disease and have worse survival rates. Older
3 studies have suggested a delay in diagnosis, smoking, and
chemical exposure as potential reasons. A more recent
2a
study showed differences in treatment as the main cause
[15]; however, the difference disappears after 2 yr of follow-
3 up [16].
Genetic susceptibility and familial shared environmental
exposure are still under investigation.
3. Pathology
Strength
rating
Approximately 25% of patients with BC present with
Strong muscle-invasive or metastatic disease. An adequate (trans-
urethral) resection should be followed by proper patholog-
Strong
ical handling and documentation of all margins, adjacent
tissue, and lymph nodes (LNs) [17].
Morphological variants should be identified and de-
scribed according to the latest World Health Organization
Strong
(WHO) update because of their prognostic relevance
[18,19]. Currently, the following differentiations are used:
1 UC (>90% of all cases).
2 UC with partial squamous and/or glandular or tropho-
blastic differentiation.
3 Micropapillary or microcystic UC.
4 Nested variant (including large nested variant).
5 Lymphoepithelioma-like.
6 Plasmocytoid, signet ring, diffuse.
7 Some UCs with small-cell carcinomas.
8 Sarcomatoid carcinomas.
9 Poorly differentiated.
Other, extremely rare, variants exist, which are not listed
above.
Aside from the guideline recommendations, statements
were added based on the EAU/European Society for Medical
Oncology consensus meeting (Table 2) [4,5].
4. Diagnostic evaluation of (muscle)-invasive BC
Ultimately, the diagnosis is made by cystoscopy, the
findings of which should be documented in detail, and
histological evaluation of resected tissue. If imaging studies
show a bladder tumour clearly, diagnostic cystoscopy may
be omitted (Table 3). Before resection, bimanual examina-
tion under anaesthesia should be done, although interpre-
tation is subjective [20]. Photodynamic diagnosis could be
considered to identify associated carcinoma in situ (CIS),
since the presence of CIS may lead to a modified treatment
plan (eg, in case of chemoradiation). Transurethral resection
(TUR) should include a deeper part, which has to be sent in
separately, and prostatic biopsies in males as well as
bladder neck biopsies in women who might be candidates
for orthotopic diversion. For general information on the
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 85

Table 2 – Summary of recommendations and consensus statements for pathology.

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
top.
Record the total number of LNs, the number of positive LNs, and extranodal spread.
Record lymphatic or blood vessel invasion.
Record the presence of carcinoma in situ.
EAU-ESMO consensus statements [4,5] a
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.

EAU = European Association of Urology; ESMO = European Society for Medical Oncology; LN = lymph node.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).

Table 3 – Summary of evidence, recommendations, and consensus statements for the primary assessment of presumably invasive bladder
tumours.

Summary of evidence LE

Cystoscopy is necessary for the diagnosis of bladder cancer. 1

Urinary cytology has high sensitivity in high-grade tumours including carcinoma in situ. 2b

Recommendations Strength
rating

Describe all macroscopic features of the tumour (site, size, number, and appearance) and mucosal abnormalities during Strong
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 Strong
suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the
prostatic urethra are visible.
Take a biopsy at the time of the second resection, if no biopsy was taken during the initial procedure. Strong
In women undergoing subsequent orthotopic neobladder construction, obtain procedural information (including Strong
histological evaluation) of the bladder neck and urethral margin, either prior to or at the time of cystoscopy.
Specify the grade, depth of tumour invasion, and whether the lamina propria and muscle tissue are present in the specimen Strong
in the pathology report.
EAU-ESMO consensus statements [4,5] a
Differentiating between urachal and nonurachal subtypes of adenocarcinoma is essential when making treatment decisions.

EAU = European Association of Urology; ESMO = European Society for Medical Oncology; LE = level of evidence.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).

assessment of bladder tumours, see EAU guidelines on non–
muscle-invasive BC (NMIBC) [21].
5. Imaging
Both computerised tomography (CT) and magnetic reso-
nance imaging (MRI) may be used for assessment of local
invasion, with the principal aim of detecting T3b disease or
higher. However, a recent meta-analysis showed 91%
sensitivity and 96% specificity for 3.0-T device MRI
combined with diffusion-weighted imaging to differentiate
 T1 tumours from  T2 tumours before surgery [22]. Sen-
sitivity and specificity of CT and MRI to detect LN metastasis
are low, where pelvic nodes >8 mm and abdominal nodes
>10 mm should be regarded as pathologically enlarged.
Upper urinary tract imaging is best done with CT urography,
whereas MR urography should be reserved for patients who
cannot undergo CT urography.
Staging for pulmonary, hepatic, and LN metastases can
best be done with CT [23,24]. Staging of other sites should
be done in case of specific complaints.
There is no consensus yet regarding the role of 18F-
fluorodeoxyglucose positron emission tomography/CT for
metastatic staging (Table 4).
6. Comorbidity and radical cystectomy
Complications related to RC may, amongst others, be related
to pre-existing comorbidity (Table 5). Age above 70 or 80 yr
did not appear to be related to complications, but mortality
86 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4

Table 4 – Summary of evidence and recommendations for staging in MIBC.

Summary of evidence LE

Imaging as part of staging in MIBC provides information about prognosis and assists in selection of the most appropriate 2b
treatment.
There are currently insufficient data on the use of diffusion-weighted imaging and 18F-fluorodeoxyglucose positron emission
tomography/computed tomography 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 Strength
rating

In patients with confirmed MIBC, use CT of the chest, abdomen, and pelvis as the optimal form of staging. Strong
Perform a CT urography for upper tract evaluation and for staging. Strong
For upper tract evaluation, use diagnostic ureteroscopy and biopsy only in cases where additional information will impact Strong
treatment decisions.
Use magnetic resonance urography when CT urography is contraindicated for reasons related to contrast administration or Strong
radiation dose.
Use CT or MRI for staging locally advanced or metastatic disease in patients in whom radical treatment is considered. Strong
Use CT to diagnose pulmonary metastases. Computed tomography and MRI are generally equivalent for diagnosing local Strong
disease and distant metastases in the abdomen.
CT = computed tomography; LE = level of evidence; MIBC = muscle-invasive bladder cancer; MRI = magnetic resonance imaging.

Table 5 – Summary of evidence and recommendations for comorbidity scales.

Summary of evidence LE

Chronological age is of limited relevance. 3

A comorbidity score developed in particular for the assessment of patients diagnosed with bladder cancer would be helpful. 3

Recommendations Strength
rating

Base the decision on bladder-sparing treatment or radical cystectomy in elderly/frail patients with invasive bladder cancer Strong
on tumour stage and comorbidity.
Assess comorbidity by a validated score, such as the Charlson Comorbidity Index. The American Society of Anesthesiologists Strong
score should not be used in this setting
LE = level of evidence.

was higher in octogenarians than in septuagenarians (4.3%
vs 2.3%) [25]. Sarcopenia, on the contrary, was an
independent predictor for overall survival (OS) and
cancer-specific survival (CSS) in case of radical cystectomy
(RC) [26]. Other risk factors have been described, which
means that a thorough (geriatric) multidisciplinary assess-
ment for comorbidity is important. A population-based
competing risk analysis showed age to carry the highest risk
for other-cause mortality, while local tumour stage was the
strongest predictor for decreased CSS [27].
The Charlson Comorbidity Index (CCI) can be used to
assess comorbidity, since it has been studied widely in
patients with BC and found to be an independent prognostic
factor for perioperative mortality [28,29], overall mortality
[30], and cancer-specific mortality (CSM) [31,32]. The age-
adjusted version of the CCI correlated with both CSM and
other-cause mortality [33].
7. Markers
In the 2020 guideline, both prognostic and predictive
markers are discussed in one paragraph.
The most important histopathological prognostic vari-
ables after RC and lymph node dissection (LND) are tumour
stage and LN status [34]. In addition, other LN-related
variables investigated include (but not limited to) the
number of (positive) LNs removed, LN density, and
extranodal extension. Although LN density is subject to
surgical and pathological factors, it appeared to be
independently associated with OS (hazard ratio [HR]:
1.45) in a meta-analysis [35]. Other prognostic histopatho-
logical variables are lymphovascular invasion [36] and
concomitant CIS in organ-confined disease [37], both with
an independent, approximately 1.5-fold increased risk for
recurrence and CSM. In addition, tumour location (trigone,
bladder neck, and prostatic urethra) has been associated
with decreased survival [34,37]. The value of the neutro-
phil-to-lymphocyte ratio remains controversial [38,39].
Recently, much attention was directed to the molecular
subtypes of BC based on The Cancer Genome Atlas (TCGA)
cohort. A consensus meeting on this subject identified six
MIBC molecular classes that reconcile all previously
published classification schemes [40]. The molecular
subgroup classes include luminal papillary, luminal non-
specified, luminal unstable, stroma rich, basal/squamous,
and neuroendocrine like, each having distinct differentiation
patterns, oncogenic mechanisms, tumour microenviron-
ments, and histological and clinical associations. However,
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 87

Table 6 – Summary of evidence and consensus statements for urothelial markers.

