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Muscle-invasive and Metastatic Bladder Cancer

1.INTRODUCTION

1.1.Aims and scope

The European Association of Urology (EAU) Guidelines Panel for Muscle-invasive and Metastatic Bladder Cancer (MIBC) have prepared these guidelines to help urologists assess the evidence-based management of MIBC and to incorporate guideline recommendations into their clinical practice.

Separate EAU guidelines documents are available addressing upper urinary tract tumours [1], non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) [2], and primary urethral carcinomas [3].

It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2.Panel Composition

The EAU Guidelines Panel consists of an international multidisciplinary group of clinicians, including urologists, a pathologist, a radiologist and an oncologist.

All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/bladder-cancermuscle-invasive-and-metastatic/?type=panel.

1.3.Available publications

A quick reference document (Pocket Guidelines) is available, both in print and in a number of versions for mobile devices. These are abridged versions which may require consultation together with the full text version.

Several scientific publications are available (the most recent paper dating back to 2016 [4]), as are a number of translations of all versions of the EAU MIBC Guidelines. All documents are accessible through the EAU website: http://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.

1.4.Publication history and summary of changes

1.4.1.Publication history

The EAU published its first guidelines on bladder cancer in 2000. This document covered both superficial (non-muscle-invasive) bladder cancer and MIBC. Since these conditions require different treatment strategies, it was decided to give each condition its own guidelines, resulting in the first publication of the MIBC Guidelines in 2004. This 2017 document presents a limited update of the 2016 version.

1.4.2.Summary of changes

New relevant references have been identified through a structured assessment of the literature and incorporated in the various chapters of the 2017 EAU NMIBC Guidelines.

Key changes in the 2017 print are:

Section 3.2.6 Gender - This section has been expanded with additional data.

Section 5.1.4 Urinary cytology and urinary markers - This section has been expanded with additional data.

Section 6.2.4 Prognostic markers - A new section has been included.

Section 7.4.4.1 Preparations for surgery - A new section on pain management has been included as well as additional data on estimated glomerular filtration rate.

Section 7.4.4.2.1 Ureterocutaneostomy - This section has been expanded with additional data.

Table 7.6 Management of neobladder morbidity - Additional information has been added.

Section 7.8.10 Role of immunotherapy - This is a new section.

1.4.2.1.Change in summary of evidence

7.8.11 Summary of evidence and recommendations for metastatic disease

7.8.11 Summary of evidence for metastatic disease	LE
PD-L1 inhibitor atezolizumab has been FDA approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase-II trial.	2a

7.DISEASE MANAGEMENT

7.1.Treatment failure of non-muscle invasive bladder cancer

7.1.1.High-risk non-muscle-invasive urothelial carcinoma

The recurrence and progression rate of non-muscle invasive BC (NMIBC) strongly correlates with the factors as described in the European Organisation for Research and Treatment of Cancer (EORTC) risk calculator [168]. According to this calculator, the risk of progression after five years is 45% for high-risk tumours. In 2015, however, the EORTC group presented new nomograms based on two large phase III trials with a median follow up of 7.4 years. With one to three years of maintenance bacillus Calmette-Guérin (BCG), the risk for progression at five years was much lower: 19.3% for T1G3 tumours [169].

Meta-analyses have demonstrated that BCG-therapy prevents the risk of tumour recurrence [170] and the risk of tumour progression [171,172] but so far, no significant overall- or disease-specific survival advantages have been shown, as compared to no intravesical therapy [171-173]. The EAU NMIBC Guidelines present data supporting cystectomy in selected patients with NMIBC.

Large cystectomy series show a risk of an understaging error in TaT1 tumours of 35-62%. This may be caused by the presence of persisting or recurrent tumours due to omission of a second TURB or re-TURB, and the absence of neoadjuvant therapy [174-176]. Second TURB identifies upstaging to > T2 tumours in 10-20% of patients [177,178].

Progression to MIBC significantly decreases CSS. In a review of nineteen trials including 3,088 patients, CSS after progression from NMIBC to MIBC was 35%, which is significantly worse compared to patients with MIBC without a history of NMIBC. This underlines the need to recommend early radical treatment, such as RC, in case of intravesical therapy failure [2,179,180].

According to the EAU NMIBC Guidelines, it is reasonable to propose immediate RC to patients with non-muscle-invasive tumour who are at highest risk of progression [168,181-183]. Risk factors are any of the following:

T1 tumours;
high-grade/G3 tumours;
CIS;
multiple and recurrent and large (> 3 cm) Ta G1G2 tumours (all conditions must be presented in this point).

Subgroup of highest-risk tumours:

T1G3/high-grade associated with concurrent bladder CIS;
multiple and/or largeT1G3/HG and/or recurrent T1G3/high-grade;
T1G3/high-grade with CIS in the prostatic urethra;
unusual histology of urothelial carcinoma;
lymphovascular invasion;
BCG failures.

Although the percentage of patients with primary TaT1 tumours and the indication for cystectomy in TaT1 tumours is not specified in large cystectomy series, the ten-year recurrence-free survival rate is 80% and similar to that of TURB and BCG maintenance therapy [2,175,184,185] (LE: 3).

Radical cystectomy is also strongly recommended in patients with BCG-refractory tumours, defined in the NMIBC guideline as:

whenever muscle-invasive tumour is detected during follow-up;
if high-grade, non-muscle-invasive papillary tumour is present at three months;
if CIS (without concomitant papillary tumour) is present at both three and six months;
if high-grade tumour appears during BCG therapy [186];
high-grade recurrence after BCG (recurrence of high-grade/grade 3 [WHO 1973/2004] tumour after completion of BCG maintenance, despite an initial response).

Patients with disease recurrence within two years of initial TURB plus BCG therapy have a better outcome than patients who already have muscle-invasive disease, indicating that cystectomy should be performed at first recurrence, even in non-muscle-invasive disease [187] (LE: 3; GR: C).

There are now several bladder-preservation strategies available; immunotherapy, chemotherapy, device-assisted therapy, and combination therapy [188]. However, experience is limited and treatments other than RC must be considered oncologically inferior at the present time [188].

7.1.2.Recommendations for treatment failure of non-muscle-invasive bladder cancer

Recommendations	GR
Consider immediate radical treatment in all T1 tumours at high risk of progression (i.e., high grade, multifocality, carcinoma in situ, and tumour size, as outlined in the EAU Guidelines for Non-muscle-invasive Bladder Cancer).	C
Offer radical treatment to all T1 patients failing intravesical therapy.	B

7.2.Neoadjuvant chemotherapy

7.2.1.Introduction

The standard treatment for patients with MIBC is RC. However, RC only provides five-year survival in about 50% of patients [176,189-192]. To improve these results, neoadjuvant chemotherapy (NAC) has been used since the 1980s [193,194].

There are many advantages and disadvantages of administering chemotherapy before planned definitive surgery to patients with resectable muscle-invasive urothelial carcinoma of the bladder and cN0M0 disease:

Chemotherapy is delivered at the earliest time-point, when the burden of micrometastatic disease is expected to be low.
Potential reflection of in-vivo chemosensitivity.
Tolerability of chemotherapy and patient compliance are expected to be better pre-cystectomy.
Patients might respond to NAC and reveal a favourable pathological status, determined mainly by achieving pT0, pN0 and negative surgical margins.
Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy [195,196], although published studies on the negative effect of delayed cystectomy only include chemo-naive patients. There are no trials indicating that delayed surgery, due to NAC, has a negative impact on survival.
Neoadjuvant chemotherapy does not seem to affect the outcome of surgical morbidity. In one randomised trial the same distribution of grade 3-4 post-operative complications was seen in both treatment arms [197]. In the combined Nordic trials (n=620), NAC did not have a major adverse effect on the percentage of performable cystectomies. The cystectomy frequency was 86% in the experimental arm and 87% in the control arm, 71% received all three chemotherapy cycles [198].
Clinical staging using bimanual palpation, CT or MRI may often result in over- and understaging and have a staging accuracy of only 70% [199,200]. Overtreatment is a possible negative consequence.
Neoadjuvant chemotherapy should only be used in patients eligible for cisplatin combination chemotherapy; other combinations (or monotherapies) are inferior in metastatic BC and have not been fully tested in a neoadjuvant setting [197,201-213].

7.2.2.The role of imaging and biomarkers to identify responders

Data from small imaging studies, aiming to identify responders in patients treated with NAC, suggest that response after two cycles of treatment is related to outcome. So far, neither PET, CT, nor conventional MRI or DCE MRI can accurately predict response [214-217]. In addition, the definition of stable disease after two cycles of NAC is still undefined. To identify progression during NAC, imaging is being used in many centres, notwithstanding the lack of supporting evidence.

For responders to NAC, especially in those with a complete response (pT0 N0), treatment has a major positive impact on OS [218]. The overtreatment of non-responders and patients in the non-target population (i.e. patients without micrometastatic disease) are major drawbacks. Pre-operative identification of responders based on molecular tumour profiling in TURB specimens might guide the use of NAC [219,220] (see Section 7.8.12 - Biomarkers).

7.2.3.Summary of available data

Several randomised phase III trials addressed the potential survival benefit of NAC administration, with conflicting results [197,201-210,221-226]. The main differences in trial designs were the type of chemotherapy (i.e. single-agent cisplatin or combination chemotherapy) and the number of cycles provided. Patients had to be fit for cisplatin. Since these studies differed considerably for patient numbers, patient characteristics (e.g. clinical T-stages included) and the type of definitive treatment offered (cystectomy and/or RT), pooling of results was not possible.

Three meta-analyses were undertaken to establish if NAC prolongs survival [211-213]. In the most recent meta-analysis, published in 2005 [213], with updated patient data from 11 randomised trials (n=3,005), a significant survival benefit was shown in favour of NAC. The results of this analysis confirmed the previously published data and showed a 5% absolute improvement in survival at five years.

The Nordic combined trial showed an absolute benefit of 8% survival at five years and 11% in the clinical T3 subgroup, translating into nine patients needed to treat [198]. Only cisplatin combination chemotherapy with at least one additional chemotherapeutic agent resulted in a meaningful therapeutic benefit [211,213]; the regimens tested were methotrexate, vinblastine, adriamycin plus cisplatin (MVA(E)C), cisplatin, methotrexate plus vinblastine (CMV), cisplatin and methotrexate (CM), cisplatin/adriamycin, cisplatin/5-fluorouracil (5-FU), and carboplatin, methotrexate, vinblastine (CarboMV).

More modern chemotherapeutic regimens such as gemcitabine/cisplatin have shown similar pT0/pT1 rates as methotrexate, vinblastine, adriamycin plus cisplatin (MVAC) in the most recent retrospective series and pooled data analyses, but have not been used in randomised controlled trials (RCTs) [227-230]. The updated analysis of the largest randomised phase III trial [201] with a median follow-up of eight years confirmed previous results and provided some additional interesting findings:

16% reduction in mortality risk;
improvement in ten-year survival from 30% to 36% with neoadjuvant CMV;
benefit with regard to distant metastases;
no benefit for locoregional control and locoregional disease-free survival, with the addition of neoadjuvant CMV independent of the definitive treatment.

The presence of micrometastases is postulated to be lower in smaller tumours (T2) compared to more extensive tumours (T3b-T4b). T4 stage tumours are prone to a higher degree of clinical understaging because macrometastatic nodal deposits are detected more often in post-cystectomy specimens [198]. Data support the use of NAC in the T2b-T3b tumour subgroup (former classification T3), and has shown a modest, but substantial, improvement in long-term survival as well as significant downstaging [218].

7.2.4.Summary of evidence and recommendations for neoadjuvant chemotherapy

Conclusions	LE
Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of surgical techniques, and current chemotherapy combinations.	3
Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival (OS) (5-8% at five years).	1a
Neoadjuvant treatment of responders and especially patients who show complete response (pT0 N0) has a major impact on OS.	2
Currently, no tools are available to select patients who have a higher probability of benefitting from neoadjuvant chemotherapy (NAC). In the future, genetic markers, in a personalised medicine setting, might facilitate the selection of patients for NAC and differentiate responders from non-responders.

Recommendations

Offer neoadjuvant chemotherapy (NAC) for T2-T4a, cN0M0 bladder cancer.

