EUROPEAN UROLOGY 65 (2014) 778–792

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

Guidelines

EAU Guidelines on Muscle-invasive and Metastatic Bladder

Cancer: Summary of the 2013 Guidelines

J. Alfred Witjes a,*, Eva Compérat b, Nigel C. Cowan c, Maria De Santis d, Georgios Gakis e,
Thierry Lebret f, Maria J. Ribal g, Antoine G. Van der Heijden a, Amir Sherif h
a b
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Pathology, Groupe Hospitalier
c d
Pitié–Salpêtrière, Paris, France; Department of Radiology, The Manor Hospital, Oxford, UK; 3rd Medical Department and ACR-ITR and LBI-ACR
Vienna-CTO, Kaiser Franz Josef Spital, Vienna, Austria; e Department of Urology, Eberhard-Karls-University Tuebingen, Tuebingen, Germany; f Hôpital Foch,
g
Department of Urology, University of Versailles-Saint-Quentin-en-Yvelines, Suresnes, France; Uro-Oncology Unit, Urology Department, Hospital Clinic,
h
University of Barcelona, Barcelona, Spain; Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden

Article info Abstract

Article history: Context: The European Association of Urology (EAU) guidelines panel on Muscle-inva-
Accepted November 29, 2013 sive and Metastatic bladder cancer (BCa) updates its guidelines yearly. This updated
Published online ahead of summary provides a synthesis of the 2013 guidelines document, with emphasis on the
latest developments.
print on December 12, 2013 Objective: To provide graded recommendations on the diagnosis and treatment of
patients with muscle-invasive BCa (MIBC), linked to a level of evidence.
Keywords: Evidence acquisition: For each section of the guidelines, comprehensive literature
searches covering the past 10 yr in several databases were conducted, scanned,
EAU guidelines
reviewed, and discussed both within the panel and with external experts. The final
Bladder cancer results are reflected in the recommendations provided.
Invasive Evidence synthesis: Smoking and work-related carcinogens remain the most important
Infiltrative risk factors for BCa. Computed tomography (CT) and magnetic resonance imaging can be
Cystectomy used for staging, although CT is preferred for pulmonary evaluation. Open radical
cystectomy with an extended lymph node dissection (LND) remains the treatment of
Bladder sparing treatments choice for treatment failures in non-MIBC and T2–T4aN0M0 BCa. For well-informed,
Chemotherapy well-selected, and compliant patients, however, multimodality treatment could be
Cisplatin-based offered as an alternative, especially if cystectomy is not an option. Comorbidity, not
Comorbidities age, should be used when deciding on radical cystectomy. Patients should be encouraged
to actively participate in the decision-making process, and a continent urinary diversion
Quality of life
should be offered to all patients unless there are specific contraindications. For fit
patients, cisplatinum-based neoadjuvant chemotherapy should always be discussed,
since it improves overall survival. For patients with metastatic disease, cisplatin-con-
taining combination chemotherapy is recommended. For unfit patients, carboplatin
combination chemotherapy or single agents can be used.
Conclusions: This 2013 EAU Muscle-invasive and Metastatic BCa guidelines updated
summary aims to increase the quality of care and outcome for patients with muscle-
invasive or metastatic BCa.
Patient summary: In this paper we update the EAU guidelines on Muscle-invasive and
Metastatic bladder cancer. We recommend that chemotherapy be administered before
radical treatment and that bladder removal be the standard of care for disease confined
to the bladder.
# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* 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 16712; Fax: +31 24 35 41031.
E-mail address: f.witjes@uro.umcn.nl (J.A. Witjes).

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.2013.11.046
 EUROPEAN UROLOGY 65 (2014) 778–792 779

1. Introduction Tobacco smoking is the most established risk factor for

The previous summary of the European Association of
Urology (EAU) guidelines on Muscle-invasive and Meta-
static bladder cancer (BCa) was published in 2011 [1]. Since
2011, the guidelines have been regularly updated, and the
current summary presents a synthesis of the 2013 guide-
lines document of March 2013. New scientific publications
published after March 2013 will be incorporated into the
2014 update. The guidelines panel comprises an interna-
tional multidisciplinary group of experts from the fields of
urology, pathology, radiology, and oncology.
For each section of the muscle-invasive BCa (MIBC)
guidelines, comprehensive literature searches covering
the last 10 yr in several databases were set up. Searches
were discussed internally and with an expert external
consultant. Extensive use of free text ensured the
sensitivity of the searches. Search results were scanned
by the panel members, reviewed, and finally used to
provide levels of evidence (LEs) and grades of recommen-
dation (GRs). Definitions of LEs and GRs follow the listings
in the full text version [2]. The link between LE and GR is
not directly linear. For example, randomised controlled
trials are not necessarily given a grade A recommendation
if there are methodological limitations or disparity in
published results. Conversely, overwhelming clinical
experience and consensus can translate into a grade A
recommendation.
2. Epidemiology and risk factors
BCa is the ninth most common cancer worldwide, with
>330 000 new cases each year, >30 000 deaths per year,
and an estimated male-to-female ratio of 3.8 to 1.0 [3].
At presentation, approximately 30% of patients have
MIBC.
BCa, responsible for 50–65% of male cases and 20–30%
of female cases [4]. A recent meta-analysis found a relative
risk of 2.77 (95% confidence interval [CI], 2.17–3.54) for
current smokers and 1.72 (95% CI, 1.46–2.04) for former
smokers [5]. Since stopping smoking lowers the risk of BCa
by 60% after 25 yr [6], encouraging people to stop smoking is
worthwhile. The second most important risk factor is
occupational exposure [7], accounting for 20–25% of all BCa
cases in a number of series. The latency period following
exposure may be as long as 30 yr [8]. In Western countries
the incidence of BCa due to occupational exposure is
decreasing [9]. Radiotherapy to pelvic organs (eg, external
radiotherapy for prostate cancer [PCa]) has also been
related to an increased risk of BCa [10]. Since longer
follow-up data are not yet available and BCa requires a long
period to develop, close surveillance of irradiated patients
with a long life expectancy is appropriate [11].
Women are more likely to be diagnosed with primary
muscle-invasive disease than men (85% vs 51%) [12], and
female gender has a significant negative impact on cancer-
specific survival (CSS) in specific patient groups, suggesting
different clinical phenotypes [13]. Conclusions and recom-
mendations for epidemiology and risk factors are listed in
Tables 1 and 2.
3. Tumour classification
The seventh edition of the TNM classification of malignant
tumours, effective as of 2010 [14], is recommended
(Table 3). The last change in the grading system was in
2004 [15]. However, since all muscle-invasive bladder
tumours are considered high grade, grading is not consid-
ered very important for MIBC [8].
After radical cystectomy, specimen handling should
follow published rules [16] to study all parts of the specimen

Table 1 – Conclusions on epidemiology and risk factors

Conclusion LE

The incidence of muscle-invasive disease has not changed for 5 yr.

Active and passive tobacco smoking is the main risk factor. Exposure-related incidence is decreasing. 2a
Patients undergoing EBRT, brachytherapy, or a combination of EBRT and brachytherapy are at increased risk of developing bladder cancer. 3
Patients treated with radiotherapy at a young age are at high risk for bladder cancer and should be followed up closely.
The estimated male-to-female ratio for bladder cancer is 3.8 to 1.0. Women are more likely to have primary muscle-invasive disease than men. 3
Currently, treatment decisions cannot be based on molecular markers. 3

EBRT = external-beam radiotherapy; LE = level of evidence.

Table 2 – Recommendations on epidemiology and risk factors

Recommendation GR

The principal preventable risk factor for muscle-invasive bladder cancer is active and passive smoking. B
Workers should be informed about the potential carcinogenic effects of a number of recognised substances, duration of exposure, and latency periods. A
Protective measures should be recommended.

GR = grade of recommendation.
780 EUROPEAN UROLOGY 65 (2014) 778–792

Table 3 – TNM classification of urinary bladder cancer (2009) [14] Table 4 – Recommendations for assessing tumour specimens