Summary of evidence LE

Currently, treatment decisions cannot be based on molecular markers. 3

EAU-ESMO consensus statements [4,5] a
In patients with metastatic disease, genetic profiling should always be done.
Before prescribing a checkpoint inhibitor, tumour mutation burden does not need to be assessed.
In all fit metastatic patients receiving chemotherapy, established prognostic factors for first- and second-line therapy must be considered when making treatment
decisions (Bajorin for first-line and Bellmunt for second-line therapy).
In all fit metastatic patients receiving chemotherapy, established prognostic factors for first- and second-line therapy should be considered when making
treatment decisions (Bajorin for first-line and Bellmunt for second-line therapy).
Before prescribing checkpoint inhibitor therapy, ribonucleic acid subtypes need not be identified.
Before radical cystectomy or chemotherapy, the neutrophil-to-lymphocyte ratio does not need to be assessed.

EAU = European Association of Urology; ESMO = European Society for Medical Oncology; LE = level of evidence.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).

Table 7 – Recommendations and consensus statements for treatment failure of non–muscle-invasive bladder cancer.

Recommendations Strength
rating

Discuss immediate radical treatment (RC) with patients at the highest risk of tumour progression (ie, high grade, Strong
multifocality, carcinoma in situ, and tumour size, as outlined in the EAU guidelines for non–muscle-invasive bladder cancer).
Offer RC to patients with BCG-unresponsive tumours. Strong
Offer patients with BCG-unresponsive tumours, who are not candidates for RC due to comorbidities, preservation strategies Weak
(intravesical chemotherapy, chemotherapy and microwave-induced hyperthermia, electromotive administration of
chemotherapy, and intravesical or systemic immunotherapy, preferably within clinical trials).
EAU-ESMO consensus statements [4,5] a
T1 high-grade bladder urothelial cancer with micropapillary histology (established after complete TURBT and/or re-TURBT) should be treated with immediate RC
and lymphadenectomy.
An important determinant for patient eligibility in case of bladder-preserving treatment is absence of carcinoma in situ.

BCG = bacille Calmette-Guérin; EAU = European Association of Urology; ESMO = European Society for Medical Oncology; RC = radical cystectomy;
TURBT = transurethral resection of bladder tumour.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).

currently this classification should still be considered as a
research tool. Clinical predictive markers for a worse
response to neoadjuvant chemotherapy (NAC) are secondary
MIBC (ie, progression after NMIBC) as compared with
primary MIBC [41], and possibly variant histologies [42].
Several predictive biomarkers have been studied and
reported, but, although promising, they are not used currently
in clinical practice (Table 6). In a single-arm phase 2 study
evaluating neoadjuvant pembrolizumab, tumour mutational
burden and PD-L1–positive status were associated with a
higher ratio of pT0 disease at RC [43,44]. However, no
significant correlation between PD-L1 expression and pT0
rate was observed in another single-arm phase 2 trial
evaluating neoadjuvant atezolizumab before RC.
8. RC in NMIBC
Although bacille Calmette-Guérin (BCG) is demonstrated to
prevent progression, this still occurs in up to 19.3% at 5 yr for
T1G3 tumours treated with maintenance BCG [45], and
progression to MIBC has been shown to decrease signifi-
cantly CSS to 35% after 4 yr (Table 7) [46]. One reason for
progression and an unfavourable outcome can be initial
understaging. Therefore, EAU NMIBC guidelines support RC
in selected (high-risk) patients with NMIBC [21]. RC is also
strongly recommended in patients with BCG-refractory
tumours, BCG relapse, and BCG-unresponsive tumours,
which are also defined in the NMIBC guideline.
9. Neoadjuvant therapy
NAC with cisplatin-based combinations has been standard
for decades in patients with resectable N0M0-invasive BC
(Fig. 1 and Table 8). The neoadjuvant approach has potential
advantages (a low micrometastasis burden; chemosensi-
tivity can be assessed, and a good pathological response
means a better prognosis [47] and better chemo tolerability
before surgery, whereas surgical morbidity is not increased
by chemotherapy [48]) and disadvantages (delay of surgery
in nonresponders; the decision is based on clinical staging
with the risk of overstaging and overtreatment). Finally,
only cisplatin-fit patients are candidates. The most recent
meta-analysis on the value of NAC used new and updated
data of 15 randomised controlled trials (RCTs) [49]. Previ-
ously published data were confirmed showing an 8%
absolute improvement in 5-yr survival with a number
needed-to-treat of 12.5. Only cisplatin-based combination
chemotherapy resulted in a meaningful benefit [50]. The
88 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4

Fig. 1 – Flow chart for the management of T2-T4a N0M0 urothelial bladder cancer.
CT = computed tomography; MRI = magnetic resonance imaging; UUT = upper urinary tract.
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 89

Table 8 – Summary of evidence and recommendations for neoadjuvant therapy.

Summary of evidence LE

Neoadjuvant cisplatin-containing combination chemotherapy improves OS (8% at 5 yr). 1a

Neoadjuvant treatment of responders and especially patients who show complete response (pT0 N0) has a major impact on 2
OS.
Currently, immunotherapy with checkpoint inhibitors as monotherapy, or in different combinations, is being tested in phase
2 and 3 trials. Initial results are promising.
Still no tools are 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 nonresponders.
Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of surgical techniques, and 3
current chemotherapy combinations.
Recommendations Strength
rating

Offer NAC for T2-T4a, cN0M0 bladder cancer. In this case, always use cisplatin-based Strong
combination therapy.
Do not offer NAC to patients who are ineligible for cisplatin-based combination Strong
chemotherapy.
Offer only neoadjuvant immunotherapy to patients within a clinical trial setting. Strong

LE = level of evidence; NAC = neoadjuvant chemotherapy; OS = overall survival.

benefit was for distant metastases only, and not for
locoregional control [51].
Gemcitabine and cisplatin (GemCis), frequently used in
metastatic disease, has not been used in RCTs for NAC,
although pT0/pT1 rates seem to be similar to those achieved
with methotrexate, vinblastine, adriamycin, and cisplatin
(MVAC) [50]. Dose dense (dd) MVAC demonstrated high
rates of pathological response, but data are limited [52]. A
phase 2 study with dd GemCis showed high pathological
response rates (<pT2, 45–57%) but with increased vascular
toxicity [53]. In case of variant histology, NAC seems to be
beneficial in diffuse/plasmacytoid/signet ring cell, mixed
variants, and neuroendocrine/small cell/large cell [18].
While randomised prospective clinical trial data dem-
onstrate a clinically relevant OS benefit for NAC, retrospec-
tive data are less clear. A recent retrospective analysis based
on data from the US National Cancer Database showed that
only 19% of all patients received NAC before RC [54]. They
found no clear survival advantage despite propensity score
adjustment to include patients based on South West
Oncology Group (SWOG) 8710 study criteria [55]. Limita-
tions are the retrospective design and the lack of informa-
tion on the type of NAC used.
Response to NAC cannot be predicted by imaging or
markers yet.
Neoadjuvant immunotherapy using checkpoint inhi-
bitors (PD-1/L1, cytotoxic T-lymphocyte associated pro-
tein 4 [CTLA-4]) is currently tested as immunotherapy
alone or in combination with chemotherapy in several
on-going phase 3 trials. Research in the neoadjuvant
setting is done either as monotherapy or in combination
with chemotherapy or CTLA-4 checkpoint inhibition.
Updated results of a single-arm phase 2 trial evaluating
PD-1 inhibitor pembrolizumab have been published with
a pT0 rate of 37% and pathological response (<pT2) in 55%
of patients [43,44].
10. Perioperative radiotherapy
Data on perioperative radiotherapy are retrospective and
old, not reflecting modern radiotherapy techniques with
concurrent chemotherapy (Table 9). Available data suggest
downstaging of the tumour due to preoperative radiother-
apy and longer progression-free survival (PFS), but no
impact on survival [56].
There are also no solid data to defend postoperative
radiotherapy, although in locally advanced BC (T3-T4, N0/
N1, M0), the local recurrence rate was reported to decrease
with postoperative RT [57].