In this case, always use cisplatin-based combination therapy.

Do not offer NAC to patients who are ineligible for cisplatin-based combination chemotherapy.

7.3.Pre- and post-operative radiotherapy in muscle-invasive bladder cancer

7.3.1.Post-operative radiotherapy

There are only very limited, old, data on adjuvant RT after RC. However, advances in targeting, and reducing the damage to surrounding tissue, may yield better results in the future [231]. A recent RCT in 100 patients, comparing pre-operative vs. post-operative RT and RC, showed comparable OS, DFS and complication rates [232]. Approximately half of these patients had urothelial cancer (UC), while the other half had SCC. In locally advanced BC (T3-T4, N0/N1, M0), the local recurrence rate seems to decrease with post-operative RT [233].

7.3.2.Pre-operative radiotherapy

7.3.2.1.Retrospective studies

Older data and retrospective studies alone cannot provide an evidence base for modern guideline recommendations due to the major study limitations, which include concomitant chemotherapy and differences between surgery and RT. This conclusion was supported by a 2003 systemic review [234]. A retrospective study from 2015 [235] did show a decreased cause-specific mortality and overall mortality for pre-operative RT in clinical T2b and T3 patients only. Another recent retrospective study with pre-operative RT in clinical T1-3 tumours showed that downstaging to T0 tumours occurs in > 50% of the irradiated patients, as compared to < 10% of patients without having received pre-operative RT [236]. Additionally, downstaging resulted in a longer progression-free survival (PFS).

7.3.2.2.Randomised studies

Six randomised studies have been published so far, investigating pre-operative RT, although all are from several decades ago. In the largest trial, pre-operative RT at a dose of 45 Gy was used in patients with muscle-invasive tumours resulting in a significant increase in pathological complete response (pCR) (9% to 34%) in favour of pre-operative RT, which was also a prognostic factor for survival [237]. The OS data were difficult to interpret since chemotherapy was used in a subset of patients only and more than 50% of patients (241/475) did not receive the planned treatment and were excluded from the final analyses. Two smaller studies using a dose of 20 Gy showed only a small survival advantage in > T3 tumours [238,239]. Two other small trials confirmed downstaging after pre-operative RT [240,241].

A meta-analysis of the five randomised trials showed a difference in five-year survival of (OR: 0.71; 95% CI: 0.48-1.06) in favour of pre-operative RT [242]. However, the meta-analysis was potentially biased by the patients in the data from largest trial who were not given the planned treatment. When the largest trial was excluded, the OR became 0.94 (95% CI: 0.57-1.55), which is not significant.

7.3.3.Summary of evidence and recommendations for pre- and post-operative radiotherapy

Summary of evidence	LE
No data exist to support that pre-operative radiotherapy (RT) for operable muscle-invasive bladder cancer (MIBC) increases survival.	2a
Pre-operative RT for operable MIBC, using a dose of 45-50 Gy in fractions of 1.8-2 Gy, results in downstaging after four-six weeks.	2
Limited high-quality evidence supports the use of pre-operative RT to decrease the local recurrence of MIBC after radical cystectomy.	3

Recommendations	GR
Do not offer pre-operative radiotherapy (RT) to improve survival.	A
Offer pre-operative RT for operable MIBC since it can result in tumour downstaging after four to six weeks.	C

7.4.Radical surgery and urinary diversion

7.4.1.Removal of the tumour-bearing bladder

7.4.1.1.Introduction

Radical cystectomy is the standard treatment for localised MIBC in most Western countries [176,243]. Recent interest in patients’ quality of life (QoL) has promoted the trend toward bladder-preserving treatment modalities, such as radio- and/or chemotherapy (see Sections 7.2 and 7.6). Performance status (PS) and age influence the choice of primary therapy, as well as the type of urinary diversion, with cystectomy being reserved for younger patients without concomitant disease and with a better PS. The value of assessing overall health before recommending and proceeding with surgery was emphasised in a multivariate analysis [149]. The analysis found an association between comorbidity and adverse pathological- and survival outcome following RC [149]. Performance status and comorbidity have a different impact on treatment outcomes and must be evaluated independently [155].

Controversy remains regarding age, RC and the type of urinary diversion. Cystectomy is associated with the greatest risk reduction in disease-related and non-disease-related death in patients aged > 80 years [149]. The largest, retrospective, single-institution study on cystectomy to date found that patients aged > 80 years had increased post-operative morbidity, but not increased mortality. Although some patients successfully underwent a neobladder procedure, most patients were treated with an ileal conduit diversion [244].

It is particularly important to evaluate functioning and QoL of elderly patients using a standardised geriatric assessment, as well as carrying out a standard medical evaluation (see Section 6.2) [245].

7.4.2.Timing and delay of cystectomy

Nielsen et al. reported that a delay of RC > 3 months in three American centres was not associated with a worse clinical outcome [246]. Ayres et al. investigated whether a delay > 3 months would have the same effect in the United Kingdom [247]. Initially they found, in agreement with Nielsen et al., that cystectomy within 90 days of diagnosis had no effect on OS for MIBC (n=955). However, analysis of T2 tumours showed a statistically significant survival benefit if patients had surgery within 90 days of diagnosis (n=543; HR: 1.40; 95% CI: 1.10-1.79). A population-based study from the USA SEER database analysed patients who underwent a cystectomy between 1992 and 2001, also concluded that a delay of more than twelve weeks has a negative impact on outcome and should be avoided [248].

7.4.2.1.Indications

Traditionally, RC was recommended for patients with MIBC T2-T4a, N0-Nx, M0 [243]. Other indications include high risk and recurrent superficial tumours, BCG-resistant Tis, T1G3 (see Section 7.1), as well as extensive papillary disease that cannot be controlled with TURB and intravesical therapy alone.

Salvage cystectomy is indicated in non-responders to conservative therapy, recurrence after bladder-sparing treatment, and non-urothelial carcinoma (these tumours respond poorly to chemotherapy and RT). It is also used as a purely palliative intervention, including for fistula formation, pain and recurrent visible haematuria (macrohaematuria) (see Section 7.5.1 - Palliative cystectomy).

When there are positive LNs, in the case of N1 involvement (metastasis in a single node in the true pelvis) orthotopic neobladder can still be considered, but not in N2 or N3 tumours [249].

7.4.3.Radical cystectomy: technique and extent

In men, standard RC includes removal of the bladder, prostate, seminal vesicles, distal ureters, and regional LNs. Prostate-sparing cystectomy is an option in a subset of carefully selected patients with BC without involvement of the prostatic urethra and without prostate cancer. This procedure is oncologically safe with good functional results as long as it is performed in an experienced centre [250]. In women, standard RC includes removal of the bladder, entire urethra and adjacent vagina, uterus, distal ureters, and regional LNs [251]. Controversies in evaluating the clinical significance of lymphadenectomy are related to two main aspects of nodal dissection: therapeutic procedure and/or staging instrument.

Two important autopsy studies for RC have been performed so far. The first study showed that in 215 patients with MIBC and nodal dissemination, the frequency of metastasis was 92% in regional (perivesical or pelvic), 72% in retroperitoneal, and 35% in abdominal LNs. There was also a significant correlation between nodal metastases and concomitant distant metastases (p < 0.0001).

Approximately 47% of the patients had both nodal metastases and distant dissemination and only 12% of the patients had nodal dissemination as the sole metastatic manifestation [252]. The second autopsy study focused on the nodal yield when super-extended pelvic LN dissection (LND) was performed. Substantial inter-individual differences were found with counts ranging from 10 to 53 nodes [253]. These findings demonstrate the limited utility of node count as a surrogate for extent of dissection.

Regional LNs have been shown to consist of all pelvic LNs below the bifurcation of the aorta [254-258]. Mapping studies have also found that skipping lesions at locations above the bifurcation of the aorta, without more distally located LN metastases, is rare [258,259].

The extent of LND has not been established to date. Standard lymphadenectomy in BC patients involves removal of nodal tissue cranially up to the common iliac bifurcation, with the ureter being the medial border, and including the internal iliac, presacral, obturator fossa and external iliac nodes [260]. Extended lymphadenectomy includes all LNs in the region of the aortic bifurcation, and presacral and common iliac vessels medial to the crossing ureters. The lateral borders are the genitofemoral nerves, caudally the circumflex iliac vein, the lacunar ligament and the LN of Cloquet, as well as the area described for standard lymphadenectomy [260-264]. A super-extended lymphadenectomy extends cranially to the level of the inferior mesenteric artery [265,266].

In order to assess how and if cancer outcome is influenced by the extent of lymphadenectomy in patients with clinical N0M0 MIBC, a SR of the literature was undertaken [267]. Out of 1,692 abstracts retrieved and assessed, nineteen studies fulfilled the review criteria [260-264,266,268-280]. All five studies comparing LND vs. no LND reported a better oncological outcome for the LND group. Seven out of twelve studies comparing (super-)extended with limited or standard LND reported a beneficial outcome for (super)extended in at least a subset of patients which is in concordance with several other recently performed meta-analyses [281,282]. No difference in outcome was reported between extended and super-extended LND in the two high-volume-centre studies identified [266,278]. Further data from on-going randomised trials on the therapeutic impact of the extent of lymphadenectomy are awaited.

It has been suggested that PFS as well as OS might be correlated with the number of LNs removed during surgery, although there are no data from RCTs on the minimum number of LNs that should be removed. Nevertheless, survival rates increase with the number of dissected LNs [283]. Removal of at least ten LNs has been postulated as sufficient for evaluation of LN status, as well as being beneficial for OS in retrospective studies [284-286]. In conclusion, extended LND might have a therapeutic benefit compared to less-extensive LND, but due to study bias, no firm conclusions can be drawn [267].

7.4.3.1.Pelvic organ preservation techniques in men: oncological and functional outcomes

Different approaches have been described to improve voiding and sexual function in patients undergoing RC for BC. No consensus exists regarding which approach preserves function best. Concern remains regarding the impact of “sparing-techniques” on oncological outcomes.

To determine the effect of sexual function-preserving cystectomy (SPC) on functional and oncological outcomes a SR was undertaken [287].

Four main types of sexual-preserving techniques have been described:

1.Prostate sparing cystectomy: part or the whole prostate is preserved including seminal vesicles, vas deferens and neurovascular bundles.

2.Capsule sparing cystectomy: the capsule or peripheral part of the prostate is preserved with adenoma (including prostatic urethra) removed by TURP or en bloc with bladder. Seminal vesicles, vas deferens and neurovascular bundles are also preserved.

3.Seminal sparing cystectomy: seminal vesicles, vas deferens and neurovascular bundles are preserved.

4.Nerve sparing cystectomy: the neurovascular bundles are the only tissue left in place.

Out of 8,517 screened abstracts twelve studies recruiting a total of 1,098 patients (823 in the intervention group vs. 275 in the control group) were identified, including nine comparative studies (one RCT and two retrospective non-RCTs with matched pair design [250,288-297] and three single-arm case series [298-300]. Sexual function-preserving cystectomy described included prostate-, capsule-, seminal vesicle- and nerve-sparing techniques. In the majority of cases, the open surgical approach was used and the urinary diversion of choice was an orthotopic neobladder. Median follow-up was longer than three years in nine studies, with three studies presenting results at a median follow-up longer than five years.

The majority of the studies included patients who were potent pre-operatively with organ-confined disease without tumour in the bladder neck and/or prostatic urethra. Prostate cancer was ruled out in all of the SPC techniques, except in those performing nerve-sparing cystectomy.

Oncological outcomes did not differ between groups in any of the comparative studies that measured local recurrence, metastatic recurrence, DSS and OS, at a median follow-up of three to five years. Local recurrence after SPC was commonly defined as any urothelial cancer (UC) recurrence below the iliac bifurcation within the pelvic soft tissue and ranged from 1.2-61.1% vs. 16-55% in the control group. Metastatic recurrence ranged from 0-33.3%.

For those techniques preserving prostatic tissue (prostate or capsule sparing) rates of incidental prostate cancer in the intervention group ranged from 0 to 15%. In no case, incidental prostate cancer with Gleason score > 8 was reported.