Tx Primary tumour cannot be assessed Mandatory evaluations

T0 No evidence of primary tumour Histologic subtype
Ta Noninvasive papillary carcinoma Depth of invasion
Tis Carcinoma in situ: ‘‘flat tumour’’ Resection margins, including carcinoma in situ
T1 Tumour invades subepithelial connective tissue Lymph node representation; normal and tumoural lymph node count,
T2 Tumour invades muscle including measuring the tumoural lymph nodes according to
T2a Tumour invades superficial muscle (inner half) the TNM, 7th edition
T2b Tumour invades deep muscle (outer half) Optional evaluation
T3 Tumour invades perivesical tissue Lymphatic and/or vascular invasion
T3a microscopically
T3b macroscopically (extravesical mass)
T4 Tumour invades any of the following: prostate stroma,
Table 5 – Recommendations for classification of muscle-invasive
seminal vesicles, uterus, vagina, pelvic wall, abdominal bladder cancer
wall
T4a Tumour invades prostate stroma, seminal Recommendation LE GR
vesicles, uterus, or vagina
T4b Tumour invades pelvic wall or abdominal wall The pathologic depth of muscle invasion should be reported 3 B
N – Regional lymph nodes by the pathologist in patients with node-negative
Nx Regional lymph nodes cannot be assessed pT2 bladder cancer after cystectomy.
N0 No regional lymph node metastasis
GR = grade of recommendation; LE = level of evidence.
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 (hypogastric, obturator, external iliac,
4. Diagnosis and staging
or presacral)
N3 Metastasis in common iliac lymph node(s) 4.1. Primary assessment
M – Distant metastasis
M0 No distant metastasis
M1 Distant metastasis
Physical examination should include bimanual palpation,
but there is considerable discrepancy between bimanual
examination findings and pT stage after cystectomy (11%
clinical overstaging and 31% clinical understaging) [22]. The
tumour should be resected completely if possible, but in case
and margins (Table 4). Lymph node count, tumour involve- of a suspected invasive bladder tumour, at least a deeper part
ment of the node (in millimetres), and extracapsular and of the tumour should be resected and offered to the pathologist
extranodal spread should be documented. If it is important in a separate labelled container to enable a correct diagnosis.
for treatment strategy, nodal frozen section (FS) is a reliable In invasive BCa, the role of random biopsies, fluorescence
tool to accurately identify malignancy [17]. Most bladder cystoscopy, and a second resection seems limited. Under
tumours are urothelial carcinomas, but morphologic certain circumstances, a biopsy of the prostatic urethra is
subtypes exist. Recognition of these subtypes is important warranted (Table 6) [23]. This biopsy can be done during the
for assessing prognosis and selecting treatment options. The primary transurethral resection (TUR) or by FS during radical
pT2 substaging was defined in the TNM staging system in surgery. An FS has a higher negative predictive value and is
1997, but its value for improved risk stratification in patients more accurate [24]. The perceived benefit of a TUR biopsy
with node-negative pT2 BCa was questioned recently [18]. is that it avoids the need for intraoperative FS. Ruling out
Several recent series confirm significant differences in PCa is important, since 25–46% of patients undergoing
survival between the two substages in node-negative pT2 cystectomy for BCa have concomitant PCa [25].
disease [19–21] and confirm the important prognostic value
of recognising these subtypes. In conclusion, present data 4.2. Imaging for staging muscle-invasive bladder cancer
support the concept that substratification in node-negative (Table 7)
pT2 BCa patients is important and can be used to select
patients who will not benefit from adjuvant treatment Computed tomography (CT) and magnetic resonance
(Table 5). imaging (MRI) are the principal diagnostic imaging

Table 6 – Recommendations for primary assessment of presumably invasive bladder tumours

Recommendation GR

Cystoscopy should describe all macroscopic features of the tumour (site, size, number, and appearance) and epithelial abnormalities. C
A bladder diagram is recommended.
 Biopsy of the prostatic urethra is recommended for cases of bladder neck tumour, when bladder carcinoma in situ is present or C
suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible.
 If a biopsy is not performed during the initial procedure, biopsies should be taken at the time of the second resection.
In women undergoing an orthotopic neobladder, procedure information (including a histologic evaluation) is required for the bladder C
neck and urethral margin either prior to or at the time of cystoscopy.

GR = grade of recommendation.
 EUROPEAN UROLOGY 65 (2014) 778–792 781

Table 7 – Conclusions and recommendations for staging in muscle-invasive bladder cancer

Conclusions LE

Imaging as part of staging in MIBC provides information about prognosis and assists in selection of the most appropriate treatment. 2b
There is insufficient data on the use of DW MRI and FDG-PET/CT in MIBC to allow a recommendation to be made.

Recommendations GR

In patients with confirmed MIBC, CT of the chest, abdomen, and pelvis is the optimal form of staging, including excretory-phase B
CT urography for complete examination of the upper urinary tract.
Excretory-phase CT urography is preferred to magnetic resonance urography for diagnosing UTUCs in terms of greater diagnostic accuracy, C
less cost, and greater patient acceptability. Magnetic resonance urography is used when CT urography is contraindicated for
reasons related to contrast administration or radiation dose.
Ureteroscopy-guided biopsy is recommended for histopathologic confirmation of diagnosis in the preoperative assessment of UTUC. C
CT or MRI is recommended for staging locally advanced or metastatic disease in patients for whom radical treatment is being considered. B
CT and MRI are generally equivalent in diagnosing local and distant abdominal metastases, but CT is preferred to diagnose pulmonary metastases. C

CT = computed tomography; DW MRI = diffusion-weighted magnetic resonance imaging; FDG-PET = fludeoxyglucose positron emission tomography;
GR = grade of recommendation; LE = level of evidence; MIBC = muscle-invasive bladder cancer; MRI = magnetic resonance imaging; UTUC = upper urinary
tract urothelial carcinoma.

techniques for staging MIBC. The purpose of imaging is to
show the extent of local tumour invasion and any
involvement of the upper urinary tract, lymph nodes, or
other distant organs (eg, bones, liver, adrenals, lungs, and
peritoneal space).
For local tumour assessment, MRI is reported to be more
accurate than CT. Both CT and MRI have limited capability
for detecting microscopic invasion of the perivesical fat, but
they may be used to find T3b disease or higher [26] with
greater diagnostic accuracy. Diffusion-weighted MRI may
predict histopathologic response after induction chemo-
therapy with high specificity [27]. Results from further
studies are awaited.
Dynamic contrast-enhanced MRI is reported to allow
differentiation of the bladder tumour from surrounding
tissues or postbiopsy reaction, as enhancement of the
tumour occurs earlier than enhancement of normal bladder
wall because of neovascularisation [26].
Excretory-phase CT urography is the imaging technique
with the highest diagnostic accuracy for upper urinary tract
urothelial carcinoma. It has replaced conventional intrave-
nous urography and ultrasonography as the first-line
imaging test for investigating high-risk patients [28].
The sensitivity of CT and MRI for detection of enlarged
lymph nodes is similar. However, the diagnostic accuracy
for metastases in normal-sized or minimally enlarged
lymph nodes by CT and MRI is limited.
CT and MRI are the principal diagnostic techniques to
detect metastases to the lungs, liver, adrenals, bones,
and peritoneal space. Fludeoxyglucose positron emission
tomography/CT is reported to improve staging in BCa because
of its higher sensitivity for metastatic disease [29], especially in
lymph nodes and bones. The actual change in management,
however, is relatively small, and more prospective data are
required to confirm the clinical and cost effectiveness.
5. Treatment failure in non–muscle-invasive
bladder cancer
In high-risk non-MIBC (NMIBC), such as pT1 tumours, high-
grade tumours, and carcinoma in situ (CIS), the risk of
progression and the risk of understaging at initial diagnosis
can be as high as 50% [30]. Although there is debate about
the effectiveness of intravesical bacillus Calmette-Guérin
(BCG) on delaying progression [31], a recent prospective
multicentre trial showed lower progression rates than
previously reported, even in the presence of concomitant
CIS [32]. Potential reasons for this finding were the
combination of a second resection prior to inclusion in
the trial and maintenance treatment as part of the protocol.
Progression, however, remains a very important clinical end
point, since progression to MIBC significantly decreases CSS
to 35% after 4 yr [33]. Therefore, according to the EAU
NMIBC guidelines [30], it is reasonable to propose
immediate radical cystectomy to patients in a newly
defined highest-risk category (Table 8). A high-risk tumour
is defined as a T1 tumour with any of the following
characteristics [30]: G3 (high-grade) tumour; CIS; or Ta
G1G2 tumour, but only in case of recurrence of multiple
large (>3 cm) tumours (all three characteristics must be
present) [30].
The definition of patients failing BCG treatment is given in
the NMIBC guidelines [29]. Cystectomy should be performed
for these patients within 9 mo, because additional BCG
therapy yields a response rate of only 27–51% and is of
unknown duration [34,35]
6. Neoadjuvant chemotherapy
Since 5-yr survival after radical cystectomy for clinically
localised MIBC is only approximately 50% [36], chemotherapy
Table 8 – Recommendations for treatment failure in non–muscle-
invasive bladder cancer
Recommendation GR
In all T1 tumours at high risk of progression, immediate radical C
treatment is an option (as outlined in the EAU guidelines for
Non–muscle-invasive Bladder Cancer [30]).
For all T1 patients failing intravesical therapy, radical treatment B
should be offered.
EAU = European Association of Urology; GR = grade of recommendation.
782 EUROPEAN UROLOGY 65 (2014) 778–792