Table 9 – Summary of evidence and recommendations for pre- and postoperative radiotherapy.

Summary of evidence LE

No data exist to support that preoperative RT for operable MIBC increases survival. 2a
Preoperative RT for operable MIBC, using a dose of 45–50 Gy in fractions of 1.8–2 Gy, results in downstaging after 4–6 wk. 2
Limited high-quality evidence supports the use of preoperative RT to decrease local recurrence of MIBC after RC. 3

Recommendations Strength
rating

Do not offer preoperative RT for operable MIBC since it will only result in downstaging, but will not improve survival. Strong
Do not offer preoperative RT when subsequent RC with urinary diversion is planned. Strong

LE = level of evidence; MIBC = muscle-invasive bladder cancer; RC = radical cystectomy; RT = radiotherapy.

90 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4

Table 10 – Recommendations for unresectable tumours.

Recommendations Strength rating

Offer radical cystectomy as a palliative treatment to patients with inoperable locally advanced tumours (T4b). Weak
Offer palliative cystectomy to patients with symptoms. Weak

Table 11 – Summary of evidence and recommendations for sexual function–preserving techniques.

Summary of evidence LE

The majority of patients motivated to preserve their sexual function will benefit from sexual function–preserving 2a
techniques.
None of the sexual function–preserving techniques (prostate/capsule/seminal/nerve sparing) have shown to be superior, 3
and no particular technique can be recommended.
Data regarding pelvic organ–preserving radical cystectomy for female patients remain immature. 3

Recommendations Strength
rating

Do not offer sexual function–preserving cystectomy to men as standard therapy for MIBC. Strong
Offer sexual-preserving techniques to men motivated to preserve their sexual function since the majority will benefit. Strong
Select men based on: Strong
 Organ-confined disease
 Absence of any kind of tumour at the level of the prostate, prostatic urethra, or bladder neck
Do not offer pelvic organ–preserving radical cystectomy to women as standard therapy for MIBC. Strong
Offer sexual function–preserving techniques to women motivated to preserve their sexual function since the majority will benefit. Weak
Select women based on: Strong
 Organ-confined disease
 Absence of tumour in bladder neck or urethra

LE = level of evidence; MIBC = muscle-invasive bladder cancer.

11. Radical surgery: introduction
RC is recommended for patients with MIBC stage T2-T4a,
N0-Nx, M0, high-risk and unresponsive NMIBC, and
tumours that cannot be controlled with TUR of the bladder
(TURB) and intravesical therapy alone (Table 10). Salvage
cystectomy is indicated in nonresponders to bladder-
sparing treatment and for palliative reasons such as fistula
formation, pain, and recurrent visible haematuria.
Studies on the impact of delayed RC on survival
outcomes are conflicting. Some studies have suggested a
delay of 3 mo to be associated with worse survival outcomes
[58], whereas others have found this to be safe [59,60]. A
study from the UK suggested that patients with a T2 tumour
could profit from earlier cystectomy [60].
12. Radical surgery: preparation
Bowel preparation is not considered necessary anymore,
instead the “fast track” early recovery after surgery (ERAS)
protocol stimulates emotional and physical functioning
scores and bowel recovery with, amongst others, early
mobilisation and oralisation, and gastrointestinal stimula-
tion with metoclopramide and chewing gum [61]. Another
cornerstone of the ERAS protocol is postoperative pain
management, which involves significantly reducing the use
of opioids [62]. Alvimopan has been shown to induce
quicker bowel recovery compared with patients receiving
placebo, but this drug is, as yet, not approved in Europe
[63]. Venous thromboembolism (VTE) prophylaxis may be
implemented as part of an ERAS protocol. Of note, a recent
study indicated that patients after NAC had higher VTE rates
(12% vs 8%; p = 0.002) [64].
13. RC: technique and extent
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,
entire urethra and adjacent vagina, uterus, distal ureters,
and regional LNs. Recently, the EAU MMIBC Guideline Panel
undertook two systematic reviews addressing sexual
function–preserving cystectomy in men and women to
determine functional and oncological outcomes (Table 11)
[65,66].
In men, four sparing techniques have been described:
prostate and seminal vesicle sparing, prostate capsule
sparing (after TUR of the prostate or en bloc removal of
the adenoma with the bladder), seminal sparing, and nerve-
sparing cystectomy. The review included 12 studies with
predominantly open cystectomy and neobladder as diver-
sion. Tumour in the bladder neck, prostatic urethra, and
prostate were ruled out, except PCa in nerve-sparing
cystectomy. Oncological outcomes were similar to control
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 91

Table 12 – Summary of evidence and recommendations for laparoscopic/robotic-assisted laparoscopic cystectomy.

Summary of evidence LE

RARC has longer operative time (1–1.5 h) and major costs, but shorter length of hospital stay (1–1.5 d) and less blood loss compared with ORC. 1
Retrospective RARC series suffer from a significant stage selection bias as compared with ORC. 1
Grade 3, 90-d complication rate is lower with RARC. 2
Most endpoints, if reported, including intermediate-term oncological endpoint and quality of life, are not different between RARC and ORC. 2
Surgeons experience and institutional volume are considered the key factors for outcome of both RARC and ORC, and not the technique. 2
Recommendations on how to define challenging patients and an experienced RARC surgeon are still under discussion. 3
The use of neobladder after RARC still seems underutilised, and functional results of intracorporeally constructed neobladders should be studied. 4

Recommendations Strength rating

Inform the patient of the advantages and disadvantages of ORC and RARC to allow selection of the proper procedure. Strong
Select experienced centres, not specific techniques, both for RARC and ORC. Strong

LE = level of evidence; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.