Sexual outcomes were evaluated using validated-questionnaires (International Index of Erectile Function [IIEF], Erection Hardness Scale [EHS], Bladder Cancer Index [BCI]) in eight studies. Post-operative potency was significantly better in patients who underwent any type of sexual-preserving technique compared to conventional RC (p < 0.05), ranging 80-90%, 50-100% and 29-78% for prostate-, capsule- or nerve-sparing techniques, respectively. Data did not show superiority of any sexual-preserving technique.

Urinary continence, defined as the use of no pads in the majority of studies, ranged from 88 to 100% (day-time continence) and from 31-96% (night-time continence) in the prostate-sparing cystectomy patients. No major impact was shown with regard to continence rates for any of the three approaches.

The evidence base suggests that these procedures may yield better sexual outcomes than standard cystectomy without compromising oncological outcomes. However, the overall quality of the evidence was moderate, and hence if a sexual-preserving technique is offered, patients must be carefully selected, counselled and closely monitored.

7.4.3.1.1.Summary of evidence and recommendations for sexual-preserving techniques in men

Summary of evidence	LE
The majority of patients motivated to preserve their sexual function will benefit from sexual-preserving techniques.	2
None of the sexual-preserving techniques (prostate/capsule/seminal/nerve sparing) have shown to be superior and no particular technique can be recommended.

Recommendations	LE	GR
Offer sexual-preserving techniques to men motivated to preserve their sexual function since the majority will benefit.	2	B
Select patients based on: organ-confined disease; absence of any kind of tumour at the level of the prostate, prostatic urethra or bladder neck.	2	A
Do not offer sexual-preserving cystectomy as standard therapy for muscle-invasive bladder cancer.		C

7.4.3.2.Pelvic organ preservation techniques in women: oncological and functional outcomes

Sexual and voiding dysfunction in female patients is prevalent after RC and orthotopic neobladder. Patients’ QoL has promoted the trend toward pelvic organ-preserving techniques. Better imaging modalities, increased knowledge of the function of the pelvic structures and improved surgical techniques has enabled less destructive methods for treating high-risk BC. These techniques involve preserving the neurovascular bundle, vagina, uterus or variations of any of the stated techniques.

A SR was conducted to evaluate the advantages and disadvantages of sexual-function preserving RC and orthotopic neobladder for female patients [301].

After screening 11,941 abstracts, fifteen studies recruiting a total of 874 patients were eligible for inclusion. Three papers had a matched pair study design, and the remainder of the included studies were retrospective surgical series with small case numbers and a high risk of selection bias favouring less advanced cancers.

Sexual outcomes were reported in seven studies with 167/194 patients (86%) having resumed sexual activity within six months post-operatively, with median patients’ sexual satisfaction scores of 88.5%, ranging from 80% to 100%.

Survival outcomes were reported in seven studies on 197 patients, with a mean follow-up of between 12 and 132 months. At three and five year, CSS was 70-100% and OS was 65-100%. Positive surgical margins were reported in six studies, ranging from 0 to 13.7%. Local and metastatic recurrence rates were reported as ranging between 0-13% and 0-16.7%, respectively. Mean time to local recurrence was seven months.

Eleven studies reported continence outcomes. Overall daytime and nighttime continence was 58-100% and 42-100%, respectively. Overall self-catheterisation rate was 9.5-78%.

Although, this SR provides the best evidence currently available, including basically all reported cases, the data remains immature. Most studies were retrospective and non-comparative with small numbers of patients included, meaning that any estimates are uncertain and likely to be biased. Heterogeneity in outcome definition, measurement and reporting hampers the usefulness of the current evidence base. The overall risk of bias was high across all studies. However, for well-selected patients, sparing female reproductive organs during RC appears to be oncologically safe and provides improved functional outcomes.

7.4.3.2.1.Summary of evidence and recommendations for sexual-preserving techniques in women

Summary of evidence	LE
Data regarding pelvic organ-preserving radical cystectomy for female patients remain immature.	3

Recommendations	LE	GR
Offer sexual-preserving techniques to female patients motivated to preserve their sexual function since the majority will benefit.	3	C
Select patients based on: • organ-confined disease; • absence of tumour in bladder neck or urethra.		C
Do not offer pelvic organ-preserving radical cystectomy for female patients as standard therapy for muscle-invasive bladder cancer.		C

7.4.3.3.Laparoscopic/robotic-assisted laparoscopic cystectomy

Due to data limitations, until recently, laparoscopic radical cystectomy (LRC) and robot-assisted radical cystectomy (RARC) were considered as investigational procedures for which no advantages could be shown as compared to open surgery. Most of the available studies suffered from patient selection bias (age, stage).

A number of new publications have become available (cut-off date for the literature search was Oct 1st, 2015), in particular on RARC; a SR [302], a consensus panel report [303], an RCT from the Memorial Sloan Kettering Cancer Center (MSKCC) group [304] a SR on oncologic and functional outcomes after RARC [305] and a retrospective review on the recurrence patterns after open radical cystectomy (ORC) and RARC [306]. Since there is a continuous flow of reports on RARC, this text section and the recommendations will be be subject to significant updates in the coming years.

For the methodology of the SR we refer to the manuscript [302]. In short, out of 1,071 abstracts assessed, 105 studies were selected as meeting the inclusion criteria. Of the 105 papers 102 had a level of evidence of 4, and only three publications had a level of evidence of 2b.

For RARC with urinary diversion, the mean operative time was six to seven hours. Although the intracorporeal technique is more demanding, operating times are comparable, most likely reflecting more experience with the procedure. The operation time decreased over time, but remained longer than for ORC. The average operative time for ORC is listed as 297 minutes in the three higher quality RCTs, which still seems relatively long.

In the comparative studies, mean length of hospital stay for RARC decreases with time and experience, and is 1 to 1.5 days shorter as compared to ORC. In the RCT’s however, operative time and length of hospital stay showed no significant difference for either procedure. Blood loss and transfusion rate favour RARC. Intraoperative, 30-day complication rate and mortality were similar for RARC and ORC, but complication grade and grade 3, 90-day, complication rates favoured RARC. Overall complication rates were reported as > 50% which illustrates that cystectomy and diversion remains major surgery. Complication rates did not change with time or experience.

A major limitation of this review is the low level of evidence of the included studies. Of the three RCT’s, only one was adequately powered and there was no correction for baseline characteristics (selection bias). In some of the larger series in the review 59-67% of tumours are < pT2 tumours. In the largest RCT 91.5% were clinically < T2 and 71.7% pathologically < T2 [304] compared to a large series of ORC (n=1,054) 47% of included patients had a < pT2 tumour [176].

The Pasadena Consensus Panel (a group of experts on RC, lymphadenectomy and urinary reconstruction) reached similar conclusions as the Novara review based on the same methodology and literature [303]. They presented similar outcomes comparing RARC and ORC for operative endpoints, pathological and intermediate oncological endpoints (positive surgical margins and LN yield), functional endpoints and complication outcomes. Additionally, RARC was associated with increased costs, although there are ergonomic advantages for the surgeon, as compared to laparoscopic radical cystectomy (LRC). For both techniques surgeons’ experience and institutional volume strongly predicted outcome. According to the literature, proficiency is reached after 20-250 cases. However, the Pasadena Consensus Panel performed statistical modelling and came to the conclusion that 30 cases should be enough to achieve proficiency in RARC, but they also concluded that challenging cases (high BMI, post chemo- or RT, pelvic surgery, T4 or bulky tumours or positive nodes) should be performed by experienced robotic surgeons only. Experience is defined as a high volume centre, > 30 RARCs/year and experience in ORC.

In the only sufficiently powered RCT, comparing ORC (n=58) vs. RARC (n=60) and open diversion, the primary endpoint was an advantage in 90 days grade 2-5 complications for RARC [304]. Since the complication rates were similar (62% for RARC vs. 66% for ORC), the trial was closed after a planned interim analysis. Robotic-assisted radical cystectomy resulted in less blood loss but had a longer operative time and higher costs. Length of hospital stay, pathology, and QoL were similar. Limitations of this study are lack of long-term outcomes and limited experience in RARC as compared to ORC in this group of patients. A similar health-related QoL (HRQoL) was also found in an initial report of a prospective RCT comparing ORC and RARC [307]. Similar functional and oncological outcomes with five years follow up were also reported by Yuh et al. [305]. Ngyuyen et al. also reported that RARC was not an independent predictor of recurrence after surgery in a retrospective review of 383 consecutive patients [306].

Most reviewed series used extracorporeal reconstruction which leaves room for improvement.

Although an intracorporeal neobladder is a very complex robotic procedure [308] the choice for neobladder or cutaneous diversion, must not depend on the surgical approach.

For LRC, a recent review came to similar conclusions as described for RARC [308]. The review included sixteen eligible studies on LRC. As compared to ORC, LRC had a significantly longer operative time, fewer overall complications, blood transfusions and analgesic use, less blood loss and a shorter length of hospital stay. However, the review was limited by the inherent limitations of the included studies. Although this review also showed better oncological outcomes, these appeared comparable to ORC series in the largest LRC multicentre study to date [308].

7.4.3.3.1.Summary of evidence and recommendations for laparoscopic/robotic-assisted laparoscopic cystectomy

Summary of evidence	LE
Robot-assisted radical cystectomy (RARC) provides longer operative time (1-1.5 hours), major costs, but shorter length of hospital stay (1-1.5 days) and less blood loss compared to open radical cystectomy (ORC).	1
RARC series suffer from a significant stage selection bias as compared to ORC.	1
Grade 3, 90-day 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 factor for outcome of both RARC and ORC, 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 under-utilised, and functional results of intracorporeally constructed neobladders should be studied.	4

Recommendations	GR
Inform the patient of the advantages and disadvantages of open radical cystectomy (ORC) and robot-assisted radical cystectomy (RARC) to allow selection of the proper procedure.	C
Select experienced centres, not specific techniques, both for RARC and ORC.	B
Beware of neobladder under-utilisation and outcome after RARC.	C

7.4.4.Urinary diversion after radical cystectomy

From an anatomical standpoint, three alternatives are currently used after cystectomy:

abdominal diversion, such as an ureterocutaneostomy, ileal or colonic conduit, and various forms of a continent pouch;
urethral diversion, which includes various forms of gastrointestinal pouches attached to the urethra as a continent, orthotopic urinary diversion (neobladder, orthotopic bladder substitution);
rectosigmoid diversions, such as uretero-(ileo-)rectostomy.

Different types of segments of the intestinal tract have been used to reconstruct the urinary tract, including the stomach, ileum, colon and appendix [309]. Several studies have compared certain aspects of HRQoL, such as sexual function, urinary continence and body image, in patient cohorts with different types of urinary diversion. However, further research is needed on pre-operative tumour stage and functional situation, socio-economic status, and time interval to primary surgery.

7.4.4.1.Preparations for surgery

The ASA score has been validated to assess the risk of post-operative complications prior to surgery. In the BC setting, ASA scores > 3 are associated with major complications [132,310], particularly those related to the type of urinary diversion (Table 7.4) [311]. However, the ASA score is not a comorbidity scale and should not be used as such.

Table 7.4: ASA score [312]

ASA
1	No organic pathology, or patients in whom the pathological process is localised and does not cause any systemic disturbance or abnormality.
2	A moderate but definite systemic disturbance caused either by the condition that is to be treated or surgical intervention, or which is caused by other existing pathological processes.
3	Severe systemic disturbance from any cause or causes. It is not possible to state an absolute measure of severity, as this is a matter of clinical judgment.
4	Extreme systemic disorders that have already become an imminent threat to life, regardless of the type of treatment. Because of their duration or nature, there has already been damage to the organism that is irreversible.
5	Moribund patients not expected to survive 24 hours, with or without surgery.

In consultation with the patient, both an orthotopic neobladder and ileal conduit should be considered in case where reconstructive surgery exposes the patient to excessive risk (as determined by comorbidity and age).

Diagnosis of urethral tumour before cystectomy or positive urethral frozen section leads to urethrectomy and therefore excludes neobladder reconstruction. If indicated, in males, urethral frozen section has to be performed on the cystoprostatectomy specimen just under the verumontanum and on the inferior limits of the bladder neck for females.