before surgery (neoadjuvant chemotherapy [NAC]) has
been used to treat micrometastatic disease and improve
overall survival (OS). Advantages of chemotherapy before
surgery are that chemotherapy is delivered when the
burden of micrometastatic disease is low and chemo-
sensitivity can be better observed; in addition, tolerability
of chemotherapy is expected to be better before cystec-
tomy than after. Indeed, responders to NAC—especially
complete responders—have a significantly improved OS
[37]. However, overtreatment of nonresponders and
overtreatment of patients without micrometastases re-
main major drawbacks, and delayed cystectomy in
nonresponders might compromise final outcome. Unfor-
tunately, molecular profiling of the tumour is not yet able
to identify responders. Also, imaging during treatment
does not allow firm conclusions about response [38].
Another disadvantage is that only clinical staging is
available in case of NAC, with known limitations of
staging accuracy in 70% of patients [39] and staging errors
more common in cT2 tumours than in cT3–4 tumours.
Although this situation is a potential concern, there is no
negative impact of NAC on the percentage of performable
cystectomies; in the combined Nordic trials (n = 620),
cystectomy frequency was 86% in the NAC arm and 87% in
the control arm [40].
The true survival advantage of NAC has been studied on
several occasions. However, conflicting results are
reported because of differences in trial design (chemo-
therapy regimens, study size, patient characteristics, and
different additional treatments). Three meta-analyses
were undertaken to determine the survival advantage of
NAC [41–43]. All three meta-analyses showed an increase
in OS of 5%. Of note, only combinations with cisplatin
resulted in a meaningful benefit [41,43]. A recent update
of the largest trial, with a median follow-up of 8 yr,
confirmed an improvement in 10-yr survival from 30% to
36% with neoadjuvant cisplatin, methotrexate, and vin-
blastine but without any locoregional benefit [44].
Conclusions and recommendations for NAC are shown
in Table 9.
7. Radical surgery and urinary diversion
7.1. Preoperative evaluation
Radical cystectomy is the standard treatment for localised
MIBC. Performance status (PS) [45], biologic age, and
preexisting comorbidities are important factors in the
primary treatment choice and complications after surgery.
For example, in a population-based competing risks
analysis of >11 260 patients from the Surveillance
Epidemiology and End Results registries, age carried the
highest risk for other-cause mortality, but not for increased
cancer-specific death [46]. Comorbidity in patients who
plan to undergo radical cystectomy can best be studied with
the age-adjusted Charlson Comorbidity Index, since this
score has been found to be an independent prognostic
factor for perioperative mortality [47,48], overall mortality
[49,50], and cancer-specific mortality [45]. Although the
American Society of Anesthesiologists score has predictive
value for postoperative complications [51], it does not
address comorbidities and should not be used in this
setting (Table 10).
Several studies have shown worse survival if cystectomy
is delayed for >3 mo after TUR, except with the use of NAC
[52,53].
7.2. Extent and technique of radical cystectomy
Radical cystectomy also includes regional bilateral lymph
node dissection (LND). There are substantial data on the
extent of LND. In BCa, it is uncommon to find metastatic
lymph nodes outside the true pelvis if the pelvic lymph
nodes are free of tumour [54]. Consensus has not been
reached on whether extension of LND outside the standard
pelvic region has diagnostic or therapeutic value. An
extended LND basically reaches the aortic bifurcation,
and a superextended LND extends to the level of the inferior
mesenteric artery [55].
To evaluate how cancer outcomes are influenced by the
different anatomic LND templates for patients with clinical

Table 9 – Conclusions and recommendations for neoadjuvant chemotherapy

Conclusion LE

Overtreatment of nonresponders and patients in the nontarget population (ie, patients without micrometastatic disease) is a major drawback –
in using neoadjuvant chemotherapy.
Neoadjuvant chemotherapy has limitations regarding patient selection, current development of surgical technique, and current –
chemotherapy combinations.
In current routine clinical practice, it is difficult to select patients who will respond to neoadjuvant chemotherapy because of the lack of –
a widely applicable test. In the future, genetic markers, in a ‘‘personalised medicine’’ setting, will make it easier to select patients for
treatment and to differentiate responders from nonresponders.
Neoadjuvant treatment of responders, and especially patients who show complete response (pT0 N0), has a major impact on overall survival. 2
Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival. 1a

Recommendation GR

In case of progression under neoadjuvant chemotherapy, this treatment should be discontinued. B

Neoadjuvant chemotherapy is recommended for T2–T4a, cN0 M0 bladder cancer and should always be cisplatinum-based combination therapy. A
Neoadjuvant chemotherapy is not recommended for patients with PS 2 and/or impaired renal function. B

GR = grade of recommendation; LE = level of evidence; PS = performance status.

 EUROPEAN UROLOGY 65 (2014) 778–792 783

Table 10 – Conclusions and recommendations for comorbidity scales

Conclusion 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 most helpful. 3

Recommendation GR

The decision regarding bladder-sparing or radical cystectomy in the elderly/geriatric patient with invasive bladder cancer should be B
based on tumour stage and comorbidity best quantified by a validated score, such as the Charlson Comorbidity Index.
The ASA score does not address comorbidities and should not be used in this setting. B

ASA = American Society of Anesthesiologists; GR = grade of recommendation; LE = level of evidence.

N0M0 MIBC and in the absence of controlled studies, the
EAU Muscle-invasive and Metastatic BCa guidelines com-
mittee initiated a systematic review of the literature for
comparative studies. The methodology is outlined in detail
elsewhere [56]. Of nine studies comparing superextended
LND with standard or limited LND, six reported a survival
benefit in favour of superextended LND. No difference in
outcome was reported between extended and super-
extended LND in the two studies identified. These results
confirm the findings of two other reviews. One study
concluded that a more limited pelvic LND resulted in
suboptimal staging and poorer outcomes compared with a
standard or extended LND, in patients with and without
node-positive disease [57]. A second review found an
extended LND to be superior to a limited LND [58].
All studies that were identified have significant limita-
tions, including stage migration and retrospective nature.
As data from ongoing randomised trials on the therapeutic
impact of extent of lymphadenectomy are awaited, firm
conclusions on the therapeutic benefit of extended LND
cannot be drawn.
Laparoscopic cystectomy and robot-assisted laparoscop-
ic cystectomy and intracorporeal construction of urinary
diversion are feasible but are currently considered experi-
mental because of the limited number of cases reported, the
absence of long-term oncologic and functional outcome
data, and a possible selection bias. Data from two ongoing
randomised trials are awaited.
7.3. Urinary diversion
Four methods of urinary diversion are used after cystec-
tomy: incontinent cutaneous, continent cutaneous, ortho-
topic, and rectosigmoid diversions. All forms of wet and
dry urinary diversions are possible in elderly patients
after careful selection [59]. The choice of diversion depends
on PS, preexisting comorbidities, and (to a lesser extent)
age, as has been indicated. A transuretero-ureterocutaneost-
omy or ureterocutaneostomy is associated with fewer
complications compared with an intestinal conduit [60–
62]. However, clinical experience suggests that stricturing on
skin level and ascending urinary tract infections are seen
more frequently when compared with an ileal conduit
diversion.
The ileal conduit is an established option. Nevertheless,
depending on the follow-up interval, a significant propor-
tion of patients will develop complications including
infections, stomal problems, and ureteroileal stenosis,
although the rate of the latter complication will be low.
Continent cutaneous urinary diversions aim to provide a
well-functioning reservoir with satisfactory daytime and
nighttime continence for the majority of patients [63].
Long-term problems are stomal stenosis, renal deteriora-
tion due to ureteral strictures/reflux, and stone formation in
the pouch. The rate of stone formation is low, as long as
metal staples are not used.
An orthotopic bladder substitution is now commonly
used in both genders. The procedure is safe, with good long-
term reliability [64]. Long-term complications include
diurnal incontinence (8–10%), nocturnal incontinence
(20–30%), ureterointestinal stenosis (3–18%), and urinary
retention (4–12%) both in males and female patients;
metabolic disorders and vitamin B12 deficiency were seen
in two recent large series [60,65]. A potential advantage of
an orthotopic neobladder is the low frequency of secondary
urethral tumours as compared with ileal conduits [65].
Quality of life (QoL) after a neobladder or conduit seems
comparable [66]. In general, a lower morbidity and a lower
mortality have been observed by surgeons and hospitals
with a higher caseload, and therefore more experience [67].
Recommendations related to radical cystectomy and
urinary diversions are listed in Table 11.
8. Palliative cystectomy and supportive care
Locally advanced tumours such as T4b or node-positive
tumours may be accompanied by severe debilitating
symptoms (eg, pain, bleeding, and obstruction). Successful
treatment is difficult. Of the treatment options, radical
surgery has the greatest morbidity and should be consid-
ered only if there are no other options [68]. Obstruction of
the upper urinary tract can be treated with urinary
diversion without cystectomy. Bleeding can be treated
with coagulation or bladder rinsing with 1% silver nitrate or
1–2% alum [69]. Coagulation disorders and anticoagulant
drug use should be reviewed. Radiation therapy can be used
to control haemorrhage and pain (Table 12).
9. Preoperative radiotherapy in muscle-invasive
bladder cancer (Table 13)
Literature about radiotherapy after cystectomy is extremely
scarce, and no conclusions can be drawn. Preoperative
radiotherapy is addressed in several retrospective and
784 EUROPEAN UROLOGY 65 (2014) 778–792

Table 11 – Conclusions and recommendations for radical cystectomy and urinary diversion

Conclusion LE

For MIBC, radical cystectomy is the curative treatment of choice. 3

A higher caseload reduces the morbidity and mortality of cystectomy. 3
Radical cystectomy includes bilateral removal of regional lymph nodes. 3
There are data to support the idea that an extended LND (vs a standard or limited LND) improves survival after radical cystectomy. 3
Radical cystectomy in patients of both sexes must not include the removal of the entire urethra in all cases, which may then serve as an 3
outlet for an orthotopic bladder substitution. The terminal ileum and colon are the intestinal segments of choice for urinary diversion.
The type of urinary diversion does not affect the oncologic outcome. 3
Laparoscopic cystectomy and robot-assisted laparoscopic cystectomy are feasible but still investigational. 3
In patients >80 yr with MIBC, cystectomy is an option. 3
Surgical outcome is influenced by comorbidity, age, previous treatment of bladder cancer or other pelvic diseases, surgeon and hospital 2
cystectomy volumes, and type of urinary diversion.
Surgical complications of cystectomy and urinary diversion should be reported in a uniform grading system. Currently, the best-adapted grading 2
system for cystectomy is the Clavien grading system.
Recommendation GR