groups and within groups with regard to local or metastatic
recurrence, disease-specific survival (DSS), and OS, at a
median follow-up of 3–5 yr. In case the prostate was spared,
the rates of incidental PCa in the intervention group ranged
from 0% to 15%, and no International Society of Urologic
Pathologists (ISUP) grade 4 was reported. Postoperative
potency was significantly better for all techniques as
compared with conventional RC (p < 0.05), without superi-
ority of any technique. No major impact was shown with
regard to continence rates for any of the three approaches.
However, the overall quality of the evidence was moderate;
hence, candidates must be carefully selected, counselled,
and closely monitored.
In women, to prevent pelvic floor disorders (such as
prolapse) and sexual dysfunction, a gynaecological history
should be obtained and pelvic organ-preserving techniques
can be applied, preserving the neurovascular bundle,
vagina, uterus, and/or ovaries. From an oncological point
of view, concomitant malignancy in gynaecological organs
is rare and local recurrences reported after RC are infrequent
[67]. In case of an increased risk of hereditary breast or
ovarian cancer, salpingo-oophorectomy should be advised
[68]. The conclusion of the review, based on retrospective,
low-quality data, was that for well-selected patients,
sparing female reproductive organs during RC appears to
be oncologically safe and provides improved functional
outcomes [66].
14. Laparoscopic/robotic-assisted laparoscopic
cystectomy
Most of the available literature on minimal invasive
cystectomy is retrospective with limited numbers. Earlier
reviews of this literature with a low level of evidence have
learned that robotic-assisted laparoscopic RC (RARC),
compared with open RC, has a longer operative time,
increased costs, less blood loss, a 1–1.5-d shorter hospital
stay, and a lower 90-d complication rate (Table 12)
[69,70]. A recent Cochrane review including data from all
five published RCTs, however, showed no difference
between RARC and open RC with regard to the time to
recurrence, positive surgical margin rate, grade 3–5
complications, and QoL [71]. The transfusion rate was likely
lower after RARC. For other endpoints, outcomes were
uncertain due to study limitations.
For both techniques, surgeons’ experience and institu-
tional volume strongly predicted outcome, with 30 cases
estimated to be enough to achieve proficiency in RARC
[70]. Oncological results also seem comparable [72],
although port-site metastasis (in addition to other meta-
static sites) after RARC was suggested to be under-reported
[73]. The largest RCT to date is the RAZOR trial [74]. This
study showed RARC to be noninferior to open RC in terms of
2-yr PFS (72.3% vs 71.6%), adverse events (67% vs 69%), and
QoL. Most series offer extracorporeal reconstruction, which
is associated with a longer operative time, more blood
transfusions, but fewer high-grade complications than an
intracorporeal reconstruction [75]. For laparoscopic RC, a
review came to similar conclusions as described for RARC
[76].
15. Lymphadenectomy: role and extent
Regional LNs have been shown to consist of all pelvic LNs
below the bifurcation of the aorta [77,78]. Mapping studies
also found that skipping lesions at locations above the
bifurcation of the aorta, without more distally located LN
metastases, is rare [78].
The optimal extent of LND has not been established to
date. Standard LND includes nodes up to the common iliac
bifurcation, extended LND goes up to the aortic bifurcation
including presacral nodes, and a superextended LND
extends cranially to the level of the inferior mesenteric
artery. The impact on oncological outcome of the extent of
LND was reviewed [79]. Although the quality of data was
poor, any LND was better than no LND and a (super)
extended was better than a standard LND, but no difference
in outcome was reported between extended and super-
extended LND. In a recent prospective phase 3 RCT,
however, an extended LND failed to show a significant
advantage [80]. In conclusion, an extended LND might have
a therapeutic benefit, and if this is the case, it remains to be
seen whether the counted number of removed nodes or the
template is the most important prognosticator.
92 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4

16. Urinary diversion after RC
Most of the complications after RC and diversion are related
to the use of bowel for the urinary diversion (Table 13)
[81]. Three alternatives with different segments of the
intestinal tract are currently used after cystectomy: a
continent or incontinent abdominal diversion, a urethral
diversion, and a rectosigmoid diversion. An ileal conduit or
an orthotopic neobladder is mostly used. In case a
neobladder is planned with the presence of CIS in the
prostatic urethra or bladder neck (females), frozen sections
have to be performed, and patients have to undergo regular
follow-up cystoscopy and urinary cytology [82]. Positive
LNs do not exclude an orthotopic neobladder. Secondary
urethral tumours seem to be less common after a
neobladder compared with cutaneous diversions [83]. Cer-
tainly, for continent diversions, patients need to be
motivated, well informed, and selected. For a neobladder,
there is no strict age criterion, and in case of N1 disease, it
still is feasible [84]. Although there are no RCTs comparing
different diversions, retrospective data suggest that a
decline in estimated glomerular filtration rate did not differ
significantly after ileal conduit versus neobladder in
patients with preoperative chronic kidney disease [85].
Ureterocutaneostomy is the simplest form of cutaneous
diversion with lower operative time, complication rate, and
length of hospital stay than ileal conduit [86], and is
therefore a good option in older and frail patients [87]. QoL
showed equal urinary bother and function to an ileal
conduit [86]. Connection to the skin can be done separately
or with one stoma (after ureteroureteral anastomosis).
Although the ileal conduit is still the most performed and
well-established option with predictable results, it is not
without complications such as UTIs, ureteroileal leakage
and stenosis, stones, and stomal problems [88]. Complica-
tions increase in frequency with longer follow-up to 94% in
those surviving >15 yr [89].
A continent cutaneous urinary diversion can be made
from different bowel parts. Although it is not done
frequently, patients have been reported to have a well-
functioning reservoir with day- and night-time continence
approaching 93%, with 15% stomal stenosis and 10% stone
formation [90].
An orthotopic bladder substitution is a safe and reliable
option in both men and women. Long-term complications
include diurnal and nocturnal incontinence, ureterointest-
inal stenosis, metabolic disorders, and vitamin B12 defi-
ciency. The oncological outcome is not influenced by the
choice of diversion, although urethral recurrences in
neobladder patients seem to be rare [91]. Various forms
of upper urinary tract reflux protection have been
described, without long-term differences in outcome.
In all, it is not possible to recommend a particular type of
urinary diversion. However, mostly performed are ileal

Table 13 – Summary of evidence and recommendations for radical cystectomy and urinary diversion.

Summary of evidence LE

For MIBC, RC is the curative treatment of choice. 3

Higher hospital volume likely improves quality of care and reduction in perioperative mortality and morbidity. 3
Radical cystectomy includes removal of regional lymph nodes. 3
There are data to support that extended LND (vs standard or limited LND) improves survival after RC. 3
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 3
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. 3
Laparoscopic cystectomy and robotic-assisted laparoscopic cystectomy are feasible but still investigational. Current best practice is open 3
RC.
The use of extended prophylaxis significantly decreases the incidence of venous thromboembolism after RC. 3
In patients aged >80 yr with MIBC, cystectomy is an option. 3
Surgical outcome is influenced by comorbidity, age, previous treatment for bladder cancer or other pelvic diseases, surgeon and hospital 2
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- 2
adapted grading system for cystectomy is the Clavien grading system.
No conclusive evidence exists as to the optimal extent of LND. 2a

Recommendations Strength rating

Do not delay RC for >3 mo, as it increases the risk of progression and cancer-specific mortality. Strong
Perform at least 10, and preferably >20, RCs per hospital per year. Strong
Before RC, fully inform the patient about the benefits and potential risks of all possible alternatives. The final decision should be based Strong
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 Strong
dissection.
Preoperative bowel preparation is not mandatory. “Fast track” measurements may reduce the time to bowel recovery. Strong
Offer pharmacological prophylaxis, such as low-molecular-weight heparin to RC patients, starting the 1st day after surgery, for a period Strong
of 4 wk.
Offer RC in T2-T4a, N0M0, and high-risk non–muscle-invasive BC. Strong
Perform a lymph node dissection as an integral part of RC. Strong
Do not preserve the urethra if margins are positive. Strong

BC = bladder cancer; LE = level of evidence; LND = lymph node dissection; MIBC = muscle-invasive bladder cancer; RC = radical cystectomy.
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 93

Table 14 – Recommendations and consensus statements for supportive care.

Recommendations Strength rating

Offer radical cystectomy as a palliative treatment to patients with inoperable locally advanced tumours (T4b). Weak
Offer palliative cystectomy to patients with symptoms. Weak
EAU-ESMO consensus statements [4,5] a
Chemoradiation should be given to improve local control in cases of inoperable locally advanced tumours.
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.