When there are positive LNs, orthotopic neobladder can nevertheless be considered in the case of N1 involvement (metastasis in a single node in the true pelvis) but not for N2 or N3 tumours [313].

Oncological results after orthotopic neobladder substitution or conduit diversion are similar in terms of local or distant metastasis recurrence, but secondary urethral tumours seem less common in patients with neobladder compared to those with conduits or continent cutaneous diversions [314].

For cystectomy, general preparations are necessary as for any other major pelvic and abdominal surgery. If the urinary diversion is constructed from gastrointestinal segments, the length or size of the respective segments and their pathophysiology when storing urine must be considered [315]. Despite the necessary interruption and re-anastomosis of bowel, a formal bowel preparation may not be necessary [316]. Bowel recovery time can be reduced by the use of early mobilisation and early oralisation, gastrointestinal stimulation with metoclopramide and chewing gum [317]. Patients treated according to the “fast tract”/ERAS (Early Recovery After Surgery) protocol have shown to score better on the emotional and physical functioning scores and suffer less from wound healing disorders, fever and thrombosis [318].

A cornerstone of the ERAS protocol is post-operative pain management which involves significantly reducing the use of opioids; offering opioids mainly as breakthrough pain medication. Instead of patient-controlled analgesia (PCA) and epidural opioids, most patients receive high-dose acetaminophen and/or ketorolac, starting intra-operatively. Patients on ERAS experience more pain as compared to patients on a traditional protocol (VAS 3.1 vs. 1.1, p < 0.001), but post-operative ileus decreased from 22% to 7.3%
(p=0.003) [319].

A multicentre randomised placebo-controlled trial showed that patients receiving alvimopan, a peripherally acting μ-opioid receptor antagonist, experienced quicker bowel recovery compared to patients receiving placebo [320]. However, this drug is, as yet, not approved in Europe.

Patients undergoing continent urinary diversion must be motivated to learn about their diversion and to be manually skilful in manipulating their diversion. Contraindications to more complex forms of urinary diversion include:

debilitating neurological and psychiatric illnesses;
limited life expectancy;
impaired liver or renal function;
transitional cell carcinoma of the urethral margin or other surgical margins.

Relative contraindications specific for an orthotopic neobladder are high-dose pre-operative RT, complex urethral stricture disease, and severe urethral sphincter-related incontinence [321].

7.4.4.2.Patient selection for orthotopic diversion

Radical cystectomy and urinary diversion are the two steps of one operation. However, the literature uniformly reports complications of RC, while ignoring the fact that most complications are diversion related [322]. Age alone is not a criterion for offering continent diversion [321,323]. Comorbidity, cardiac and pulmonary function, and cognitive function, are all important factors that should be considered, along with the patient’s social support and preference.

Age > 80 years is often considered to be the threshold after which neobladder reconstruction is not recommended. However, there is no exact age for a strict contraindication. In most large series from experienced centres, the rate of orthotopic bladder substitution after cystectomy for bladder tumour is up to 80% in men and 50% in women [324-327]. Nevertheless, no RCTs comparing conduit diversion with neobladder or continent cutaneous diversion have been performed.

Recently, a retrospective study including 1,383 patients showed that the risk of a decline in estimated glomerular filtration rate (eGFR) did not significantly differ after ileal conduit vs. neobladder in patients with pre-operative chronic kidney disease 2 (eGFR 60-89 mL/min/1.73 m2) or 3a (eGFR 45-59 mL/min/1.73 m2) [328]. Only age and anastomic strictures were found to be associated with a decline in eGFR.

7.4.4.2.1.Ureterocutaneostomy

Ureteral diversion to the abdominal wall is the simplest form of cutaneous diversion. Operating time, complication rate, stay at intensive care and length of hospital stay are lower in patients treated with ureterocutaneostomy as compared to ileal conduit [329]. Therefore, in older, or otherwise compromised, patients who need a supravesical diversion, ureterocutaneostomy is the preferred procedure [330,331]. Quality of life, which was assessed using the Bladder Cancer Index, showed equal urinary bother and function for patients treated with ileal conduit and ureterocutaneostomy [329].

However, others have demonstrated that, in carefully selected elderly patients, all other forms of wet and dry urinary diversions, including orthotopic bladder substitutions, are possible [244]. Technically, either one ureter, to which the other shorter one is attached end-to-side, is connected to the skin (transureteroureterocutaneostomy) or both ureters are directly anastomosed to the skin. Due to the smaller diameter of the ureters, stoma stenosis has been observed more often than in intestinal stomas [330].

In a retrospective multicentre study peri-operative morbidity was evaluated for urinary diversion using bowel as compared to ureterocutaneostomy. Patients selected for a ureterocutaneostomy were older and had a higher ASA score, while their mean Charlson score was lower (4.2 vs. 5.6, p < 0.001) [332].

Despite the limited comparative data available, it must be taken into consideration that older data and clinical experience suggest ureter stenosis at the skin level and ascending UTI are more frequent complications in ureterocutaneostomy compared to an ileal conduit diversion. In a retrospective study comparing various forms of intestinal diversion, ileal conduits had fewer late complications than continent abdominal pouches or orthotopic neobladders [333].

7.4.4.2.2.Ileal conduit

The ileal conduit is still an established option with well-known/predictable results. However, up to 48% of patients develop early complications including UTIs, pyelonephritis, ureteroileal leakage and stenosis [333]. The main complications in long-term follow-up studies are stomal complications in up to 24% of cases and functional and/or morphological changes of the UUT in up to 30% [334-336]. An increase in complications was seen with longer follow-up in the Berne series of 131 patients who were followed for a minimum of five years (median follow-up 98 months) [337]; the rate of complications increased from 45% at five years to 94% in those surviving > 15 years. In the latter group, 50% of patients developed UUT changes and 38% developed urolithiasis.

7.4.4.2.3.Continent cutaneous urinary diversion

A low-pressure detubularised ileal reservoir can be used as a continent cutaneous urinary diversion for self-catheterisation; gastric, ileocecal and sigma pouches have also been described [338-340]. Different anti-reflux techniques can be used [341]. Most patients have a well-functioning reservoir with day-time and night-time continence approaching 93% [342]. In a retrospective study of > 800 patients, stomal stenosis was seen in 23.5% of patients with an appendix stoma and 15% of those with an efferent intussuscepted ileal nipple [342]. Stone formation in the pouch occurred in 10% of patients [341-343]. In a small series of previously irradiated female patients, incontinence and stomal stenosis was seen in 8/44 patients (18%) [344].

7.4.4.2.4.Ureterocolonic diversion

The oldest and most common form of ureterocolonic diversion was primarily a refluxive and later an anti-refluxive connection of ureters to the intact rectosigmoid colon (uretero-rectosigmoidostomy) [345,346]. Most indications for this procedure have become obsolete due to a high incidence of upper UTIs and the long-term risk of developing colon cancer [313,314]. Bowel frequency and urge incontinence are additional adverse effects of this type of urinary diversion. However, it may be possible to circumvent the above-mentioned problems by interposing a segment of ileum between the ureters and rectum or sigmoid in order to augment capacity and avoid direct contact between the urothelium and colonic mucosa, as well as faeces and urine [347].

7.4.4.2.5.Orthotopic neobladder

An orthotopic bladder substitution to the urethra is now commonly used both in men and women. Contemporary reports document the safety and long-term reliability of this procedure. In several large centres, this has become the diversion of choice for most patients undergoing cystectomy [189,243,321]. In elderly patients (> 80 years), however, it is rarely performed, even in high-volume expert centres [348,349]. The terminal ileum is the gastrointestinal segment most often used for bladder substitution. There is less experience with the ascending colon, including the caecum, and the sigmoid [243]. Emptying of the reservoir anastomosed to the urethra requires abdominal straining, intestinal peristalsis, and sphincter relaxation. Early and late morbidity in up to 22% of the patients is reported [350,351]. In two studies with 1,054 and 1,300 patients [321,352], long-term complications included diurnal (8-10%) and nocturnal (20-30%) incontinence, ureterointestinal stenosis (3-18%), metabolic disorders, and vitamin B12 deficiency. In a recent study that compared cancer control and patterns of disease recurrence in patients with neobladder and ileal conduit, there was no difference in CSS between the two groups when adjusting for pathological stage [353]. Urethral recurrence in neobladder patients seems rare (1.5-7% for both male and female patients) [321,354]. These results indicate that neobladder in male and female patients does not compromise the oncological outcome of cystectomy. It remains debatable whether neobladder is better for QoL compared to non-continent urinary diversion [355-357].

Various forms of UUT reflux protection, including a simple isoperistaltic tunnel, ileal intussusception, tapered ileal prolongation implanted subserosally, and direct (sub)mucosal or subserosal ureteral implantation, have been described [341,351]. According to the long-term results, the UUT is protected sufficiently by either method.

In conclusion, standard RC in male patients with bladder neoplasms includes removal of the entire bladder, prostate, seminal vesicles, distal ureters (segment length undefined), and corresponding LNs (extent undefined) (LE: 2b). In female patients, standard RC includes removal of the entire bladder, urethra and adjacent vagina, uterus, distal ureters, and corresponding LNs.

A detailed investigation of the bladder neck prior to RC is important for women who are scheduled for an orthotopic bladder substitute [358]. In women undergoing RC the rate of concomitant urethral malignancy has been reported to range from 12-16% [359]. Localisation of the primary tumour at the bladder neck correlated strongly with concomitant urethral malignancy. Additionally, the tumours were at higher risk of advanced stage and nodal involvement [360].

Currently, it is not possible to recommend a particular type of urinary diversion. However, most institutions prefer ileal orthotopic neobladders and ileal conduits, based on clinical experience [361,362]. In selected patients, such as patients with a single kidney, ureterocutaneostomy is surgically the least burdensome type of diversion (LE: 3). Recommendations related to RC and urinary diversions are listed in section 7.5.

7.4.5.Morbidity and mortality

In three long-term studies, and one population-based cohort study, the peri-operative mortality was reported as 1.2-3.2% at 30 days and 2.3-8.0% at 90 days [189,322,324,363,364]. In a large single-centre series, early complications (within three months of surgery) were seen in 58% of patients [322]. Late morbidity was usually linked to the type of urinary diversion (see also above) [325,365]. Early morbidity associated with RC for NMIBC (at high risk for disease progression) is similar and no less than that associated with muscle-invasive tumours [366]. In general, lower morbidity and (peri-operative) mortality have been observed by surgeons and in hospitals with a higher case load and therefore more experience [363,367-371].

Table 7.6: Management of neobladder morbidity (30-64%) [372].

CLAVIEN System		Morbidity	Management
Grade I	Any deviation from the normal post-operative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions. Allowed therapeutic regimens are: drugs such as antiemetics, antipyretics, analgetics, diuretics and electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside.	Immediate complications:
		Post-operative ileus	Nasogastric intubation (usually removed at J1) Chewing gum Avoid fluid excess and hypovolemia (provoke splanchnic hypoperfusion)
		Post-operative nausea and vomiting	Antiemetic agent (decrease opioids) Nasogastric intubation
		Urinary infection	Antibiotics (ATB), no ureteral catheter removal Check the 3 drainages (ureters and neobladdder)
		Ureteral catheter obstruction	Inject 5cc saline in the ureteral catheter to resolve the obstruction Increase volume infusion to increase dieresis
		intra-abdominal urine leakage (anastomosis leakage)	Check drainages and watchful waiting
		Anaemia well tolerated	Martial treatment (give iron supplement)
		Late complications:
		Non compressive lymphocele	Watchful waiting
		Mucus cork	Cough Indwelling catheter to remove the obstruction
		Incontinence	Urine analysis (infection), echography (post-void residual) Physiotherapy
		Retention	Drainage and self-catheterisation education
Grade II	Requiring pharmacological treatment with drugs other than those allowed for grade I complications. Blood transfusions and total parenteral nutrition are also included.	Anaemia badly tolerated or if myocardial cardiopathy history	Transfusion1,2
		Pulmonary embolism	Heparinotherapy3
		Pyelonephritis	ATB and check kidney drainage (nephrostomy if necessary)
		Confusion or neurological disorder	Neuroleptics and avoid opioids
Grade III	Requiring surgical, endoscopic or radiological intervention	Ureteral catheter accidentally dislodged	Indwelling leader to raise the ureteral catheter
		Anastomosis stenosis (7%)	Renal drainage (ureteral catheter or nephrostomy)
		Ureteral reflux	No treatment if asymptomatic
III-a	Intervention not under general anaesthesia	Compressive lymphocele	Transcutaneous drainage or intra-operative marsupialisation (cf grade III)
III-b	Intervention under general anaesthesia	Ileal anastomosis leakage	Ileostomy, as soon as possible
		Evisceration	Surgery in emergency
		Compressive lymphocele	Surgery (marsupialisation)
Grade IV	Life-threatening complication (including central nervous system complications: brain haemorrhage, ischaemic stroke, subarachnoid bleeding, but excluding transient ischaemic attacks) requiring intensive care/intensive care unit management.	Rectal necrosis	Colostomy
		Neobladder rupture	Nephrostomy and indwelling catheter/surgery for repairing neobladder
		Severe sepsis	ATB and check all the urinary drainages and computed tomography scan in emergency
IV-a	Single organ dysfunction (including dialysis)	Non-obstructive renal failure	Bicarbonate/aetiology treatment
IV-b	Multi-organ dysfunction	Obstructive pyelonephritis and septicaemia	Nephrostomy and ATB
Grade V	Death of a patient
Suffix ‘d’	If the patient suffers from a complication at the time of discharge, the suffix “d” (for ‘disability’) is added to the respective grade of complication. This label indicates the need for a follow-up to fully evaluate the complication.