Radical cystectomy is recommended in T2–T4a, N0M0, and high-risk non–muscle-invasive bladder cancer (as outlined above). A*
Do not delay cystectomy >3 mo, since doing so increases the risk of progression and cancer-specific death. B
Bilateral LND should be an integral part of cystectomy. An extended LND is an option. B
The urethra can be preserved if margins are negative but must be checked regularly, especially in patients with heterotopic diversions. B
Laparoscopic cystectomy and robot-assisted laparoscopic cystectomy are management options. However, current data have not sufficiently C
proven the advantages or disadvantages for oncologic and functional outcomes of laparoscopic cystectomy and robot-assisted laparoscopic
cystectomy.
Before cystectomy, the patient should be fully informed about the benefits and potential risks of all possible alternatives, and the final B
decision should be based on a balanced discussion between patient and surgeon.
Preoperative bowel preparation is not mandatory. ‘‘Fast-track’’ measurements may reduce the time of bowel recovery. C
An orthotopic bladder substitute should be offered to male and female patients who lack any contraindications and who have no tumour B
in the urethra and at the level of the urethral dissection.
GR = grade of recommendation; LE = level of evidence; LND = lymph node dissection. MIBC = muscle-invasive bladder cancer.
*
Upgraded following European Association of Urology Working Panel consensus.

Table 12 – Conclusions and recommendations for nonresectable tumours and palliative care

Conclusion

Primary radical cystectomy in T4b bladder cancer is not a curative option.

If there are symptoms, radical cystectomy may be a therapeutic/palliative option.
Intestinal or nonintestinal forms of urinary diversion can be used with or without palliative cystectomy.

Recommendation LE GR

In patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is a palliative option and cannot be offered as 4 B
curative treatment.
In patients with symptoms, palliative cystectomy may be offered. 4 C
Prior to any further interventions, surgery-related morbidity and quality of life should be fully discussed with the patient. 3 B

GR = grade of recommendation; LE = level of evidence.

Table 13 – Conclusions and recommendations for preoperative radiotherapy

Conclusion LE

No data exist to support the idea that preoperative radiotherapy for operable MIBC increases survival. 2
Preoperative radiotherapy 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
Preoperative radiotherapy with a dose of 45–50 Gy in fractions of 1.8–2 Gy does not significantly increase toxicity after surgery. 3
There are suggestions in the older literature that preoperative radiotherapy decreases local recurrence of MIBC. 3

Recommendation GR

Preoperative radiotherapy is not recommended to improve survival. B

Preoperative radiotherapy for operable MIBC results in tumour downstaging after 4–6 wk. C

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

randomised trials. Results from retrospective studies show
tumour downstaging with a dose of 40–50 Gy, a lower risk
of local recurrence, and improved survival. Six randomised
trials investigating preoperative radiotherapy have been
published. In the trials in which downstaging was reported,
complete response rates were higher in the radiotherapy
arms, and a pathologic complete response was a prognostic
factor for improved survival. Local recurrence rates were
not addressed. Preoperative radiotherapy did not increase
surgical toxicity.
 EUROPEAN UROLOGY 65 (2014) 778–792 785

A meta-analysis of five of the six randomised trials on the
value of preoperative radiotherapy showed an odds ratio for
the difference in 5-yr survival of 0.71 (95% CI, 0.48–1.06)
[70]. However, the meta-analysis was potentially biased by
the largest trial, in which almost 50% of patients did not
receive the planned treatment [71]. When the results of this
trial were excluded, the odds ratio became 0.95 (95% CI,
0.57–1.55), indicating that improved survival had not been
proven [72]. The most recent report on preoperative
radiotherapy also showed downstaging to pT0 in 57%
versus 7%, with an increased progression-free survival (PFS)
in pT0 patients [73]. Again, this study was retrospective and
small (n = 187). Whether modern radiotherapy techniques
would improve these results remains to be studied, but to
date there is no role for preoperative radiotherapy in the
management of MIBC.
10. Bladder-sparing treatments for localised
disease
10.1. Transurethral resection of bladder tumour
Transurethral resection of the bladder (TURB) only could be
an alternative in patients unfit for surgery, patients with
limited invasive (T2) tumours, and patients with a negative
re-resection. A prospective study by Solsona et al. included
133 patients treated with radical TURB and negative
biopsies, for whom 15-yr follow-up was reported [74]. In
all, only 6.7% of the patients were understaged during the
initial TURB, 30% had recurrent NMIBC, and 30% progressed,
of whom 27 died of BCa. After 5, 10, and 15 yr, CSS was
81.9%, 79.5%, and 76.7%, and PFS with intact bladder was
75.5%, 64.9%, and 57.8%, respectively. These data are based
on a nonrandomised trial including highly selected patients.
10.2. External-beam radiotherapy monotherapy
The target dose for curative radiotherapy for BCa is
60–66 Gy, with a subsequent tumour boost. The use of
modern standard radiotherapy techniques results in major
morbidity of the urinary bladder or bowel in <5% of tumour-
free patients [75]. Prognostic factors for outcome include
tumour size, hydronephrosis, and a radical initial TURB.
Five-year survival rates in patients with MIBC range
between 30% and 60%, and CSS is between 20% and 50%,
which appears lower than after radical cystectomy, as
demonstrated by a Cochrane analysis based on available
trials [76]. Similar results were reported by Chung et al. in
340 patients with long-term follow-up [77]. The investi-
gators found a 10-yr disease-specific survival of 35%, which
was better after external-beam radiotherapy (EBRT) and
concurrent chemotherapy than after EBRT alone. EBRT is an
alternative for patients unfit for radical surgery (Table 14).
10.3. Chemotherapy
In older series, chemotherapy given as primary or neoad-
juvant therapy did result in downstaging and produced
complete responses. Response to chemotherapy has been
reported as a prognostic factor for treatment outcome and

Table 14 – Conclusions and recommendations for bladder-sparing treatments for localised disease

Recommendation for TURB only LE GR

TURB alone is not a curative treatment option in most patients. 2a B

Conclusion for EBRT LE

External-beam radiotherapy alone should be considered as a therapeutic option only when the patient is unfit for cystectomy or 3
a multimodality bladder-preserving approach.
Recommendation for EBRT GR

Surgical intervention or multimodality treatment are the preferred curative therapeutic approaches, since they are more effective B
than radiotherapy alone.
Conclusion for chemotherapy for MIBC LE

With cisplatin-based chemotherapy as the primary therapy for locally advanced tumours in highly selected patients, complete and 2b
partial local responses have been reported.
Recommendation for chemotherapy for MIBC GR

Chemotherapy alone is not recommended as primary therapy for localised bladder cancer. A

Conclusion for multimodality treatment in MIBC LE

In a highly selected patient population, long-term survival rates of multimodality treatment are comparable to the rates for early cystectomy. 3
Delay in surgical therapy can compromise survival rates. 2b