EAU = European Association of Urology; ESMO = European Society for Medical Oncology.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).

orthotopic neobladders and ileal conduits. In selected lower quality, the available evidence suggests that perform-
patients, such as patients with a single kidney, ureterocu- ing >10 RCs per year per hospital reduces 30- and 90-d
taneostomy is an option to consider. mortality. Performing >20 RCs per hospital per year might
even reduce these mortality rates further.
17. Morbidity, survival, and impact of hospital and
surgeon volume on outcome 18. Supportive care

In a large single-centre series, early complications (within
3 mo of surgery) were seen in 58% of patients [81]. Late
morbidity is usually linked to the type of urinary diversion
(see also above). Large studies have shown 5-yr recurrence-
free survival (RFS) rate to be around 60% and CSS around
65% [92,93]. RFS is dependent on nodal involvement and
stage. In a surgery-only study, the 5-yr RFS was 76% in
patients with pT1 tumours, 74% in patients with pT2
tumours, 52% in patients with pT3 tumours, and 36% in
patients with pT4 tumours [94].
A recent systemic review addressed the impact of
hospital and/or surgeon volume on perioperative outcomes
of RC [95]. The results suggest that a higher hospital volume
is likely associated with lower in-hospital, 30-d, and 90-d
mortality rates. In addition, 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. In spite of the
In the case of on-going visible haematuria, coagulation
disorders and anticoagulant drugs must be reviewed
(Table 14). Intravesical rinsing of the bladder with 1% silver
nitrate or 1–2% alum can be effective [96]. Instillation of
formalin (2.5–4% for 30 min) is a more effective, but painful,
and usually requiring anaesthesia and with a higher risk of,
for example, bladder fibrosis [96]. Vesicoureteral reflux
should be excluded to prevent renal complications. Radia-
tion therapy is another common strategy to control bleeding
and pain. Embolisation of specific arteries in the small pelvis
has been reported with success rates as high as 90% [96].
19. Bladder-sparing treatments for localised disease
Although a thorough TUR is also important in MIBC, the TUR
alone in patients with MIBC can only be a therapeutic option
in T2 tumours with a negative restaging TUR. One study
reported a 77% 15-yr CSS with this approach [97].

Table 15 – Summary of evidence, recommendations, and consensus statements for bladder-sparing treatments.

Summary of evidence LE

External beam radiotherapy alone should be considered only as a therapeutic option when the patient is unfit for cystectomy or as part 3
of a multimodality bladder-preserving approach.
Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation 3
because of extensive local tumour growth.
Complete and partial local responses have been reported with cisplatin-based chemotherapy as primary therapy for locally advanced 2b
tumours in highly selected patients.
Recommendation Strength rating

Do not offer transurethral resection of bladder tumour alone as a curative treatment option as most patients will not benefit. Strong
Do not offer radiotherapy alone as primary therapy for localised bladder cancer. Strong
Do not offer chemotherapy alone as primary therapy for localised bladder cancer. Strong
a
EAU-ESMO consensus statements [4,5]
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.

EAU = European Association of Urology; ESMO = European Society for Medical Oncology; IGRT = image-guided radiotherapy; IMRT = intensity-modulated
radiotherapy; LE = level of evidence.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).
94 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4

Current EBRT techniques with soft-tissue matching
result in superior bladder coverage and a reduced integral
dose to the surrounding tissues with a target dose for
curation of 64–66 Gy [98] (Table 15). A complete initial TUR
is an important prognostic factor. Late morbidity is low and
reduced even more with IMRT [99]. Still, EBRT alone was
shown to be significantly less effective (2-yr OS 42%) than
concurrent chemoradiotherapy (2-yr OS 56%, p < 0.001, see
below) in a review of patients treated between 2004 and
2013 [100].
A recent large retrospective study reported on TURB and
multiagent chemotherapy [101]. The 2- and 5-yr OS values
were 49% and 32.9% for all patients, and 52.6% and 36.2% for
cT2 patients, respectively. While these data show that long-
term survival with intact bladder can be achieved in a
subset of patients, it is not recommended for routine use.
20. Multimodality bladder-preserving treatment
Multimodality treatment (MMT) or trimodality treatment
combines TUR of bladder tumour, radiosensitising chemo-
therapy, and RT (1) with the aim of bladder preservation
without compromising oncological outcome in patients fit
for cystectomy or (2) as an effective alternative for patients
unfit or unwilling for cystectomy (Table 16). For optimal
results, the TUR/re-TUR should be as radical as possible,
suggesting proper patient selection (T2 tumours, no CIS)
[102]. The different principles of radiation (dose, field, and
schedule) in case of MMT have been described [103]. Used
chemotherapy regimens are cisplatin, mitomycin C plus 5-
fluorouracil, gemcitabine, and nicotinamide/carbogen,
without clear preference for a specific radiosensitiser [4,5].
Five-year CSS and OS rates vary between 50–82% and 36–
74%, respectively, with salvage cystectomy rates of 10–30%
[4,5,9]. Similar results have been described in a small series
of variant histologies [104]. OS was lower than with RC in
two recent large retrospective analyses [105,106]. After
propensity score matching, both analyses show lower
survival after 2 yr of follow-up, with a significant hazard
ratio (HR) of 1.4–1.5, although one study [105] found lower
1–7-yr mortality for MMT (HR: 0.84, 95% confidence
interval [CI]: 0.74–0.96). On the contrary, a large systematic
review found similar OS and DSS for RC and MMT
[107]. Obvious prognostic factors for MMT are comorbidity,
age, stage, and downstaging/complete response (CR) after
MMT. Noninvasive recurrences after MMT are found in
around 25% of patients who can be treated conservatively
[108]. In case of salvage cystectomy, major complication
rates are not increased. In all, bladder preservation with
MMT leads to acceptable outcomes and may be considered a
reasonable treatment option in well-selected patients as
compared with RC [103]. There are no definitive data
supporting the benefit of using neoadjuvant or adjuvant
chemotherapy in case of MMT [103]. Whether a node
dissection should be performed before MMT, as in RC, also
remains unclear [4,5]. Finally, a bladder-preserving multi-
modality strategy requires very close multidisciplinary
cooperation and a high level of patient compliance
(follow-up) [4,5].
21. Adjuvant therapy
An updated meta-analysis from 2014 with the results of
nine trials with different cisplatin-based combinations and
courses, underpowered, and with significant heterogeneity
and methodological flaws showed that there remains a very
low level of evidence supporting the use of adjuvant
chemotherapy (Table 17) [109]. Still, the HR for OS was 0.77

Table 16 – Summary of evidence, recommendations, and consensus statements for multimodality treatment.

Summary of evidence LE

In a highly selected patient population, long-term survival rates of multimodality treatment are comparable with those of early 2b
cystectomy.
Recommendations Strength rating
Offer surgical intervention or MMT as a primary curative therapeutic approach since they are more effective than radiotherapy alone. Strong
Offer MMT as an alternative to selected, well-informed, and compliant patients, especially for whom radical cystectomy is not an option. Strong
EAU-ESMO consensus statements [4,5] a
Candidates for curative treatment, such as cystectomy or bladder preservation, should be assessed clinically by at least an oncologist, a urologist, 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/MMC, 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.
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.

EAU = European Association of Urology; ESMO = European Society for Medical Oncology; 5FU = 5-fluorouracil; HCP = healthcare professional; IGRT = image-
guided radiotherapy; IMRT = intensity-modulated radiotherapy; LE = level of evidence; MMT = multimodality treatment.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 95

Table 17 – Recommendations and consensus statements for adjuvant therapy.

Recommendations Strength rating

Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or pN + disease if no Strong
neoadjuvant chemotherapy has been given.
Only offer immunotherapy with a checkpoint inhibitor in a clinical trial setting. Strong
EAU-ESMO consensus statements [4,5] a
When adjuvant chemotherapy is offered, patients should be selected based on the result of LND (if done).

EAU = European Association of Urology; ESMO = European Society for Medical Oncology; LND = lymph node dissection.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).