1 A recent SR showed that peri-operative blood transfusion (PBT) in patients who undergo RC correlates with increased all-cause mortality, cancer specific mortality and cancer recurrence. The authors hypothesised that this may be caused by the suggested immunosuppressive effect of PBT. The foreign antigens in transfused blood induce immune suppression, which may lead to tumour cell spread, tumour growth and reduced survival in already immunosuppressed cancer patients. As other possible causes for this finding increased post-operative infections and blood incompatibility were mentioned [373].

2 Intraoperative tranexamin acid infusion reduces peri-operative blood transfusion rates from 57.7% to 31.1%. There was no increase seen in peri-operative venous thromboembolism [374].

3 Hammond and co-workers reviewed 20,762 cases of venous thromboembolism (VTE) after major surgery and found cystectomy patients to have the second highest rate of VTE among all cancers studied [375]. These patients benefit from 30 days low-molecular-weight heparin prophylaxis. Subsequently, it was demonstrated that BMI > 30 and non-urothelial BCs are independently associated with VTE after cystectyomy. In these patients extended (90 days) heparin prophylaxis should be considered [376].

7.4.6.Survival

According to a multi-institutional database of 888 consecutive patients undergoing RC for BC, the five-year recurrence-free survival was 58% and the CSS was 66% [377]. Recent external validation of post-operative nomograms for BC-specific mortality showed similar results, with bladder-CSS of 62% [378].

Recurrence-free survival and OS in a large single-centre study of 1,054 patients was 68% and 66% at five years and 60% and 43%, at ten years, respectively [176]. However, the five-year recurrence-free survival in node-positive patients who underwent cystectomy was considerably less at 34-43% [175,176,379]. In a surgery-only study, the five-year recurrence-free survival was 76% in patients with pT1 tumours, 74% for pT2, 52% for pT3, and 36% for pT4 [176].

A trend analysis according to the five-year survival and mortality rates of BC in the U.S.A., between 1973 and 2009 with a total of 148,315 BC patients, revealed an increased stage-specific five-year survival rate for all stages, except for metastatic disease [380].

7.4.7.Summary of evidence and recommendations for radical cystectomy and urinary diversion

Summary of evidence	LE
For muscle-invasive bladder cancer, offer radical cystectomy as the curative treatment of choice.	3
A higher case load reduces morbidity and mortality of cystectomy.	3
Radical cystectomy includes removal of regional lymph nodes.	3
There are data to support that extended lymph node dissection (LND) (vs. standard or limited LND) improves survival after radical cystectomy.	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 orthotopic bladder substitution. The terminal ileum and colon are the intestinal segments of choice for urinary diversion.	3
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 radical cystectomy.	3
In patients aged > 80 years 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 volumes of cystectomy, and type of urinary diversion.	2
Surgical complications of cystectomy and urinary diversion should be reported using a uniform grading system. Currently, the best-adapted, graded system for cystectomy is the Clavien grading system.	2
No conclusive evidence exists as to the optimal extent of LND.	2a

Recommendations	GR
Do not delay cystectomy for > 3 months as it increases the risk of progression and cancer-specific mortality.	B
Before cystectomy, fully inform the patient about the benefits and potential risks of all possible alternatives. The final decision should be based on a balanced discussion between the patient and the surgeon.	B
Offer an orthotopic bladder substitute or ileal conduit diversion to male and female patients lacking any contraindications and who have no tumour in the urethra or at the level of urethral dissection.	B
Do not offer pre-operative radiotherapy when subsequent cystectomy with urinary diversion is planned.	A
Pre-operative bowel preparation is not mandatory. “Fast track” measurements may reduce the time of bowel recovery.	C
Offer radical cystectomy in T2-T4a, N0M0, and high-risk non-MIBC (as outlined above).	A*
Perform a lymph node dissection as an integral part of cystectomy.	A
Preserve the urethra if margins are negative.	B
Check the urethra regularly if no bladder substitution is attached.	B

*Upgraded following EAU Working Panel consensus.

7.1: Flow chart for the management of T2-T4a N0M0 urothelial bladder cancer

CT=computed tomography; MRI=magnetic resonance imaging; UUT=upper urinary tract.

7.5.Unresectable tumours

7.5.1.Palliative cystectomy for muscle-invasive bladder carcinoma

Locally advanced tumours (T4b, invading the pelvic or abdominal wall) may be accompanied by several debilitating symptoms, including bleeding, pain, dysuria and urinary obstruction. These patients are candidates for palliative treatments, such as palliative RT. Palliative cystectomy with urinary diversion carries the greatest morbidity and should be considered for symptom relief only if there are no other options [381-383].

Locally advanced MIBC can be associated with ureteral obstruction due to a combination of mechanical blockage by the tumour and invasion of ureteral orifices by tumour cells. In a series of 61 patients with obstructive uraemia, RC was not an option in 23 patients, and obstruction was relieved using permanent nephrostomy tubes [384]. Another ten patients underwent palliative cystectomy, but local pelvic recurrence occurred in all ten patients within the first year of follow-up. Another small study (n=20) showed that primary cystectomy for T4 BC was technically feasible and associated with a very tolerable therapy-related morbidity and mortality [385].

7.5.1.1.Recommendations for unresectable tumours

Recommendations	GR
Offer radical cystectomy as a palliative treatment to patients with inoperable locally advanced tumours (T4b).	B
Offer palliative cystectomy in patients with symptoms.	B

7.5.2.Supportive care

7.5.2.1.Obstruction of the UUT

Unilateral (best kidney) or bilateral nephrostomy tubes provide the easiest solution for UUT obstruction, but patients find the tubes inconvenient and prefer ureteral stenting. However, stenting can be difficult to achieve, stents must be regularly replaced and there is the risk of stent obstruction or displacement. Another possible solution is a urinary diversion with, or without, a palliative cystectomy.

7.5.2.2.Bleeding and pain

In the case of bleeding, the patient must be screened first for coagulation disorders or the patient’s use of anticoagulant drugs must be reviewed. Transurethral (laser) coagulation may be difficult in a bladder full of tumour or with a bleeding tumour. Intravesical rinsing of the bladder with 1% silver nitrate or 1-2% alum can be effective [386]. It can usually be done without any anaesthesia. The instillation of formalin (2.5-4% for 30 minutes) is a more aggressive and painful procedure, requiring anaesthesia. Formalin instillation has a higher risk of side-effects, e.g. bladder fibrosis, but is more likely to control the bleeding [386]. Vesicoureteral reflux should be excluded to prevent renal complications.

Radiation therapy is another common strategy for control of bleeding, and is also used to control pain. An older study reported control of haematuria in 59% of patients and pain control in 73% [387]. Irritative bladder and bowel complaints due to irradiation are possible, but are usually mild. Non-conservative options are embolisation of specific arteries in the small pelvis, with success rates as high as 90% [386]. Radical surgery is a last resort and includes cystectomy and diversion (see above Section 7.5.1).

7.6.Bladder-sparing treatments for localised disease

7.6.1.Transurethral resection of bladder tumour (TURB)

Transurethral resection of bladder tumour alone in patients with muscle-invasive bladder tumours is only possible as a therapeutic option if tumour growth is limited to the superficial muscle layer and if re-staging biopsies are negative for residual (invasive) tumour [388]. In general, about half will still have to undergo RC for recurrent muscle-invasive cancer with a disease-specific mortality rate of up to 47% within this group [389]. A disease-free status at re-staging TURB appears to be crucial in making the decision not to perform RC [390,391]. A prospective study by Solsona et al., which included 133 patients with radical TURB and re-staging negative biopsies, reported a fifteen-year follow-up [391]. Thirty per cent had recurrent NMIBC and went on to intravesical therapy, and 30% (n=40) progressed, of which 27 died of BC. After five, ten and fifteen years the results showed a CSS of 81.9%, 79.5%, and 76.7%, respectively and PFS rates with an intact bladder of 75.5%, 64.9%, and 57.8%, respectively.

In conclusion, TURB alone should only be considered as a therapeutic option for muscle-invasive disease after radical TURB, when the patient is unfit for cystectomy or a multimodality bladder-preserving approach, or refuses open surgery [392].

7.6.1.1.Recommendation for transurethral resection of bladder tumour

Recommendation	LE	GR
Do not offer transurethral resection of bladder tumour alone as a curative treatment option as most patients will not benefit.	2a	B

7.6.2.External beam radiotherapy (EBRT)

Current RT techniques with soft-tissue matching result in superior bladder coverage and a reduced integral dose to the surrounding tissues. The target dose for curative RT in BC is 60-66 Gy, with a subsequent boost using external RT or interstitial RT. The use of modern standard RT techniques results in major, related, late morbidity of the urinary bladder or bowel in less than 5% of tumour-free patients [393]. Acute diarrhoea is even more reduced with intensity-modulated RT [394]. Important prognostic factors for outcome include response to RT, tumour size, hydronephrosis and completeness of the initial TURB. Additional prognostic factors reported were age and stage [395].

In 2007 long-term results were reported by Chung et al. [396]. A total of 340 patients with MIBC were treated with EBRT alone, EBRT with concurrent chemotherapy, or NAC followed by EBRT. The overall CR was 55% and the ten-year DSS and OS were 35% and 19%, respectively. Complete response was 64% after EBRT alone, 79% after concurrent chemotherapy (n=36), and 52% after NAC (n=57). Younger age, lower tumour stage and absence of CIS were associated with a significant improvement in survival.

A 2002 Cochrane analysis demonstrated that RC has an OS benefit compared to RT [397], although this was not the case in a 2014 retrospective review using a propensity score analysis [398].

In conclusion, EBRT can be an alternative treatment in patients unfit for radical surgery.

7.6.2.1.Summary of evidence and recommendation for external beam radiotherapy

Summary of evidence	LE
External beam radiotherapy alone should only be considered as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach.	3
Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth.	3

Recommendation	GR
Do not offer radiotherapy alone as primary therapy for localised bladder cancer.	B

7.6.3.Chemotherapy

Chemotherapy alone rarely produces durable complete remissions. In general, a clinical CR rate of up to 56%, as reported in some series, which must be weighed against a staging error of > 60% [399,400]. Response to chemotherapy is a prognostic factor for treatment outcome and eventual survival [199], though it may be confounded by patient selection.

Several groups have reported the effect of chemotherapy on resectable tumours (neoadjuvant approach), as well as unresectable primary tumours [197,226,401,402]. Neoadjuvant chemotherapy with 2-3 cycles of MVAC or CMV has led to a downstaging of the primary tumour in different prospective series [197,226,401]. Pathological complete responses of primary bladder tumours were reached in 12-50% of patients after MVAC and in 12-22% of patients after gemcitabine/cisplatin (GC) in phase II and phase III trials [197,226,401,403-410].