Recommendation for multimodality treatment in MIBC GR

Surgical intervention or multimodality treatment are the preferred curative therapeutic approaches, since these treatments are more B
effective than radiotherapy alone.
Multimodality treatment could be offered as an alternative in selected, well-informed, well-selected, and compliant patients, B
especially patients for whom cystectomy is not an option.
EBRT = external-beam radiotherapy; GR = grade of recommendation; LE = level of evidence; MIBC = muscle-invasive bladder cancer; TURB = transurethral
resection of the bladder.
786 EUROPEAN UROLOGY 65 (2014) 778–792
eventual survival [39] However, these data should be
interpreted with caution in the context of significant clinical
staging errors, the chemotherapy regimen used, and patient
selection, since contemporary series with gemcitabine/
cisplatin (GC) followed by radical cystectomy reported
inferior pT0 rates [78]. Therefore, chemotherapy alone
cannot be recommended for routine use (Table 14).
10.4. Multimodality bladder-preserving treatment
Multimodality strategies combine TURB, chemotherapy,
and irradiation, aiming for bladder preservation. Many
protocols use cisplatin, fluorouracil, and/or gemcitabine
with radiation therapy because of the established role of
chemotherapy as radiosensitisers. Cisplatin-based chemo-
therapy in combination with radiotherapy, following TURB,
results in a complete response rate of 60–80%. Many
different treatment protocols are available, and careful
patient selection is important. Like several smaller recent
series, a large recent study confirmed these results after a
mean follow-up of 42 mo [79]. Comparing TURB plus
radiochemotherapy (n = 331) with TURB plus radiotherapy
(n = 142), complete response was found to be high (70.4%).
However, the radiochemotherapy group had a clear survival
advantage (median survival: 70 mo vs 28.5 mo). Results
were dependent on stage at presentation, the presence of
lymphatic invasion, and the extent of the initial TURB.
Follow-up after bladder preservation should be meticulous.
Recurring patients usually show inferior outcomes. These
results suggest comparable long-term survival following
both multimodality bladder-preserving strategies and
cystectomy, although the two strategies have never been
directly compared, and patients in multimodality series are
highly selected.
11. Adjuvant chemotherapy
Advantages of chemotherapy after cystectomy include
the availability of accurate pathologic staging, which implies
that treatment can be reserved for high-risk patients
(extravesical and/or node-positive disease), and no delay
in local surgical treatment in patients not sensitive to
chemotherapy. Disadvantages are the absence of a measur-
able tumour and a delay of chemotherapy because of post-
operative morbidity. Data on adjuvant chemotherapy are
limited, with five published randomised trials with several
limitations and one meta-analysis with only 491 patients
[80]. In all, the data are not convincing enough to give an
unequivocal recommendation for the use of immediate
adjuvant chemotherapy as compared with chemotherapy
at the time of relapse (Table 15).
12. Metastatic disease (Table 16)
12.1. Standard first-line chemotherapy for fit patients
A worse outcome of chemotherapy in the first-line setting is
seen with a PS of 80% or the presence of visceral
metastases [81]. Additional prognostic factors are serum
Table 15 – Conclusions and recommendations for adjuvant
chemotherapy
Conclusion LE
Adjuvant chemotherapy is under debate. Neither randomised 1a
trials nor a meta-analysis has provided sufficient data to support
the routine use of adjuvant chemotherapy.
Recommendation GR
Adjuvant chemotherapy is advised within clinical trials but not A
as a routine therapeutic option.
GR = grade of recommendation; LE = level of evidence.
levels of alkaline phosphatase, number of disease sites [82],
and comorbidity [83]. Age itself has no impact on response
or toxic events [84].
No long-term disease-free survival has been reported
with single-agent chemotherapy. Therefore, cisplatin-
containing combination chemotherapy has been the stan-
dard of care since the late 1980s. Methotrexate, vinblastine,
doxorubicin (Adriamycin), and cisplatin (M-VAC) regimens
and GC regimens show prolonged median survival rates of
14.8 and 13.8 mo, respectively, as compared with cisplatin
monotherapy and cisplatin, cyclophosphamide, and Adria-
mycin [85,86]. Long-term survival results have confirmed
the anticipated noninferiority of M-VAC and GC [82], but
the lower toxicity of GC [86] has resulted in its becoming a
new standard regimen. High-dose-intensity M-VAC with
granulocyte colony-stimulating factors is less toxic and
more effective than standard M-VAC in terms of complete
response and 2-yr survival rate, but median survival is
similar [87]. The addition of paclitaxel to GC only showed a
trend to improved OS in a large randomised phase 3 trial
(15.8 vs 12.7 mo; hazard ratio: 0.85; p = 0.075), although
the response rate increased [88]. Noncisplatinum combi-
nation chemotherapy has not been compared with
standard cisplatin chemotherapy in randomised trials.
Although responses are reported, noncisplatinum combi-
nation chemotherapy is not recommended for first-line use
in patients who are fit enough for cisplatin. Finally,
although a few biomarkers have shown potential, none
has sufficient evidence to support its routine clinical use in
predicting response to chemotherapy.
12.2. Chemotherapy in patients unfit for cisplatin
More than 50% of patients are ineligible for cisplatin because
of a poor PS, impaired renal function, or comorbidities [89].
In these patients, carboplatin/gemcitabine was reported to be
more active (response rate: 42%) and less toxic compared
with methotrexate/carboplatin/vinblastine; however, OS
showed no difference [90]. Patients with PS 2 and impaired
renal function experienced limited benefit from combination
chemotherapy.
12.3. Second-line treatment
In case progression occurs 6–12 mo after first-line
cisplatin-based combination chemotherapy, a rechallenge
with a cisplatin combination is a reasonable strategy. Small
 EUROPEAN UROLOGY 65 (2014) 778–792 787

Table 16 – Conclusions and recommendations for metastatic disease

Conclusion 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, prognostic factors are liver metastasis, PS, and haemoglobin (<10 g/dl). 2
Cisplatin-containing combination chemotherapy can achieve median survival of 14 mo, with long-term disease-free survival 1b
reported in approximately 15% of 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 produced substantial responses in first- and second-line settings but has not been 2a
tested against standard chemotherapy in patients who are fit or unfit for treatment.
There is no defined standard chemotherapy for unfit patients with advanced or metastatic urothelial cancer. 2b
Vinflunine reached the highest level of evidence ever reported for second-line use. 1b
Postchemotherapy surgery after partial or complete response may contribute to long-term disease-free survival. 3
Zoledronic acid and denusomab have been approved for all cancer types, including urothelial cancer, because they reduce and 1
delay skeletal-related events in metastatic bone disease.
Recommendation GR

First-line treatment for fit patients

Use cisplatin-containing combination chemotherapy with GC, PCG, M-VAC, preferably with G-CSF, or HD M-VAC with G-CSF. A
Carboplatin and nonplatinum combination chemotherapy is not recommended. B
First-line treatment in patients ineligible (unfit) for cisplatin
Use carboplatin combination chemotherapy or single agents. C
For cisplatin-ineligible (unfit) patients, patients with PS 2 or impaired renal function, and patients with no or one poor Bajorin A
prognostic factor and impaired renal function, treatment with carboplatin-containing combination chemotherapy, preferably with
gemcitabine/carboplatin, is indicated.
Second-line treatment
In patients progressing after platinum-based combination chemotherapy for metastatic disease, vinflunine should be offered. A*
Alternatively, treatment within a clinical trial setting may be offered.
Zoledronic acid or denosumab is recommended for treatment of bone metastases. B
Recommendation for the use of biomarkers
Currently, no biomarkers can be recommended in daily clinical practice, because they have no impact on predicting outcome, A**
treatment decisions, or monitoring therapy in muscle-invasive bladder cancer.
GC = gemcitabine plus cisplatin; G-CSF = granulocyte colony-stimulating factor; GR = grade of recommendation; HD M-VAC = high-dose methotrexate,
vinblastine, doxorubicin (Adriamycin), and cisplatin; LE = level of evidence; M-VAC = methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin;
PCG = paclitaxel, cisplatin, and gemcitabine; PS = performance status.
*
Grade A recommendation is weakened by a problem of statistical significance.
**
Upgraded following panel consensus.

phase 2 trials have shown low response rates with several
drugs. Although gemcitabine has shown good response
rates in second-line use [91], most patients already received
this drug as part of their front-line treatment. A recent
randomised phase 3 trial compared vinflunine plus best
supportive care against best supportive care alone after
first-line platinum-containing treatment [92]. The results
showed a modest response rate (8.6%), a favourable safety
profile, and a survival benefit after vinflunine that was
statistically significant in the eligible patient population (not
in the intensity- to-treat population). Currently, vinflunine is
the only European Medicines Agency–approved agent in the
second-line setting.
A retrospective study of postchemotherapy surgery after
a partial or complete response has indicated that surgery
may contribute to long-term disease-free survival in
selected patients [93]. A flowchart for the management of
metastatic urothelial cancer is provided in Figure 1.
12.4. Treatment of bone metastases
Since the prevalence of bone metastases is 30–40% in
patients with muscle-invasive and metastatic BCa [94],
skeletal-related events should be anticipated. In this
respect, denosumab and zoledronic acid have been studied
and shown to be comparable in preventing or delaying
skeletal-related events, including those in patients with
urothelial carcinoma [95]. For both drugs, calcium and
vitamin D supplementation is recommended, and dose
adjustments according to preexisting medical conditions
for zoledronic acid are recommended.
13. Quality of life
Several questionnaires have been validated for assessing
health-related QoL (HRQoL) in BCa patients [96]. However,
most studies do not evaluate the association between
HRQoL and BCa-specific issues after cystectomy, such as
daytime and nighttime incontinence or potency. Impor-
tant covariables, such as a patient’s age, mental status,
coping ability, and gender, have rarely been considered
[97].
There remains controversy about which type of urinary
diversion is best for a patient’s HRQoL [96]. Some studies
have not demonstrated any difference in HRQoL [97],
although more recent studies are supportive of continent
reconstructions and neobladders, possibly because of
improved surgical techniques [98,99]. Patients with a
neobladder report better body image, social activity, and
physical functioning [100]. Finally, there is a relationship
between HRQoL and OS [101]. Conclusions and recommen-
dations for HRQoL are listed in Table 17.
788 EUROPEAN UROLOGY 65 (2014) 778–792
[(Fig._1)TD$IG]

Fig. 1 – Flowchart for the management of metastatic urothelial cancer.

BSC = best supportive care; carbo = carboplatin; comb. chemo = combination chemotherapy; GC = gemcitabine plus cisplatin; GFR = glomular filtration
rate; HD = high-dose; M-VAC = methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin; PS = performance status.

Table 17 – Conclusions and recommendations for health-related quality of life

Conclusion LE

No randomised, prospective HRQoL study has evaluated the different forms of definitive treatment of MIBC.
In most patient groups studied, the overall HRQoL after cystectomy remains good, irrespective of the type of urinary diversion used. 2b
The suggestion that continent diversions are associated with a higher HRQoL has not been sufficiently substantiated.
Important determinants of (subjective) QoL are a patient’s personality, coping style, and social support.

Recommendation GR

The use of validated questionnaires is recommended to assess HRQoL in patients with MIBC. B
Unless a patient’s comorbidities, tumour variables, and coping abilities present clear contraindications, a continent urinary C
diversion should be offered.
Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones C
for achieving good long-term results.
Patients should be encouraged to take active part in the decision-making process. Clear and exhaustive information on all potential C
benefits and side effects should be provided, allowing patients to make informed decisions.
GR = grade of recommendation; HRQoL = health-related quality of life; LE = level of evidence; MIBC = muscle-invasive bladder cancer; QoL = quality of life.