(95% CI: 0.59–0.99) and for DFS 0.66 (95% CI: 0.45–0.91),
with lower DFS in case of nodal positivity. A recent
publication of the largest RCT (European Organisation for
Research and Treatment of Cancer, EORTC 30994), although
not fully accrued, also showed a significant improvement of
PFS for immediate, compared with deferred, cisplatin-based
chemotherapy (HR: 0.54; 95% CI: 0.4–0.73), but no
significant OS benefit [110]. Two other large retrospective
database analyses also found a benefit for adjuvant
chemotherapy versus observation, especially in T3/4 or N
+ disease [111,112]. In patients with concomitant or pure
variant histology, however, no benefit was found.
For adjuvant immunotherapy, to date, no data have been
published.
22. Metastatic disease, first-line systemic therapy
Approximately 50% of patients with MIBC relapse after RC,
depending on the stage. Most relapses are with distant
metastases. Standard first-line treatment for fit patients
with a good renal function is cisplatin-based combination
chemotherapy (Table 18). Most used regimens are GemCis
or MVAC or ddMVAC demonstrating median OS of 12–14 mo
[113]. Neither of the combinations is superior to the other,
but equivalence has not been tested. The long-term survival
results have confirmed the efficacy of the two regimens,
with GemCis having less toxicity [114], although tolerability
to MVAC can be improved with granulocyte colony-
stimulating factor (G-CSF). High-dose-intensity MVAC
combined with G-CSF is less toxic and has demonstrated
a higher CR rate and better 2-yr survival than standard
MVAC in one trial; however, there is no significant
difference in median survival between the two regimens
[115]. Substitution of carboplatin for cisplatin in cisplatin-fit
patients is associated with inferior outcome and is clearly
discouraged [116].
Karnofsky performance status (PS) of 80% and presence
of visceral metastases are independent prognostic factors of
poor survival for first-line treatment with MVAC [117]. The
sites of metastases also have an impact on long-term
survival. In LN-only disease, 20.9% of patients were alive at
5 yr compared with only 6.8% of patients with visceral
metastases [114].
Cisplatin unfit is defined by at least one of the
following criteria: PS > 1, glomerular filtration rate
(GFR) 60 ml/min, grade 2 audiometric loss, peripheral
neuropathy, and New York Heart Association (NYHA)
class III heart failure [118], which comprises over 50% of
patients with BC. Cisplatin has also been administered in
small studies to patients with a lower GFR (40–60 ml/
min) using different split-dose schedules, in part because
carboplatin is considered less effective than cisplatin
[116]. Gemcitabine and carboplatin (GemCarbo) has long
been the standard systemic treatment for cisplatin-unfit
patients based on a phase 2/3 RCT by the EORTC where
GemCarbo was more effective (overall response rate
[ORR] 42% vs 30%) with less toxicity than methotrexate/
carboplatin/vinblastine (Fig. 2) [119].
The role of first-line immunotherapy is being studied,
but currently published data from only two single-arm
phase 2 monotherapy trials in cisplatin-ineligible patients
are available. Pembrolizumab showed an ORR of 29% and a
CR in 7% of patients [120]. Atezolizumab showed an ORR of
23%, a CR in 9%, and median OS of 15.9 mo [121]. The results
are difficult to interpret due to the missing control arm and
the heterogeneity of the study population with regard to
PD-L1 status. The toxicity profile, however, was favourable
for both drugs. Both drugs are approved by the FDA and
European Medicines Agency for first-line treatment in
cisplatin-ineligible patients, but only in case of a positive
PD-L1 status.
23. Second-line systemic therapy for metastatic
disease
The only chemotherapy drug ever approved as second-line
treatment in Europe was vinflunine, based on a phase 3 RCT,
showing 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 signifi-
cant in the per-protocol patient population (not in the
intention-to-treat [ITT] population) [122]. A reasonable
strategy has been to rechallenge former cisplatin-sensitive
patients if progression occurred at least 6–12 mo after first-
line cisplatin-based combination chemotherapy. Currently,
vinflunine is reserved for patients with contraindications to
immunotherapy or as third- or later-line treatment. A recent
phase 3 RCT evaluated the addition of the angiogenesis
inhibitor ramucirumab to docetaxel versus docetaxel alone
[123]. The primary endpoint of PFS prolongation was
reached, the clinical benefit appears small, and OS data
have not yet been reported.
96 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4

Table 18 – Summary of evidence, recommendations, and consensus statements for metastatic disease.

Summary of evidence LE

In a first-line setting, PS and the presence or absence of visceral metastases are independent prognostic factors for survival. 1b
In a second-line setting, negative prognostic factors are liver metastasis, PS  1, and low haemoglobin (<10 g/dl). 1b
Cisplatin-containing combination chemotherapy can achieve median survival of up to 14 mo, with long-term DFS reported in 15% of 1b
patients with nodal disease and good PS.
Single-agent chemotherapy provides low response rates of usually short duration. 2a
Carboplatin combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of complete response and survival. 2a
Nonplatinum combination chemotherapy produces substantial responses in first- and second-line settings. 2a
Nonplatinum combination chemotherapy has not been tested against standard chemotherapy in patients who are fit or unfit for 4
cisplatin combination chemotherapy.
There is no defined standard chemotherapy for unfit patients with advanced or metastatic UC. 2b
Postchemotherapy surgery after partial or complete response may contribute to long-term DFS in selected patients. 3
Zoledronic acid and denosumab have been approved for supportive treatment in case of bone metastases of all cancer types including 1b
UC, because they reduce and delay skeletal-related events.
PD-1 inhibitor pembrolizumab has been approved for patients who have progressed during or after previous platinum-based 1b
chemotherapy based on the results of a phase 3 trial.
PD-L1 inhibitor atezolizumab has been approved by the FDA for patients who have progressed during or after previous platinum-based 2a
chemotherapy based on the results of a phase 2 trial.
PD-1 inhibitor nivolumab has been approved for patients who have progressed during or after previous platinum-based chemotherapy 2a
based on the results of a phase 2 trial.
PD-1 inhibitor pembrolizumab has been approved for patients with advanced or metastatic urothelial cancer ineligible for cisplatin- 2a
based first-line chemotherapy based on the results of a phase 2 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 urothelial cancer ineligible for cisplatin- 2a
based first-line chemotherapy based on the results of a phase 2 trial, but the use of atezolizumab is restricted to PD-L1–positive patients.
Recommendations Strength rating

First-line treatment for cisplatin-eligible patients

Use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with G-CSF, HD-MVAC with G-CSF or PCG. Strong
Do not offer carboplatin and nonplatinum combination chemotherapy. Strong
First-line treatment in patients ineligible (unfit) for cisplatin
Offer checkpoint inhibitors such as pembrolizumab or atezolizumab depending on PD-L1–positive status. Strong
Offer carboplatin combination chemotherapy if PD-L1 is negative. Strong
Second-line treatment
Offer the checkpoint inhibitor pembrolizumab to patients progressing during, or after, platinum-based combination chemotherapy for Strong
metastatic disease. Alternatively, offer treatment within a clinical trial setting.
Offer zoledronic acid or denosumab for supportive treatment in case of bone metastases. Weak
Offer only vinflunine to patients for metastatic disease as subsequent-line treatment if immunotherapy or combination chemotherapy, Weak
or FGFR3-inhibitor therapy, or inclusion in a clinical trial is not feasible.
EAU-ESMO consensus statements [4,5] a
Pseudoprogression has not been demonstrated in urothelial cancer.
In patients with advanced/metastatic urothelial cancer who are ineligible for cisplatin-based therapy but with high PD-L1 expression (as per approved drug-
specific methodology), both treatment with an ICI and chemotherapy can be offered.
Since no data exist for cisplatin-ineligible PD-L1–positive patients in order to differentiate between different ICIs (atezolizumab and pembrolizumab), either
agent can be administered.
Enrolment in a clinical trial remains the preferred option for patients with cisplatin-eligible advanced/metastatic urothelial cancer until on-going randomised
trials report in this population.
Treatment with an ICI should be offered to patients with advanced/metastatic urothelial cancer with progression after platinum-based chemotherapy. This
includes tumours that have progressed within a year or following perioperative (cystectomy) chemotherapy.
Once initiated, ICI therapy should be continued until progression of disease in patients with advanced/metastatic urothelial cancer.
In contrast to the first-line setting, the PD-L1 biomarker is not useful for selecting patients for immunotherapy in platinum-refractory metastatic urothelial
cancer.
Carboplatin-based chemotherapy remains a viable first-line treatment option in cisplatin-ineligible, PD-L1–positive patients with metastatic urothelial carcinoma
until data from randomised phase 3 trials of ICIs are available.
Cisplatin-ineligible, immunotherapy-refractory patients with metastatic urothelial carcinoma should be considered for chemotherapy instead of sequencing of
immunotherapy.