Contemporary series with GC followed by RC reported inferior pT0 rates, which may have been related to a lack of dose density and inappropriate delay of surgery [230].

For highly selected patients, a bladder-conserving strategy with TURB and systemic cisplatin-based chemotherapy, preferably with MVAC, may allow long-term survival with intact bladder [199]. However, this approach cannot be recommended for routine use.

7.6.3.1.Summary of evidence and recommendation for chemotherapy for muscle-invasive bladder tumours

Summary of evidence	LE
With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and partial local responses have been reported.	2b

Recommendation	GR
Do not offer chemotherapy alone as primary therapy for localised bladder cancer.	A

7.6.4.Multimodality bladder-preserving treatment

Multimodality treatment (MMT) or trimodality treatment combines TURB, chemotherapy and radiation. The rationale for performing TURB and radiation is to achieve local tumour control. The addition of systemic chemotherapy or other radiosensitisers (mentioned below) aims at the potentiation of RT. Micrometastases are targeted by platinum-based combination chemotherapy and this topic is covered in the section on NAC (see Section 7.2). The aim of multimodality therapy is to preserve the bladder and QoL, without compromising outcome. A collaborative review addressed this approach [411].

There are no completed RCTs to compare the outcome of MMT with the gold standard, RC, but this approach has been shown to be superior to RT alone [412,413]. Many of the reported series have differing characteristics as compared to the large surgical series which typically have median ages in the mid-late 60s compared to mid-70s for some large RT series (reviewed in [412]). In the case of MMT, two distinct patterns of care may be distinguished: treatment aimed at patients fit for cystectomy and treatment aimed at older, less fit patients. For the former category MMT presents selective bladder preservation. In that case, the initial step is a radical TURB, where as much tumour as possible should be resected. This implies that proper patient selection (T2 tumours, no CIS) is critical [414]. For patients who are not candidates for cystectomy, less stringent criteria can be applied, though extensive CIS and poor bladder function should both be regarded as strong contraindications.

Following TURB and staging, treatment comprises EBRT with concurrent radiosensitising drugs. Two schedules are in common use worldwide: a split dose format with interim cystoscopy is used in North America [414] whilst single-phase treatment is more commonly used elsewhere [412]. For radiosensitising chemotherapy, cisplatin [415] or mitomycin C plus 5-fluorouracil (5-FU) can be used [412], but also other schedules have been used. In particular, hypoxic cell sensitisation with nicotinamide and carbogen has been evaluated in a large phase III trial [416]. In a recent phase I trial gemcitabine was used [417]. The regimen was well tolerated with promising results.

With MMT, five-year CSS and OS rates are achieved from 50-82% and from 36-74% respectively [393,412,415,416,418-420]. Salvage cystectomy rates are 10-30% [412,415,420]. There are data that major complication rates are similar for salvage and primary cystectomy [421]. The majority of recurrences post-MMT are non invasive and can be managed conservatively [412]. The collaborative review comes to the conclusion that there are accumulating data suggesting that bladder preservation with MMT leads to acceptable outcomes and therefore may be considered a reasonable treatment option in well-selected patients as compared to RC [422]. It should also be considered in all patients where surgery is contraindicated, either relatively or absolutely as the factors that determine fitness for surgery and chemoradiotherapy differ.

A bladder-preserving multimodality strategy requires very close multidisciplinary co-operation and a high level of patient compliance. Even if a patient has shown a CR to a multimodality bladder-preserving strategy, the bladder remains a potential source of recurrence, hence long-term bladder monitoring is essential and patients should be counselled that this will be required. A recent subanalysis from two RTOG trials looked at CR (T0) and near CR (Ta or Tis) after MMT [423]. After a median follow up of 5.9 years 41/119 (35%) of these patients experienced a bladder recurrence, and fourteen required a salvage cystectomy. There was no difference between complete and near-complete responders.

7.6.4.1.Summary of evidence and recommendations for multimodality treatment in muscle-invasive bladder cancer

Summary of evidence	LE
In a highly selected patient population, long-term survival rates of multimodality treatment are comparable to those of early cystectomy.	2b

Recommendations	GR
Offer surgical intervention or multimodality treatments as primary curative therapeutic approaches since they are more effective than radiotherapy alone.	B
Offer multimodality treatment as an alternative in selected, well-informed and compliant patients, especially for whom cystectomy is not an option.	B

7.7.Adjuvant chemotherapy

Adjuvant chemotherapy after RC for patients with pT3/4 and/or LN positive (N+) disease without clinically detectable metastases (M0) is still under debate [421,424] and is still infrequently used [193].

The general benefits of adjuvant chemotherapy include:

chemotherapy is administered after accurate pathological staging, therefore treatment in patients at low risk for micrometastases is avoided;
no delay in definitive surgical treatment.

The drawbacks of adjuvant chemotherapy are:

assessment of in vivo chemosensitivity of the tumour is not possible and overtreatment is an unavoidable problem;
delay or intolerability of chemotherapy, due to post-operative morbidity [425].

There is limited evidence from adequately conducted and accrued randomised phase III trials in favour of the routine use of adjuvant chemotherapy [424,426-431]. Individual patient data from six randomised trials [420,432-435] of adjuvant chemotherapy were included in one meta-analysis [426] with 491 patients for survival analysis (unpublished data from Otto et al., were included in the analysis). All these trials were suboptimal with serious deficiencies, including small sample size (underpowered), early cessation of patient entry, and flaws in design and statistical analysis, including irrelevant endpoints or a lack of recommendations concerning salvage chemotherapy for relapse or metastases [424]. In these trials, three or four cycles of CMV, cisplatin, cyclophosphamide, and adriamycin (CISCA), methotrexate, vinblastine, adriamycin or epirubicin, and cisplatin (MVA(E)C) and cisplatin and methotrexate (CM) were used [436], and one trial used cisplatin monotherapy [434]. These data were not convincing enough to give an unequivocal recommendation for the use of adjuvant chemotherapy.

In a 2014 meta-analysis [427], an additional three studies were included [428-430]. However, only 945 patients were included in this meta-analysis of nine trials, and none of the trials were fully accrued and no individual patient data were used [427]. For one trial, only an abstract was available at the time of the meta-analysis [429], and none of the included trials by themselves were significantly positive for OS in favour of adjuvant chemotherapy. In two of the trials, more modern chemotherapy regimens were used (gemcitabine/ cisplatin and paclitaxel/gemcitabine and cisplatin) [428,429]. The HR for OS was 0.77 and there was a trend towards an OS benefit when including all nine trials. The effect was stronger for DFS (HR: 0.66; 95% CI: 0.48-0.92) and when stratified for the ratio of nodal positivity (HR: 0.64; 95% CI: 0.45- 0.91). The background of this finding was heterogeneity in outcomes observed between the included studies. After stratification of the studies by the ratio of node positivity, no further heterogeneity was identified. The HR for DFS associated with adjuvant cisplatin-based chemotherapy in studies with higher nodal involvement was 0.39 (95% CI: 0.28-0.54), compared with 0.89 (95% CI: 0.69-1.15) in studies with less nodal involvement.

Furthermore, a retrospective cohort analysis that included 3,974 patients after cystectomy and LND showed an OS benefit in high-risk subgroups (extravesical extension and nodal involvement) [HR: 0.75; CI: 0.62-0.90] [437]. The most recent publication of the so far largest RCT (EORTC 30994), although not fully accrued, showed a significant improvement of PFS for immediate compared with deferred treatment (HR: 0.54; 95% CI: 0.4-0.73, p < 0.0001), there was, however, no significant OS benefit [438].

From the currently available evidence, it is still unclear whether immediate adjuvant chemotherapy or chemotherapy at the time of relapse is superior, or if the two approaches are equivalent with respect to the endpoint of OS. Cisplatin-based combination chemotherapy results in long-term DFS, even in metastatic disease, mainly in patients with LN metastases only, and with a good PS [407,439,440]. In the most recent meta-analysis, the positive role of adjuvant chemotherapy for BC has been strengthened, however, still with a poor level of evidence [427]. Patients should be informed about potential chemotherapy options before RC, including neoadjuvant and adjuvant chemotherapy, and the limited evidence for adjuvant chemotherapy.

7.7.1.Recommendation for adjuvant chemotherapy

Recommendation	GR
Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or pN+ disease if no neoadjuvant chemotherapy has been given.	B

7.8.Metastatic disease

7.8.1.Introduction

Half of the patients with muscle-invasive UC relapse after RC, depending on the pathological stage of the primary tumour and the nodal status. Local recurrence accounts for 30% of relapses, whereas distant metastases are more common. Ten to fifteen percent of patients are already metastatic at diagnosis [441]. Before the development of effective chemotherapy, patients with metastatic UC rarely had a median survival that exceeded three-six months [442].

7.8.1.1.Prognostic factors and treatment decisions

Prognostic factors are crucial for assessing phase II study results and stratifying phase III trials [405,409]. In a multivariate analysis, Karnofsky PS of ≤ 80% and presence of visceral metastases were independent prognostic factors of poor survival after treatment with MVAC [409]. They have also been validated for newer combination chemotherapy regimens [443-445].

For patients refractory to, or progressing shortly after, platinum-based combination chemotherapy, four prognostic groups have been established, based on three adverse factors that have been developed in patients treated with vinflunine and that have been validated in an independent data set: Hb < 10 g/dL; presence of liver metastases; and ECOG PS > 1 [446]. Cisplatin, has also been administered in patients with a GFR as low as 40 mL/min., using different schedules. The respective studies were mostly small size phase I and II trials [447-450]. In one phase III trial the cut off for cisplatin eligibility was > 50 mL/min [451].

7.8.1.2.Comorbidity in metastatic disease

Comorbidity is defined as “the presence of one or more disease(s) in addition to an index disease” (see Section 6.2.1). Comorbidity increases with age. However, chronological age does not necessarily correlate with functional impairment. Different evaluation systems are being used to screen patients as potentially fit or unfit for chemotherapy, but age alone should not be used to base treatment selection on [452].

7.8.1.3.Not eligible for cisplatin (unfit)

The EORTC conducted the first randomised phase II/III trial for urothelial carcinoma patients who were unfit for cisplatin chemotherapy [453]. The EORTC definitions were GFR < 60 mL/min and/or PS 2.

An international survey among BC experts [454] was the basis for a consensus statement on how to classify patients unfit for cisplatin-based chemotherapy. At least one of the following criteria has to be present: PS > 1; GFR ≤ 60 mL/min; grade > 2 audiometric loss; peripheral neuropathy; and New York Heart Association (NYHA) class III heart failure [455].

More than 50% of patients with UC are not eligible for cisplatin-based chemotherapy [456-459].

Renal function assessment in UC is of utmost importance for treatment selection. Calculation of creatinine clearance (CrCl) (24-h urine collection) with current formulae tend to underestimate clearance in patients aged > 65 years compared to measured CrCl [456,460].

7.8.2.Single-agent chemotherapy

Response rates to single-agent, first-line chemotherapy vary. The most robust data have shown a response rate of about 25% for first- and second-line gemcitabine in several phase II trials [461,462]. Responses with single agents are usually short-lived, complete responses are rare and no long-term DFS has been reported. The median survival in such patients is only six-nine months.

7.8.3.Standard first-line chemotherapy for fit patients

Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s (for a review see [463]). Methotrexate, vinblastine, adriamycin plus cisplatin MVAC and GC prolonged survival to up to 14.8 and 13.8 months, respectively, compared to monotherapy and older combinations. Neither of the two combinations is superior to the other, but equivalence has not been tested. Response rates were 46% and 49% for MVAC and GC, respectively. The long-term survival results have confirmed the anticipated equivalence of the two regimens [439]. The major difference between the above-mentioned combinations is toxicity. The lower toxicity of GC [158] has resulted in it becoming a new standard regimen [464]. Methotrexate, vinblastine, adriamycin plus cisplatin is better tolerated when combined with granulocyte colony-stimulating factor (G-CSF) [464,465].