14. Follow-up addresses functional deterioration at particular sites

[102].
Oncologic follow-up should address probability, timing, Pelvic recurrence typically occurs in 5–15% of patients
and possible treatment of a recurrence. General follow-up 6–18 mo after surgery, with higher stage as the most
 EUROPEAN UROLOGY 65 (2014) 778–792
important risk factor. Treatment possibilities are limited
and predominantly palliative, and prognosis is poor.
Distant recurrence occurs in 50% of patients, usually in
24 mo and, again, depending on the initial stage [103,104].
The most likely sites are the lungs, liver, and bones.
Treatment usually comprises systemic chemotherapy.
Upper urinary tract recurrence is rarely seen and usually
presents late (28–49 mo after cystectomy) [105].
Secondary urethral tumours are rare, occurring 1–3 yr
after cystectomy. Prognosis is poor. The risk of urethral
recurrence is lower after orthotopic diversion than after
nonorthotopic diversion. Although there is no consensus on
the best method of urethral follow-up, urethral wash
cytology can detect recurrence. There is a significant
survival advantage for males with asymptomatic compared
with symptomatic urethral recurrence. [105]. Treatment of
secondary upper tract or urethral tumours depends on stage
at presentation. Radical nephroureterectomy and ureter-
ectomy provide curative treatment options for patients
with nonmetastatic disease.
Functional complications related to urinary diversion are
seen in 45% of patients during the first 5 yr of follow-up and
in 54% of patients after 15 yr of follow-up. Thus, long-term
follow-up of functional outcome is mandatory [105].
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, Compérat, Cowan, Gakis, Lebret, Ribal,
De Santis, Sherif, Van der Heijden.
Acquisition of data: Witjes, Compérat, Cowan, Gakis, Lebret, Ribal,
De Santis, Sherif, Van der Heijden.
Analysis and interpretation of data: Witjes, Compérat, Cowan, Gakis,
Lebret, Ribal, De Santis, Sherif, Van der Heijden.
Drafting of the manuscript: Witjes.
Critical revision of the manuscript for important intellectual content: Witjes,
Compérat, Cowan, Gakis, Lebret, Ribal, De Santis, Sherif, Van der Heijden.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Witjes.
Other (specify): 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: J. Alfred Witjes
participated in trials for Photocure Oslo in 2010, Telormedix in 2012, and
MEL Amsterdam in 2011; was a company consultant for Astellas in 2010,
Endo Pharm in 2010, Telormedix in 2012, GE Healthcare in 2011, Sanofi
Pasteur in 2012, Ipsen in 2012, and Allergan in 2012; and received
company speaker honoraria from Ipsen in 2012, MEL Amsterdam in
2011, GE Healthcare in 2011, and Photocure in 2010. Maria De Santis
participated in trials for Exelixis, Dendreon, Pierre-Fabre, and Millenni-
um; has been a company consultant for Janssen, Pfizer, Teva, Dendreon,
Amgen, Roche, Pierre-Fabre, Novartis, Bayer, and Glaxo Smith Kline;
received fellowships and travel grants from Roche, Sanofi Aventis,
Amgen, Pfizer, Novartis, and Bayer; received research grants from Pierre-
Fabre; and received company speaker honoraria from Eli Lilly, Pfizer,
789
Janssen, Roche, Novartis, and Sanofi Aventis. Georgios Gakis received a
company speaker honorarium from, and has been a company consultant
to, Ipsen. Thierry Lebret has been a company consultant to Amgen, Ipsen,
Novartis, and Sanofi; has participated in trials for Takeda and Astellas;
and has received a company speaker honorarium from Ferring. Maria J.
Ribal has received company speaker honoraria from Astellas, Pierre-Fabre,
Ipsen, Olympus, and Jansen Pharmaceuticals and has been a company
consultant for Jansen Pharmaceuticals. Amir Sherif has received company
speaker honoraria from MEDAC AB and Orion Pharma.
Funding/Support and role of the sponsor: None.
References
[1] Stenzl A, Cowan NC, De Santis M, et al. Treatment of muscle-
invasive and metastatic bladder cancer: update of the EAU guide-
lines. Eur Urol 2011;59:1009–18.
[2] Witjes JA, Compérat E, Cowan C, et al. members of the EAU
Guidelines Panel on Muscle-invasive and Metastatic Bladder Can-
cer. Guidelines on muscle-invasive and metastatic bladder cancer.
Presented at: EAU Annual Congress 2013; March 15–19, 2013;
Milan, Italy.
[3] Ploeg M, Aben KK, Kiemeney LA. The present and future burden of
urinary bladder cancer in the world. World J Urol 2009;27:289–93.
[4] Freedman ND, Silverman DT, Hollenbeck AR, et al. Association
between smoking and risk of bladder cancer among men and
women. JAMA 2011;306:737–45.
[5] Gandini S, Botteri E, Iodice S, et al. Tobacco smoking and cancer: a
meta-analysis. Int J Cancer 2008;122:155–64.
[6] Brennan P, Bogillot O, Cordier S, et al. Cigarette smoking and
bladder cancer in men: a pooled analysis of 11 case-control
studies. Int J Cancer 2000;86:289–94.
[7] Pashos CL, Botteman MF, Laskin BL, et al. Bladder cancer: epide-
miology, diagnosis, and management. Cancer Pract 2002;10:
311–22.
[8] Harling M, Schablon A, Schedlbauer G, et al. Bladder cancer among
hairdressers: a meta-analysis. Occup Environ Med 2010;67:351–8.
[9] Kogevinas M, t’Mannetje A, Cordier S, et al. Occupation and
bladder cancer among men in Western Europe. Cancer Causes
Control 2003;14:907–14.
[10] Nieder AM, Porter MP, Soloway MS. Radiation therapy for prostate
cancer increases subsequent risk of bladder and rectal cancer: a
population based cohort study. J Urol 2008;180:2005–9, discus-
sion 2009–10.
[11] Zelefsky MJ, Housman DM, Pei X, et al. Incidence of secondary
cancer development after high-dose intensity-modulated radio-
therapy and image-guided brachytherapy for the treatment of
localized prostate cancer. Int J Radiat Oncol Biol Phys 2012;
83:953–9.
[12] Vaidya A, Soloway MS, Hawke C, et al. De novo muscle invasive
bladder cancer: is there a change in trend? J Urol 2001;165:47–50.
[13] May M, Stief C, Brookman-May S, et al. Gender-dependent cancer-
specific survival following radical cystectomy. World J Urol
2012;30:707–13.
[14] Sobin LH, Gospodariwicz M, Wittekind C, editors. TNM classifica-
tion of malignant tumors. ed. 7. Hoboken, NJ: Wiley-Blackwell;
2009. p. 262–5.
[15] Sauter G, Algaba F, Amin M, et al. Tumours of the urinary system:
non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein Jl,
Sesterhenn I, editors. WHO classification of tumors of the urinary
system and male genital organs. Lyon, France: IARC Press; 2004.
p. 29–34.
[16] Hansel DE, Amin MB, Comperat E, et al. A contemporary update on
pathology standards for bladder cancer: transurethral resection
and radical cystectomy specimens. Eur Urol 2013;63:321–32.
790 EUROPEAN UROLOGY 65 (2014) 778–792
[17] Baltaci S, Adsan O, Ugurlu O, et al. Reliability of frozen section
examination of obturator lymph nodes and impact on lymph node
dissection borders during radical cystectomy: results of a pro-
spective multicentre study by the Turkish Society of Urooncology.
BJU Int 2011;107:547–53.
[18] Yu RJ, Stein JP, Cai J, et al. Superficial (pT2a) and deep (pT2b)
muscle invasion in pathological staging of bladder cancer follow-
ing radical cystectomy. J Urol 2006;176:493–8, discussion 498–9.
[19] Tilki D, Reich O, Karakiewicz PI, et al. Validation of the AJCC TNM
substaging of pT2 bladder cancer: deep muscle invasion is associ-
ated with significantly worse outcome. Eur Urol 2010;58:112–7.
[20] Gakis G, Schilling D, Renninger M, et al. Comparison of the new
American Joint Committee on Cancer substratification in node-
negative pT2 urothelial carcinoma of the bladder: analysis of
patient outcomes in a contemporary series. BJU Int 2011;107:
919–23.
[21] Mitra AP, Skinner EC, Miranda G, et al. A precystectomy decision
model to predict pathological upstaging and oncological outcomes
in clinical stage T2 bladder cancer. BJU Int 2013;111:240–8.
[22] Ploeg M, Kiemeney LA, Smits GA, et al. Discrepancy between
clinical staging through bimanual palpation and pathological
staging after cystectomy. Urol Oncol 2012;30:247–51.
[23] Mungan MU, Canda AE, Tuzel E, et al. Risk factors for mucosal
prostatic urethral involvement in superficial transitional cell car-
cinoma of the bladder. Eur Urol 2005;48:760–3.
[24] Kassouf W, Spiess PE, Brown GA, et al. Prostatic urethral biopsy has
limited usefulness in counselling patients regarding final urethral
margin status during orthotopic neobladder reconstruction. J Urol
2008;180:164–7, discussion 167.