DFS = disease-free survival; EAU = European Association of Urology; ESMO = European Society for Medical Oncology; FDA = Food and Drug Administration;
FGFR = fibroblast growth factor receptor; GC = gemcitabine plus cisplatin; G-CSF = granulocyte colony-stimulating factor; HD = high dose; ICI = immune
checkpoint inhibitor; LE = level of evidence; MVAC = methotrexate, vinblastine, adriamycin, and cisplatin; PCG = paclitaxel, cisplatin, gemcitabine; PD-
L1 = programmed death-ligand 1; PS = performance status; UC = urothelial cancer.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups) are listed (defined as 70% agreement and 15% disagreement,
or vice versa).

Most recently, second-line immunotherapy with PD-1/ mab have demonstrated similar efficacy and safety in
PD-L1 checkpoint inhibitors has been established and is still second-line phase 1–3 trials.
being studied as standard second-line therapy. Pembroli- A phase 3 RCT with pembrolizumab, a PD-1 inhibitor,
zumab, nivolumab, atezolizumab, avelumab, and durvalu- showed significant OS benefit over chemotherapy (pacli-
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 97

Paent characteriscs
PS 0-1/ 2/ >2
GFR ≥/< 60 mL/min
Comorbidies

FIT FOR CISPLATIN?

YES NO NO

PS 0-1 and PS 2 or PS ≥ 2 and

GFR ≥ 60 mL/min GFR < 60 mL/min GFR < 60 mL/min
1. Carboplan and
STANDARD GC gemcitabine Monotherapy with either:
MVAC 2. Pembrolizumab 1. Pembrolizumab
HD MVAC (if PD-L1 posive) (if PD-L1 posive)
PCG 3. Atezolizumab 2. Atezolizumab
(if PD-L1 posive) (if PD-L1 posive)
4. Alternate regimens Or
5. Trials or best Best supporve care
supporve care

Second-line treatment
independent of teh me of progression aer first-line treatment

PS 0-1 PS ≥ 2

Progression (independent of the me 1. Consider immunotheraphy

interval aer receiving first-linechemo- 2. Clinical trial
therapy), adequate renal funcon 3. Best supporve care

Standard regimens
1. Pembrolizumab
2. Atezolizumab
3. Nivolumab
Or
1. Clinical trial
2. Combinaon chemotheraphy
3. Monotherapies

Subsequent treatment
1. Chemotherapy
2. Immunotherapy, if not given as
second-line treatment
3. Clinical trail
4. Best supporve care

GC = gemcitabine plus cisplatin; GFR = glomular filtration rate; HD-MVAC = (high-dose) methotrexate,
vinblastine, adriamycin plus cisplatin; PCG = paclitaxel, cisplatin, gemcitabine; PS = performance status.
Fig. 2 – Flow chart for the management of metastatic urothelial cancer.
GC = gemcitabine plus cisplatin; GFR = glomerular filtration rate; HD = high-dose; MVAC = methotrexate, vinblastine, adriamycin, and cisplatin;
PCG = paclitaxel, cisplatin, gemcitabine; PD-L1 = Programmed Death Ligand 1; PS = performance status.

taxel, docetaxel, or vinflunine, 10.3 vs 7.4 mo, HR: 0.73; 95% longer follow-up [125]. In addition, health-related QoL
CI: 0.59–0.91), leading to approval [124]. The benefit was (HRQoL) was stable during pembrolizumab, whereas it
independent of PD-L1 expression levels, but consistent with deteriorated on chemotherapy [126].
98 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4
Atezolizumab, a PD-L1 inhibitor, was the first checkpoint
inhibitor approved for BC based on the results of a phase
2 trial [127]. A phase 3 RCT compared atezolizumab with
second-line chemotherapy (paclitaxel, docetaxel, or vin-
flunine). There was no OS benefit for patients with high PD-
L1 expression, but OS was improved in the ITT population in
an exploratory analysis (8.6 vs 8.0 mo, HR: 0.85, 95% CI:
0.73–0.99).
The PD-1 inhibitor nivolumab was also approved based
on the results of a single-arm phase 2 trial [128]. ORR was
19.6% and OS was 8.74 mo for the entire group. Based on
results of phase 1/2 trials, only durvalumab and avelumab
are currently approved for this indication in the USA.
Novel drugs in early-phase clinical research are the
fibroblast growth factor receptor (FGFR) inhibitors erdafi-
tinib and rogaratinib demonstrating encouraging response
rates in patients with prespecified FGFR alterations
[129,130]. Another promising drug is enfortumab vedotin,
an antibody-drug conjugate targeting Nectin-4, which is
highly expressed in UC. A phase 2, single-arm study after
prior platinum chemotherapy and immunotherapy showed
objective response rates of 44%, including 12% of CRs with a
tolerable safety profile [131].
Patients with metastatic bone disease, irrespective of the
cancer type, should be considered for bone-targeted
treatment [132]. 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.
24. Postchemotherapy surgery and oligometastatic
disease
Although some studies suggest a survival benefit and QoL
improvement of surgery after partial or complete remission
after chemotherapy, the level of evidence supporting this
practice is mainly anecdotal and the respective literature
old (Table 19). However, these findings have been confirmed
in a recent systematic review including 28 studies [133].
25. Quality of life
Several questionnaires have been validated for assessing
HRQoL in patients with BC. The impact of BC was recently
reported to cause a significant decline in HRQoL in all
domains (Table 20). In MIBC, physical and social functioning
were particularly affected [134]. In case of RC, NAC does not
appear to have an impact on QoL in a recent study [135]. The
impact of the type of diversion remains unclear. One review
found no difference in overall QoL between continent and
incontinent diversions [136], with greater improvement in
physical health for incontinent diversions (p = 0.002), but no
differences in mental or social health. Another recent
review, however, showed significantly improved QoL after
an orthotopic diversion compared with the QoL after an ileal
conduit [137]. In case of a neobladder, day- and night-time
continence significantly improved to, respectively, 92% and
51% after 18 mo [138]. A specific problem in women with an
Table 19 – Summary of evidence and consensus statements for
postchemotherapy surgery and oligometastatic disease.
Summary of evidence LE
Postchemotherapy surgery after partial or complete response may 3
contribute to long-term DFS in selected patients.
EAU-ESMO consensus statements [4,5] a
In a minority of patients with one metastatic lesion, cure is possible after
radical treatment.
In patients with more than two metastatic sites, cure is not possible.
In metachronous OMD, time to relapse is an important prognostic indicator.
Liver is an unfavourable OMD site for curative therapy.
Bone is an unfavourable OMD site for curative therapy.
PET-CT scanning should be included in OMD staging when considering
radical treatment.
Radical treatment of OMD should be accompanied by adjuvant or
neoadjuvant systemic therapy.
DFS = disease-free survival; EAU = European Association of Urology;
ESMO = European Society for Medical Oncology; LE = level of evidence;
OMD = oligometastatic disease; PET-CT = positron emission tomography-
computed tomography.
a
Only statements that met the a priori consensus threshold across all three
stakeholder groups are listed (defined as 70% agreement and 15%
disagreement, or vice versa).
orthotopic neobladder is the need for clean intermittent
catheterisation (62.5%) [139]. In all, HRQoL outcomes are
good, provided there are good patient selection and
involvement of patients’ choice [136].
On study reported that QoL was better after MMT than
RC [140].
26. Follow-up of MIBC
Current oncological surveillance protocols are based on the
patterns of recurrence drawn from retrospective series with
contradictory results, although two series found better
survival for asymptomatic recurrences (Table 21) [141,142].
Contemporary cystectomy has a 5–15% probability of
pelvic recurrence that most often occurs within 6–18 mo
after surgery. Pelvic recurrences usually carry a poor
prognosis, despite treatment, with median survival from
4 to 8 mo. Treatment generally involves a combination of
chemotherapy, radiation, and surgery [143].
Distant recurrence, most likely in LNs, lungs, liver, and
bone, is seen in up to 50% of patients, is stage dependent,
and mainly appears within the first 2 yr after RC. Median
survival of patients with progressive disease treated with
platinum-based chemotherapy is 9–26 mo [144].
New urethral tumours occur in 1.3–13.7%, with a lower
frequency after an orthotopic neobladder (odds ratio [OR]:
0.44) [145]. Risk factors are malignancy in the prostatic
urethra in men and bladder neck in women. In case of risk
factors, urethral follow-up is indicated (urethral wash or
cytology) since there is a significant survival advantage in
men with urethral recurrence diagnosed asymptomatically
versus symptomatically [143]. Treatment depends on stage
and the presence of distant metastasis.
Upper urinary tract UCs (UTUCs) occur in 4–10% of cases
and represent the most common sites of late recurrence
[146]. Median OS is 10–55 mo, and 60–67% of patients die of
 E U RO P E A N U R O L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4 99

Table 20 – Summary of evidence and recommendations for health-related quality of life.