High-dose intensity MVAC (HD-MVAC) combined with G-CSF is less toxic and more efficacious than standard MVAC in terms of dose density, complete response, and two-year survival rate. However, there is no significant difference in median survival between the two regimens [466,467]. In general, all disease sites have been shown to respond to cisplatin-based combination chemotherapy. A response rate of 66% and 77% with MVAC and HD-MVAC, respectively, has been reported in retroperitoneal LNs vs. 29% and 33% at extranodal sites [466]. The disease sites also have an impact on long-term survival. In lymph-node-only disease, 20.9% of patients were alive at five years compared to only 6.8% of patients with visceral metastases [439].

Further intensification of treatment using the new paclitaxel, cisplatin and gemcitabine (PCG) triple regimen did not result in a significant improvement in OS in the intent-to-treat (ITT) population of a large randomised phase III trial, comparing PCG triple regimen to GC [468]. However, the overall response rate (ORR) was higher with the triple regimen (56% vs. 44%; p=0.0031), and the trend for OS improvement in the ITT population (15.8 vs. 12.7 months; HR=0.85, p=0.075) became significant in the eligible population. Adding paclitaxel to GC did not induce major additional side effects. Grade 4 neutropenia was more common (35.8% vs. 20% for GC), as was febrile neutropenia (13.2% vs. 4.3%), and the need for G-CSF was higher (17% vs. 11%). Gemcitabine/cisplatin alone caused more G4 thrombocytopenia and thrombocytopenia-induced bleeding (11.4% vs. 6.8%). Paclitaxel, cisplatin and gemcitabine is an additional option for first-line treatment of UC.

7.8.4.Carboplatin-containing chemotherapy for fit patients

Carboplatin-containing chemotherapy is not equivalent to cisplatin combinations, and should not be considered interchangeable or standard. Several randomised phase II trials of carboplatin vs. cisplatin combination chemotherapy have produced lower CR rates and shorter OS for the carboplatin arms [469].

7.8.5.Non-platinum combination chemotherapy

Different combinations of gemcitabine and paclitaxel have been studied as first- and second-line treatments. Apart from severe pulmonary toxicity with a weekly schedule of both drugs, this combination is well tolerated and produces response rates between 38% and 60% in both lines. Non-platinum combination chemotherapy has not been compared to standard cisplatin chemotherapy in randomised trials, therefore, it is not recommended for first-line use in cisplatin-eligible patients [470-477].

7.8.6.Chemotherapy in patients unfit for cisplatin

Up to 50% of patients are ineligible for cisplatin-containing chemotherapy [455]. The first randomised phase II/III trial in this setting was conducted by the EORTC and compared methotrexate/carboplatin/vinblastine (M-CAVI) and carboplatin/gemcitabine (GemCarbo) in patients unfit for cisplatin. Both regimens were active. Severe acute toxicity (SAT) was 13.6% in patients treated with GemCarbo vs. 23% with M-CAVI, while the ORR was 42% for GemCarbo and 30% for M-CAVI. Further analysis showed that in patients with PS 2 and impaired renal function, combination chemotherapy provided limited benefit [453]. The ORR and SAT were both 26% for the former group, and 20% and 24%, respectively, for the latter group [453]. Phase III data have confirmed these results [445].

7.8.7.Second-line treatment

Second-line chemotherapy data are highly variable and prognostic factors have been established recently (see Section 7.8.1.1) [446]. A reasonable strategy may be to re-challenge former cisplatin-sensitive patients if progression occurs at least six to twelve months after first-line cisplatin-based combination chemotherapy. Second-line response rates of paclitaxel (weekly), docetaxel, nab-paclitaxel [478] oxaliplatin, ifosfamide, topotecan, pemetrexed, lapatinib, gefitinib and bortezomib have ranged between 0% and 28% in small phase II trials [462,479,480]. Although gemcitabine has also shown excellent response rates in second-line use, most patients already receive this drug as part of their front-line treatment [461].

Paclitaxel/gemcitabine studies have shown response rates of 38-60%. No randomised phase III trial with an adequate comparator arm has been conducted to assess the true value and OS benefit of this second-line combination [442,476,481].

Vinflunine, a novel third-generation vinca alkaloid, provided promising results in phase II trials [482]. A randomised phase III trial compared vinflunine plus best supportive care (BSC) against BSC alone in patients progressing after first-line treatment with platinum-containing combination chemotherapy for metastatic disease [483]. The results showed a modest ORR (8.6%), a clinical benefit with a favourable safety profile and, most importantly, a survival benefit in favour of vinflunine, which was statistically significant in the eligible patient population (not in the ITT population). For second-line treatment of advanced or metastatic UC, this trial reached the highest level of evidence ever reported. Currently, in Europe, vinflunine is the only approved second-line treatment. Vinflunine has not been approved for this indication in the United States.

7.8.8.Low-volume disease and post-chemotherapy surgery

With cisplatin-containing combination chemotherapy, excellent response rates may be obtained in patients with LN but no other metastases, good PS, and adequate renal function, including a high number of CRs, with up to 20% of patients achieving long-term DFS [439,467,484,485]. The role of surgery after chemotherapy is still unclear. Although some studies suggest a survival benefit and QoL improvement, the level of evidence supporting this practice is very limited [486-500]. A retrospective study of post-chemotherapy surgery after a partial or complete response has indicated that surgery may contribute to long-term DFS in selected patients [410,501,502].

7.8.9.Treatment of bone metastases

The prevalence of metastatic bone disease (MBD) in patients with advanced/metastatic UC is 30-40% [503]. Skeletal complications due to MBD have a detrimental effect on pain and QoL and are also associated with increased mortality [504]. Bisphosphonates reduce and delay skeletal-related events (SREs) due to bone metastases by inhibiting bone resorption. In a small pilot study in patients with BC, SREs caused by bone metastases were delayed [505]. Denosumab is a fully human monoclonal antibody that binds to and neutralises RANKL (receptor activator of nuclear factor-KB ligand), thereby inhibiting osteoclast function and preventing generalised bone resorption and local bone destruction. Denosumab is not inferior to zoledronic acid (ZA) in preventing or delaying SREs in patients with advanced MBD, including patients with UC [506]. Denosumab has recently been approved by the European Medicines Agency (EMA) for treatment of patients with bone metastases from solid tumours. Patients with MBD, irrespective of the cancer type, should be considered for bone-targeted treatment [504].

Patients treated with ZA or denosumab should be informed about possible side effects and receive prophylactic treatment for jaw osteonecrosis and hypocalcaemia, which is more common with denosumab. Aggressive calcium and vitamin D supplementation is recommended. Dosing regimens of ZA should follow regulatory recommendations and should be adjusted according to pre-existing medical conditions [507]. For denosumab, no dose adjustments are required for variations in renal function.

7.8.10.Role of immunotherapy

Immunomodulatory therapies using checkpoint inhibition, particularly with antibodies directed against the programmed cell death-1 (PD-1) protein or its ligand (PD-L1) have been tested. Atezolizumab, the first PD-L1 inhibitor was approved by the US Food and Drug Administration (FDA) in May 2016 for patients that have progressed during or after previous platinum-based chemotherapy. In a phase-II two-cohort study including 310 patients, the objective response rate was 15% independent of the expression of PD-L1. Progression-free survival was 2.1 and OS was 7.9 months. According to the expression level of PD-L1 numbers for response rate, PFS and OS were greater for patients with high expression but responses occurred also in patients with no expression of PD-L1. The toxicity profile of atezolizumab was favourable. Results of the phase III trial (NCT02302807) comparing atezolizumab with second-line chemotherapy are pending [508,509].

7.8.11.Summary of evidence and recommendations for metastatic disease

Summary of evidence	LE
In a first-line setting, performance status (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 months, with long-term disease-free survival reported in ~15% of patients with nodal disease and good PS.	1b
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
Non-platinum combination chemotherapy produces substantial responses in first- and second-line settings.	2a
Non-platinum combination chemotherapy has not been tested against standard chemotherapy inpatients who are fit or unfit for cisplatin combination chemotherapy.	4
There is no defined standard chemotherapy for unfit patients with advanced or metastatic urothelial cancer (UC).	2b
Vinflunine reaches the highest level of evidence ever reported for second-line use.	1b
Post-chemotherapy surgery after partial or complete response may contribute to long-term disease-free survival in selected patients.	3
Zoledronic acid and denosumab have been approved for all cancer types including UC, because they reduce and delay skeletal related events in metastatic bone disease.	1b
PD-L1 inhibitor atezolizumab has been FDA approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase-II trial.	2a

Recommendations	GR
First-line treatment for fit patients:
Use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with G-CSF, HD-MVAC with G-CSF or PCG.	A
Do not use carboplatin and non-platinum combination chemotherapy.	B
First-line treatment in patients ineligible (unfit) for cisplatin:
Use carboplatin combination chemotherapy or single agents.	C
For cisplatin-ineligible (unfit) patients, with performance status 2 or impaired renal function, as well as those with 0 or 1 poor Bajorin prognostic factors and impaired renal function, offer carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin.	B
Second-line treatment:
Offer vinflunine to patients progressing after platinum-based combination chemotherapy for metastatic disease. Alternatively, offer treatment within a clinical trial setting.	A*
Offer zoledronic acid or denosumab to treat bone metastases.	B

* Grade A recommendation is weakened since the key studies did not reach statistical significance.

GC=gemcitabine plus cisplatin; G-CSF=granulocyte colony-stimulating factor; MVAC=methotrexate, vinblastine, adriamycin plus cisplatin; HD MVAC=high-dose methotrexate, vinblastine, adriamycin plus cisplatin; PCG=paclitaxel, cisplatin, gemcitabine.

7.8.12.Biomarkers

Modest disease control rates, with sporadic marked responses, in some patients with UC have led to the investigation of biomarkers for assessment of post-operative prognosis and the potential value of peri-operative chemotherapy, and as predictors of response to chemotherapy or its monitoring. Most of the biomarkers are associated with tumour angiogenesis. Small studies, usually retrospective, have investigated microvessel density, altered p53 tumour expression [510], serum vascular endothelial growth factor [511], urinary and tissue basic fibroblast growth factor [512], urinary (wild-type and mutant) and tissue fibroblast growth factor receptor-3 [513], and more recently, thrombospondin-1 [514], circulating tumour cells [515,516], and multidrug resistance gene expression [517]. Although a few biomarkers have shown potential, as yet, there is insufficient evidence to support their routine clinical use (LE: 3).

7.8.12.1.Recommendation for the use of biomarkers

Recommendation	GR
Do not use biomarkers in daily clinical practice since they have no impact on predicting outcome, treatment decisions, or monitoring therapy in muscle-invasive bladder cancer.	A*

*Upgraded following panel consensus.

Figure 7.2: Flow chart for the management of metastatic urothelial cancer

BSC=best supportive care; GC=gemcitabine plus cisplatin; GFR=glomular filtration rate; MVAC=methotrexate, vinblastine, adriamycin plus cisplatin; HD MVAC=high-dose methotrexate, vinblastine, adriamycin plus cisplatin; PS=performance status; PCG=paclitaxel, cisplatin, gemcitabine.

7.9.Quality of life

7.9.1.Introduction

The evaluation of HRQoL considers physical, psychological, emotional and social functioning.

Several questionnaires have been validated for assessing HRQoL in patients with BC, including FACT (Functional Assessment of Cancer Therapy)-G [518], EORTC QLQ-C30 [519], EORTC QLQ-BLM (muscle-invasive BC module) [520], and SF (Short Form)-36 [521,522] and recently the BCI questionnaire specifically designed and validated for BC patients [523].

A psychometric test, such as the FACT-BL, should be used for recording BC morbidity. New intensive interviewing techniques have added valuable information to our knowledge of HRQoL, which greatly depends on patients’ individual preferences [524].

7.9.2.Choice of urinary diversion

There is controversy about which type of urinary diversion is best for a patient’s HRQoL [243]. Most patients stated that, given a choice, they would still opt for an orthotopic diversion rather than an ileal conduit [525]. Another study reported that, although urinary function is better in conduit patients, at long-term follow up (> 1 year) the urinary bother is the same in both diversion groups .

A SR based on 18 studies showed a slight, but not significant, better QoL in patients with an orthotopic diversion [526]. However, analysing only the studies comparing exclusively ileal conduit vs. ileal orthotopic neobladder, the advantage in QoL of the latter group was significant.