[25] Gakis G, Schilling D, Bedke J, et al. Incidental prostate cancer at
radical cystoprostatectomy: implications for apex-sparing sur-
gery. BJU Int 2010;105:468–71.
[26] Rajesh A, Sokhi HK, Fung R, et al. Bladder cancer: evaluation of
staging accuracy using dynamic MRI. Clin Radiol 2011;66:1140–5.
[27] Yoshida S, Koga F, Kobayashi S, et al. Role of diffusion-weighted
magnetic resonance imaging in predicting sensitivity to chemor-
adiotherapy in muscle-invasive bladder cancer. Int J Radiat Oncol
Biol Phys 2012;83:e21–7.
[28] Cowan NC. CT urography for hematuria. Nat Rev Urol 2012;9:
218–26.
[29] Mertens LS, Fioole-Bruining A, Vegt E, et al. Impact of (18)
F-fluorodeoxyglucose (FDG)-positron-emission tomography/
computed tomography (PET/CT) on management of patients with
carcinoma invading bladder muscle. BJU Int 2013;112:729–34.
[30] Babjuk M, Oosterlinck W, Sylvester R, et al., members of the EAU
Guidelines Panel on Non-muscle Invasive Bladder Cancer. Guide-
lines on non-muscle-invasive bladder cancer (TaT1 and CIS).
Presented at: EAU Annual Congress 2013; March 15–19, 2013;
Milan, Italy.
[31] Malmström PU, Sylvester RJ, Crawford DE, et al. An individual
patient data meta-analysis of the longterm outcome of random-
ised studies comparing intravesical mitomycin C versus bacillus
Calmette-Guérin for non-muscle-invasive bladder cancer. Eur
Urol 2009;56:247–56.
[32] Duchek M, Johansson R, Jahnson S, et al., members of the Urothe-
lial Cancer Group of the Nordic Association of Urology. Bacillus
Calmette-Guérin is superior to a combination of epirubicin and
interferon-alpha2b in the intravesical treatment of patients with
stage T1 urinary bladder cancer: a prospective, randomized, Nor-
dic study. Eur Urol 2010;57:25–31.
[33] van den Bosch S, Witjes AJ. Long-term cancer-specific survival
in patients with high-risk, non-muscle-invasive bladder cancer
and tumour progression: a systematic review. Eur Urol 2011;60:
493–500.
[34] Brake M, Loertzer H, Horsch R, et al. Recurrence and progression
of stage T1, grade 3 transitional cell carcinoma of the bladder
following intravesical immunotherapy with bacillus Calmette-
Guerin. J Urol 2000;163:1697–701.
[35] Pansadoro V, Emiliozzi P, Defidio L, et al. Bacillus Calmette-Guerin
in the treatment of stage T1 grade 3 transitional cell carcinoma of
the bladder: long-term results. J Urol 1995;154:2054–8.
[36] Stein JP, Skinner DG. Radical cystectomy for invasive bladder
cancer: long-term results of a standard procedure. World J Urol
2006;24:296–304.
[37] Rosenblatt R, Sherif A, Rintala E, et al. Pathologic downstaging is a
surrogate marker for efficacy and increased survival following
neoadjuvant chemotherapy and radical cystectomy for muscle-
invasive urothelial bladder cancer. Eur Urol 2012;61:1229–38.
[38] Nishimura K, Fujiyama C, Nakashima K, et al. The effects of
neoadjuvant chemotherapy and chemo-radiation therapy on
MRI staging in invasive bladder cancer: comparative study based
on the pathological examination of whole layer bladder wall. Int
Urol Nephrol 2009;41:869–75.
[39] Sternberg CN, Pansadoro V, Calabrò F, et al. Can patient selection
for bladder preservation be based on response to chemotherapy?
Cancer 2003;97:1644–52.
[40] Sherif A, Holmberg L, Rintala E, et al., Nordic Urothelial Cancer
Group. Neoadjuvant cisplatinum based combination chemother-
apy in patients with invasive bladder cancer: a combined analysis
of two Nordic studies. Eur Urol 2004;45:297–303.
[41] Advanced Bladder Cancer Meta-analysis Collaboration. Neoadju-
vant chemotherapy in invasive bladder cancer: a systematic re-
view and meta-analysis. Lancet 2003;361:1927–34.
[42] Winquist E, Kirchner TS, Segal R, et al., Genitourinary Cancer
Disease Site Group, Cancer Care Ontario Program in Evidence-
based Care Practice Guidelines Initiative. Neoadjuvant chemo-
therapy for transitional cell carcinoma of the bladder: a systematic
review and meta-analysis. J Urol 2004;171:561–9.
[43] Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.
Neoadjuvant chemotherapy in invasive bladder cancer: update
of a systematic review and meta-analysis of individual patient
data. Eur Urol 2005;48:202–6, discussion 205–6.
[44] International Collaboration of Trialists; Medical Research Council
Advanced Bladder Cancer Working Party (now the National Cancer
Research Institute Bladder Cancer Clinical Studies Group);
European Organisation for Research and Treatment of Cancer
Genito-Urinary Tract Cancer Group; Australian Bladder Cancer
Study Group; National Cancer Institute of Canada Clinical Trials
Group; Finnbladder; Norwegian Bladder Cancer Study Group;
Club Urologico Espanol de Tratamiento Oncologico Group; Griffiths
G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase
III trial assessing neoadjuvant cisplatin, methotrexate, and vinblas-
tine chemotherapy for muscle-invasive bladder cancer: long-term
results of the BA06 30894 trial. J Clin Oncol 2011;29:2171–7.
[45] Bolenz C, Ho R, Nuss GR, et al. Management of elderly patients
with urothelial carcinoma of the bladder: guideline concordance
and predictors of overall survival. BJU Int 2010;106:1324–9.
[46] Lughezzani G, Sun M, Shariat SF, et al. A population-based
competing-risks analysis of the survival of patients treated
with radical cystectomy for bladder cancer. Cancer 2011;117:
103–9.
[47] Mayr R, May M, Martini T, et al. Predictive capacity of four
comorbidity indices estimating perioperative mortality after rad-
ical cystectomy for urothelial carcinoma of the bladder. BJU Int
2012;110:E222–7.
[48] Morgan TM, Keegan KA, Barocas DA, et al. Predicting the proba-
bility of 90-day survival of elderly patients with bladder cancer
treated with radical cystectomy. J Urol 2011;186:829–34.
 EUROPEAN UROLOGY 65 (2014) 778–792
[49] Abdollah F, Sun M, Schmitges J, et al. Development and validation
of a reference table for prediction of postoperative mortality rate
in patients treated with radical cystectomy: a population-based
study. Ann Surg Oncol 2012;19:309–17.
[50] Mayr R, May M, Martini T, et al. Comorbidity and performance
indices as predictors of cancer-independent mortality but not of
cancer-specific mortality after radical cystectomy for urothelial
carcinoma of the bladder. Eur Urol 2012;62:662–70.
[51] Malavaud B, Vaessen C, Mouzin M, et al. Complications for radical
cystectomy impact of the American Society of Anesthesiologists
score. Eur Urol 2001;39:79–84.
[52] Chang SS, Hassan JM, Cookson MS, et al. Delaying radical cystec-
tomy for muscle invasive bladder cancer results in worse patho-
logical stage. J Urol 2003;170:1085–7.
[53] Sánchez-Ortiz RF, Huang WC, Mick R, et al. An interval longer than
12 weeks between the diagnosis of muscle invasion and cystec-
tomy is associated with worse outcome in bladder carcinoma.
J Urol 2003;169:110–5, discussion 115.
[54] Jensen JB, Ulhøi BP, Jensen KM. Lymph node mapping in patients
with bladder cancer undergoing radical cystectomy and lymph
node dissection to the level of the inferior mesenteric artery. BJU
Int 2010;106:199–205.
[55] Zlotta AR. Limited, extended, superextended, megaextended pel-
vic lymph node dissection at the time of radical cystectomy: what
should we perform? Eur Urol 2012;61:243–4.
[56] Bruins M, Veskimae E, Hernandez V, et al. Systematic review of
role and extent of lymphadenectomy during radical cystectomy
for cN0M0 muscle invasive bladder cancer: methods protocol.
EAU MIBC Guideline 2013 update. http://www.uroweb.org/gls/
refs/Systematic_methodology_Bladder_Cancer_2013_update.pdf.
[57] Karl A, Carroll PR, Gschwend JE, et al. The impact of lymphadenec-
tomy and lymph node metastasis on the outcomes of radical
cystectomy for bladder cancer. Eur Urol 2009;55:826–35.
[58] Svatek R, Zehnder P. Role and extent of lymphadenectomy during
radical cystectomy for invasive bladder cancer. Curr Urol Rep
2012;13:115–21.
[59] Figueroa AJ, Stein JP, Dickinson M, et al. Radical cystectomy for
elderly patients with bladder carcinoma: an updated experience
with 404 patients. Cancer 1998;83:141–7.
[60] Hautmann RE, de Petriconi RC, Volkmer BG. Lessons learned from
1,000 neobladders: the 90-day complication rate. J Urol 2010;184:
990–4, quiz 1235.
[61] Kilciler M, Bedir S, Erdemir F, et al. Comparison of ileal conduit and
transureteroureterostomy with ureterocutaneostomy urinary di-
version. Urol Int 2006;77:245–50.
[62] Pycha A, Comploj E, Martini T, et al. Comparison of complications
in three incontinent urinary diversions. Eur Urol 2008;54:825–34.