Summary of evidence LE

Compared to noncancer controls, the diagnosis and treatment of bladder cancer have a negative impact on HRQoL. 2a
There is no difference in overall QoL between patients with continent or incontinent diversion. 1a
In most patient groups studied, the overall HRQoL after cystectomy remains good, irrespective of the type of urinary diversion used. 2b
Important determinants of (subjective) QoL are a patient’s personality, coping style, and social support. 3
In patients with platinum-refractory advanced urothelial carcinoma, pembrolizumab may be superior in terms of HRQoL compared with another line of 1b
chemotherapy.
Recommendations Strength rating

Use validated questionnaires to assess HRQoL in patients with muscle-invasive bladder cancer. Strong
Offer a continent urinary diversion unless a patient’s comorbidities, tumour variables, and coping abilities present clear Strong
contraindications.
Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones for Strong
achieving good long-term results.
Provide clear and exhaustive information on all potential benefits and side effects, allowing patients to make informed decisions. Strong
Encourage patients to participate actively in the decision-making process.
HRQoL = health-related quality of life; LE = level of evidence.

Table 21 – Summary of recommendations and consensus statements for specific recurrence sites.

Site of recurrence Summary of evidence LE Recommendation Strength rating

Local recurrence Poor prognosis. Treatment should be 2b Offer radiotherapy, chemotherapy, and Strong
individualised depending on the local possibly surgery as options for
extent of tumour. treatment, either alone or in
combination.
Distant recurrence Poor prognosis. 2b Offer chemotherapy as the first option, Strong
and consider metastasectomy in case
of unique metastasis site.
Upper urinary tract recurrence Risk factors are multifocal disease See EAU guidelines on upper urinary Strong
(NMIBC/CIS or positive ureteral tract urothelial carcinomas.
margins).
Secondary urethral tumour Staging and treatment should be done 3 See EAU guidelines on primary urethral Strong
as for primary urethral tumour. carcinoma.
EAU-ESMO consensus statements [4,5] a
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 (eg, 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 mo initially and then, after 3 yr, every 6 mo 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 mo 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 yr in the majority of patients.
In patients treated with radical cystectomy with curative intent and who have a neobladder, management of household acids and bases includes regular
measurements of pH and sodium bicarbonate substitution, respectively, 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 yr in the majority of
patients.
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.

CEA = carcinoembryonic antigen; CIS = carcinoma in situ; CT = computed tomography; EAU = European Association of Urology; ESMO = European Society for
Medical Oncology; LDH = lactate dehydrogenase; LE = level of evidence; NMIBC = non–muscle-invasive bladder cancer.
a
Only statements that met the a priori consensus threshold across all three stakeholder groups are listed (defined as 70% agreement and 15% disagreement, or
vice versa).
100 E U RO P E A N U RO L O GY 7 9 ( 2 0 21 ) 8 2 – 10 4
metastatic disease [143]. A meta-analysis found that 38% of
UTUC recurrence was diagnosed by follow-up investiga-
tions, whereas in the remaining 62%, diagnosis was based
on symptoms. Risk factors are noninvasive cancer, multifo-
cal disease, and positive ureteral or urethral margins.
Follow-up schedules are based on low-level evidence. A
schedule suggested by the EAU Guidelines Panel includes a
CT scan (every 6 mo) until the 3rd year, followed by annual
imaging thereafter up to 5 yr. In case of risk factors for
UTUCs, longer follow-up with CT is indicated [147]. The
length of follow-up is not well known, and depends on stage
and competing health factors. In case of locally advanced
disease or LN involvement, for example, a higher risk of
recurrence for >20 yr was reported [148]. Since data for
follow-up strategies are sparse, a number of key questions
were included in the recently held consensus project [4,5].
Functional follow-up should be long term to detect and
treat complications related to urinary diversion, which are
seen in up to 54% of patients after 15 yr of follow-up
[143]. Functional complications include vitamin B12 defi-
ciency, metabolic acidosis, worsening of renal function,
urinary infections, urolithiasis, stenosis of ureterointestinal
anastomosis, stoma complications in patients with ileal
conduit, neobladder continence problems, emptying dys-
function, and a 21% increased risk of fractures due to chronic
metabolic acidosis and subsequent long-term bone loss
[143,149].
Author contributions: J. Alfred Witjes had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Witjes.
Acquisition of data: Witjes, Bruins, Cathomas, Compérat, Cowan, Gakis,
Hernández, Espinós, Lorch, Neuzillet, Rouanne, Thalmann, Veskimäe,
Ribal, van der Heijden.
Analysis and interpretation of data: Witjes, Bruins, Cathomas, Compérat,
Cowan, Gakis, Hernández, Espinós, Lorch, Neuzillet, Rouanne, Thalmann,
Veskimäe, Ribal, van der Heijden.
Drafting of the manuscript: Witjes, van der Heijden.
Critical revision of the manuscript for important intellectual content:
Witjes, Bruins, Cathomas, Compérat, Cowan, Gakis, Hernández, Espinós,
Lorch, Neuzillet, Rouanne, Thalmann, Veskimäe, Ribal, van der Heijden.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: Witjes.
Supervision: None.
Other: None.
Financial disclosures: J. Alfred Witjes certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: Professor Dr. J.A.
Witjes receives personal fees as an advisor for Roche, Merck, and
BMS. Professor Dr. R. Cathomas received personal fees from Roche, Pfizer,
MSD, BMS, AstraZeneca, Janssen, Astellas, Bayer, Sanofi Aventis,
Debiopharm, Novartis, and Ipsen. Professor Dr. G. Gakis is a company
consultant for Erbe, Ipsen, Pierre Fabre, Medac, and MSD, and receives
research support from IPSEN. Professor Dr. A. Lorch is a principal
investigator for phase 2 and 3 trials with Roche, MSD, AstraZeneca, Ipsen,
Janssen, Bayer, Novartis, and BMS; is a member of advisory boards for
Roche, Novartis, Ipsen, MSD, BMS, and Janssen; receives honoraria for
lectures and travel fees from Roche, AstraZeneca, Novartis, and Ipsen;
and receives travel fees from MSD. Dr. Y. Neuzillet is a consultant for
Astellas, AstraZeneca, Bouchara-Recordati, BMS, Ipsen, Janssen, Medac,
MSD, Roche, Sanofi Pasteur, and Sanofi Aventis. Professor Dr. M.J. Ribal
receives speaker honoraria from Astellas, Janssen, Ipsen, and
Olympus. Dr. H.M. Bruins, Professor Dr. E.M. Compérat, Dr. N.C. Cowan,
Dr. V. Hernàndez, Dr. E. Linares-Espinós, Dr. M. Rouanne, Professor Dr. G.
N. Thalmann, Dr. E. Veskimae, Dr. A.G. van der Heijden have nothing to
disclose.
Funding/Support and role of the sponsor: None.
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