[63] Wiesner C, Bonfig R, Stein R, et al. Continent cutaneous urinary
diversion: long-term follow-up of more than 800 patients with
ileocecal reservoirs. World J Urol 2006;24:315–8.
[64] Hautmann RE, de Petriconi RC, Volkmer BG. 25 years of experience
with 1,000 neobladders: long-term complications. J Urol 2011;185:
2207–12.
[65] Hautmann RE, Volkmer BG, Schumacher MC, et al. Long-term
results of standard procedures in urology: the ileal neobladder.
World J Urol 2006;24:305–14.
[66] Porter MP, Penson DF. Health related quality of life after radical
cystectomy and urinary diversion for bladder cancer: a systematic
review and critical analysis of the literature. J Urol 2005;173:
1318–22.
[67] Eastham JA. Do high-volume hospitals and surgeons provide
better care in urologic oncology? Urol Oncol 2009;27:417–21.
[68] Ok JH, Meyers FJ, Evans CP. Medical and surgical palliative care of
patients with urological malignancies. J Urol 2005;174:1177–82.
791
[69] Goel AK, Rao MS, Bhagwat AG, et al. Intravesical irrigation with
alum for the control of massive bladder hemorrhage. J Urol
1985;133:956–7.
[70] Huncharek M, Muscat J, Geschwind JF. Planned preoperative
radiation therapy in muscle invasive bladder cancer; results of
a meta-analysis. Anticancer Res 1998;18:1931–4.
[71] Slack NH, Bross ID, Prout GR. Five-year follow-up results of a
collaborative study of therapies for carcinoma of the bladder.
J Surg Oncol 1977;9:393–405.
[72] Widmark A, Flodgren P, Damber JE, et al. A systematic overview of
radiation therapy effects in urinary bladder cancer. Acta Oncol
2003;42:567–81.
[73] Granfors T, Tomic R, Ljungberg B. Downstaging and survival
benefits of neoadjuvant radiotherapy before cystectomy for
patients with invasive bladder carcinoma. Scand J Urol Nephrol
2009;43:293–9.
[74] Solsona E, Iborra I, Collado A, et al. Feasibility of radical trans-
urethral resection as monotherapy for selected patients with
muscle invasive bladder cancer. J Urol 2010;184:475–80.
[75] Milosevic M, Gospodarowicz M, Zietman A, et al. Radiotherapy for
bladder cancer. Urology 2007;69(Suppl):80–92.
[76] Shelley MD, Barber J, Wilt T, et al. Surgery versus radiotherapy for
muscle invasive bladder cancer. Cochrane Database Syst Rev 2002:
CD002079.
[77] Chung PW, Bristow RG, Milosevic MF, et al. Long-term outcome of
radiation-based conservation therapy for invasive bladder cancer.
Urol Oncol 2007;25:303–9.
[78] Weight CJ, Garcia JA, Hansel DE, et al. Lack of pathologic down-
staging with neoadjuvant chemotherapy for muscle-invasive
urothelial carcinoma of the bladder: a contemporary series. Can-
cer 2009;115:792–9.
[79] Krause FS, Walter B, Ott OJ, et al. 15-year survival rates after
transurethral resection and radiochemotherapy or radiation in
bladder cancer treatment. Anticancer Res 2011;31:985–90.
[80] Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.
Adjuvant chemotherapy in invasive bladder cancer: a systematic
review and meta-analysis of individual patient data. Eur Urol
2005;48:189–201, discussion 199–201.
[81] Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in
metastatic transitional-cell carcinoma and prognostic factors pre-
dicting outcome of therapy. J Clin Oncol 1999;17:3173–81.
[82] von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival
results of a randomized trial comparing gemcitabine plus cisplat-
in, with methotrexate, vinblastine, doxorubicin, plus cisplatin in
patients with bladder cancer. J Clin Oncol 2005;23:4602–8.
[83] Pal SK, Hurria A. Impact of age, sex, and comorbidity on cancer
therapy and disease progression. J Clin Oncol 2010;28:4086–93.
[84] Bamias A, Efstathiou E, Moulopoulos LA, et al. The outcome of
elderly patients with advanced urothelial carcinoma after platinum-
based combination chemotherapy. Ann Oncol 2005;16:307–13.
[85] Sternberg CN, Yagoda A, Scher HI, et al. Methotrexate, vinblastine,
doxorubicin, and cisplatin for advanced transitional cell carcino-
ma of the urothelium: efficacy and patterns of response and
relapse. Cancer 1989;64:2448–58.
[86] von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and
cisplatin versus methotrexate, vinblastine, doxorubicin, and cis-
platin in advanced or metastatic bladder cancer: results of a large,
randomized, multinational, multicenter, phase III study. J Clin
Oncol 2000;18:3068–77.
[87] Sternberg CN, de Mulder P, Schornagel JH, et al., EORTC Genito-
Urinary Cancer Group. Seven year update of an EORTC phase III
trial of high-dose intensity M-VAC chemotherapy and G-CSF
versus classic M-VAC in advanced urothelial tract tumours.
Eur J Cancer 2006;42:50–4.
792 EUROPEAN UROLOGY 65 (2014) 778–792
[88] Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III
study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/
cisplatin in patients with locally advanced or metastatic urothelial
cancer without prior systemic therapy: EORTC Intergroup Study
30987. J Clin Oncol 2012;30:1107–13.
[89] Dash A, Galsky MD, Vickers AJ, et al. Impact of renal impairment on
eligibility for adjuvant cisplatin-based chemotherapy in patients
with urothelial carcinoma of the bladder. Cancer 2006;107:
506–13.
[90] De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial
assessing gemcitabine/carboplatin and methotrexate/carboplatin/
vinblastine in patients with advanced urothelial cancer who are
unfit for cisplatin-based chemotherapy: EORTC Study 30986. J Clin
Oncol 2012;30:191–9.
[91] Albers P, Siener R, Härtlein M, et al., German TCC Study Group of
the German Association of Urologic Oncology. Gemcitabine mono-
therapy as second-line treatment in cisplatin-refractory transi-
tional cell carcinoma—prognostic factors for response and
improvement of quality of life. Onkologie 2002;25:47–52.
[92] Bellmunt J, Théodore C, Demkov T, et al. Phase III trial of vinflunine
plus best supportive care compared with best supportive care
alone after a platinum-containing regimen in patients with ad-
vanced transitional cell carcinoma of the urothelial tract. J Clin
Oncol 2009;27:4454–61.
[93] Siefker-Radtke AO, Walsh GL, Pisters LL, et al. Is there a role for
surgery in the management of metastatic urothelial cancer? The
M. D. Anderson experience. J Urol 2004;171:145–8.
[94] Coleman RE. Metastatic bone disease: clinical features, patho-
physiology and treatment strategies. Cancer Treat Rev 2001;27:
165–76.
[95] Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind
study of denosumab versus zoledronic acid in the treatment of
bone metastases in patients with advanced cancer (excluding
breast and prostate cancer) or multiple myeloma. J Clin Oncol
2011;29:1125–32.
[96] World Health Organization (WHO) Consensus Conference on
Bladder Cancer. Hautmann RE, Abol-Enein H, Hafez K, et al. Uri-
nary diversion. Urology 2007;69(Suppl):17–49.
[97] Autorino R, Quarto G, Di Lorenzo G, et al. Health related quality of
life after radical cystectomy: comparison of ileal conduit to conti-
nent orthotopic neobladder. Eur J Surg Oncol 2009;35:858–64.
[98] Stenzl A, Sherif H, Kuczyk M. Radical cystectomy with orthotopic
neobladder for invasive bladder cancer: a critical analysis of long
term oncological, functional and quality of life results. Int Braz J
Urol 2010;36:537–47.
[99] Philip J, Manikandan R, Venugopal S, et al. Orthotopic neobladder
versus ileal conduit urinary diversion after cystectomy—a quality-
of-life based comparison. Ann R Coll Surg Engl 2009;91:565–9.
[100] Hedgepeth RC, Gilbert SM, He C, et al. Body image and bladder
cancer specific quality of life in patients with ileal conduit and
neobladder urinary diversions. Urology 2010;76:671–5.
[101] Roychowdhury DF, Hayden A, Liepa AM. Health-related quality-
of-life parameters as independent prognostic factors in advanced
or metastatic bladder cancer. J Clin Oncol 2003;21:673–8.
[102] Malkowicz SB, van Poppel H, Mickisch G, et al. Muscle-invasive
urothelial carcinoma of the bladder. Urology 2007;69(Suppl):
3–16.
[103] Mathers MJ, Zumbe J, Wyler S, et al. Is there evidence for a
multidisciplinary follow-up after urological cancer? an evaluation
of subsequent cancers. World J Urol 2008;26:251–6.
[104] Ghoneim MA, Abdel-Latif M, el-Mekresh M, et al. Radical cystec-
tomy for carcinoma of the bladder: 2,720 consecutive cases
5 years later. J Urol 2008;180:121–7.
[105] Soukup V, Babjuk M, Bellmunt J, et al. Follow-up after surgical
treatment of bladder cancer: a critical analysis of the literature.
Eur Urol 2012;62:290–302.