Due to improved surgical techniques in orthotopic bladder substitution, some recent studies are supportive of continent bladder substitutes [362,520,527]. Patients with an orthotopic substitution had significantly better physical function and a more active lifestyle compared to patients with an ileal conduit. It is important to note that HRQoL parameters are independent prognostic factors for OS [528]. Patients with a continent bladder-substitute generally scored more favourably than those with an incontinent diversion, as judged by body image, social activity and physical function [527,529]. Note that all studies investigated mostly male patients. Also of interest is the urinary bother in female neobladder. Bartsch and co-workers found in 56 female patients day-time and night-time incontinence rates of respectively 29.6% and 35.2%. Thirty-five patients (62.5%) performed clean intermittent catheterisation, which is much worse compared to male neobladder patients. Moreover, patients with non-organ-confined disease (p=0.04) and patients with a college degree (p=0.001) showed worse outcome on HRQoL scores [530].

Nevertheless, the HRQoL outcome is most likely a result of good patient selection. An older more isolated patient is probably better served with an ileal conduit whereas a younger patient with more interest in body image and sexuality is better off with an orthotopic diversion.

7.9.3.Non-curative or metastatic bladder cancer

In non-curative or metastatic BC, HRQoL is reduced because of associated micturition problems, bleeding, pain and therefore disturbance of social and sexual life [531]. There is limited literature describing HRQoL in BC patients receiving palliative care [532], but there are reports of bladder-related symptoms relieved by palliative surgery [385], RT [533], and/or chemotherapy [534].

Alternative definitive treatments of MIBC, e.g. trimodality bladder-sparing procedures, have shown similar survival times compared to cystectomy. However, the impact on HRQoL has been controversial [136,393,535-538].

7.9.4.Summary of evidence and recommendations for health-related quality of life

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

Recommendations	GR
Use validated questionnaires to assess HRQoL in patients with MIBC.	B
Offer a continent urinary diversion unless a patient’s comorbidities, tumour variables and coping abilities present clear contraindications.	C
Pre-operative patient information, patient selection, surgical techniques, and careful post-operative follow-up are the cornerstones for achieving good long-term results.	C
Encourage patients to actively participate in the decision-making process.
Provide clear and exhaustive information on all potential benefits and side-effects, allowing patients to make informed decisions.	A

9.REFERENCES

1.Rouprêt, M., et al. Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma. EAU Guidelines 2017. Edn presented at the 32nd EAU Annual Congress London 2017.

2.Babjuk, M., et al. Guidelines on Non-muscle-invasive bladder cancer (TaT1 and CIS). 2017. Edn presented at the 32nd EAU Annual Congress London 2017.

3.Gakis, G., et al. Guidelines on Primary Urethral Carcinoma EAU Guidelines 2017. Edn presented at the 32nd EAU Annual Congress London 2017.

4.Witjes, A.J., et al. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Eur Urol, 2017. 71: 462.

https://www.ncbi.nlm.nih.gov/pubmed/27375033

5.Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by Jeremy Howick March 2009.

http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/

6.Ferlay, J., et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer, 2013. 49: 1374.

https://www.ncbi.nlm.nih.gov/pubmed/23485231

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511.Shariat, S.F., et al. Association of angiogenesis related markers with bladder cancer outcomes and other molecular markers. J Urol, 2010. 183: 1744.

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517.Hoffmann, A.C., et al. MDR1 and ERCC1 expression predict outcome of patients with locally advanced bladder cancer receiving adjuvant chemotherapy. Neoplasia, 2010. 12: 628.

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521.Ware, J.E. Jr., et al. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care, 1992. 30: 473.

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523.Gilbert, S.M., et al. Development and validation of the Bladder Cancer Index: a comprehensive, disease specific measure of health related quality of life in patients with localized bladder cancer.
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524.Ramirez, A., et al. Exploration of health-related quality of life areas that may distinguish between continent diversion and ileal conduit patients. Can J Urol, 2005. 12: 2537.

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525.Saika, T., et al. Health-related quality of life after radical cystectomy for bladder cancer in elderly patients with an ileal conduit, ureterocutaneostomy, or orthotopic urinary reservoir: a comparative questionnaire survey. Acta Med Okayama, 2007. 61: 199.

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526.Cerruto, M.A., et al. Systematic review and meta-analysis of non RCT’s on health related quality of life after radical cystectomy using validated questionnaires: Better results with orthotopic neobladder versus ileal conduit. Eur J Surg Oncol, 2016. 42: 343.

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527.Singh, V., et al. Prospective comparison of quality-of-life outcomes between ileal conduit urinary diversion and orthotopic neobladder reconstruction after radical cystectomy: a statistical model. BJU Int, 2014. 113: 726.

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528.Roychowdhury, D.F., et al. Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer. J Clin Oncol, 2003. 21: 673.

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529.Hedgepeth, R.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.

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530.Bartsch, G., et al. Urinary functional outcomes in female neobladder patients. World J Urol, 2014. 32: 221.

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531.Fossa, S.D., et al. Quality of life in patients with muscle-infiltrating bladder cancer and hormone-resistant prostatic cancer. Eur Urol, 1989. 16: 335.

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532.Mommsen, S., et al. Quality of life in patients with advanced bladder cancer. A randomized study comparing cystectomy and irradiation--the Danish Bladder Cancer Study Group (DAVECA protocol 8201). Scand J Urol Nephrol Suppl, 1989. 125: 115.

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533.Fokdal, L., et al. Radical radiotherapy for urinary bladder cancer: treatment outcomes. Expert Rev Anticancer Ther, 2006. 6: 269.

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534.Rodel, C., et al. Organ preservation by combined modality treatment in bladder cancer: the European perspective. Semin Radiat Oncol, 2005. 15: 28.

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535.Lodde, M., et al. Four years experience in bladder preserving management for muscle invasive bladder cancer. Eur Urol, 2005. 47: 773.

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536.Rodel, C., et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol, 2002. 20: 3061.

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537.Merseburger, A.S., et al. The value of bladder-conserving strategies in muscle-invasive bladder carcinoma compared with radical surgery. Curr Opin Urol, 2007. 17: 358.

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538.Rodel, C., et al. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol, 2006. 24: 5536.

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539.Malkowicz, S.B., et al. Muscle-invasive urothelial carcinoma of the bladder. Urology, 2007. 69: 3.

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540.Karakiewicz, P.I., et al. Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder. J Urol, 2006. 176: 1354.

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541.Zaak, D., et al. Predicting individual outcomes after radical cystectomy: an external validation of current nomograms. BJU Int, 2010. 106: 342.

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542.Giannarini, G., et al. Do patients benefit from routine follow-up to detect recurrences after radical cystectomy and ileal orthotopic bladder substitution? Eur Urol, 2010. 58: 486.

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543.Volkmer, B.G., et al. Oncological followup after radical cystectomy for bladder cancer-is there any benefit? J Urol, 2009. 181: 1587.

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544.Soukup, V., et al. Follow-up after surgical treatment of bladder cancer: a critical analysis of the literature. Eur Urol, 2012. 62: 290.

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545.Huguet, J. Follow-up after radical cystectomy based on patterns of tumour recurrence and its risk factors. Actas Urol Esp, 2013. 37: 376.

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546.Ghoneim, M.A., et al. Radical cystectomy for carcinoma of the bladder: 2,720 consecutive cases 5 years later. J Urol, 2008. 180: 121.

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547.Donat, S.M. Staged based directed surveillance of invasive bladder cancer following radical cystectomy: valuable and effective? World J Urol, 2006. 24: 557.

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548.Mathers, M.J., et al. Is there evidence for a multidisciplinary follow-up after urological cancer? An evaluation of subsequent cancers. World J Urol, 2008. 26: 251.

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549.Vrooman, O.P., et al. Follow-up of patients after curative bladder cancer treatment: guidelines vs. practice. Curr Opin Urol, 2010. 20: 437.

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550.Cagiannos, I., et al. Surveillance strategies after definitive therapy of invasive bladder cancer. Can Urol Assoc J, 2009. 3: S237.

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551.Freeman, J.A., et al. Urethral recurrence in patients with orthotopic ileal neobladders. J Urol, 1996. 156: 1615.

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552.Huguet, J., et al. Management of urethral recurrence in patients with Studer ileal neobladder. Eur Urol, 2003. 43: 495.

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553.Nieder, A.M., et al. Urethral recurrence after cystoprostatectomy: implications for urinary diversion and monitoring. Urology, 2004. 64: 950.

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554.Varol, C., et al. Treatment of urethral recurrence following radical cystectomy and ileal bladder substitution. J Urol, 2004. 172: 937.

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555.Lin, D.W., et al. Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy. J Urol, 2003. 169: 961.

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556.Sherwood, J.B., et al. The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol, 2006. 24: 356.

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558.Bochner, B.H., et al. Follow-up strategies and management of recurrence in urologic oncology bladder cancer: invasive bladder cancer. Urol Clin North Am, 2003. 30: 777.

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2.METHODS »

3.EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY »

4.STAGING AND CLASSIFICATION SYSTEMS »

5.DIAGNOSTIC EVALUATION »

6.PROGNOSIS »

7.DISEASE MANAGEMENT »

8.FOLLOW-UP »

9.REFERENCES »

10.CONFLICT OF INTEREST »

Top

Recommendations	GR
Record the depth of invasion (categories pT2a and pT2b, pT3a and pT3b or pT4).	A*
Record margins with special attention paid to the radial margin, prostate, ureter, urethra and peritoneal fat and uterus and vaginal top.
Record the number of lymph nodes (LNs) and number of positive LNs.
Record lymphatic or blood vessel invasion and extranodal extension.
Record the presence of carcinoma in situ.

T - Primary Tumour
Tx	Primary tumour cannot be assessed
T0	No evidence of primary tumour
Ta	Non-invasive papillary carcinoma
Tis	Carcinoma in situ: “flat tumour”
T1	Tumour invades subepithelial connective tissue
T2	Tumour invades muscle
	T2a	Tumour invades superficial muscle (inner half)
	T2b	Tumour invades deep muscle (outer half)
T3	Tumour invades perivesical tissue:
	T3a	microscopically
	T3b	macroscopically (extravesical mass)
T4	Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
	T4a	Tumour invades prostate stroma, seminal vesicles, uterus, or vagina
	T4b	Tumour invades pelvic wall or abdominal wall
N - Regional Lymph Nodes
Nx	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral)
N2	Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral)
N3	Metastasis in a common iliac lymph node(s)
M - Distant Metastasis
M0	No distant metastasis
	M1a	Non-regional lymph nodes
	M1b	Other distant metastasis

Recommendations	GR
During cystoscopy, describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended.	C
Take a biopsy of the prostatic urethra for cases of bladder neck tumour, when bladder carcinoma in situ is present or suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible.	C
Take a biopsy at the time of the second resection, if no biopsy was taken during the initial procedure.	C
In women undergoing subsequent orthotopic neobladder construction, obtain procedural information (including histological evaluation) of the bladder neck and urethral margin, either prior to or at the time of cystoscopy.	C
Specify the grade, depth of tumour invasion, and whether the lamina propria and muscle tissue are present in the specimen in the pathological report.	C

Recommendations	GR
In patients with confirmed MIBC, use computed tomography (CT) of the chest, abdomen and pelvis as the optimal form of staging. Include excretory-phase CT urography for complete examination of the upper urinary tract.	B
Diagnose upper urinary tract urothelial carcinoma (UTUC) using excretory-phase CT urography rather than magnetic resonance (MR) urography as excretory-phase CT urography has greater diagnostic accuracy and is associated with less cost, and greater patient acceptability.	C
Use MR urography when CT urography is contraindicated for reasons related to contrast administration or radiation dose.	C
Perform endoscopically-guided biopsy for histopathological confirmation of pre-operative diagnosis of UTUC.	C
Use CT or magnetic resonance imaging (MRI) for staging locally advanced or metastatic disease in patients in whom radical treatment is considered.	B
Use CT to diagnose pulmonary metastases. CT and MRI are generally equivalent for diagnosing local disease and distant metastases in the abdomen.	C

Number of points	Conditions
1 point	50-60 years
	Myocardial infarction
	Heart failure
	Peripheral vascular insufficiency
	Cerebrovascular disease
	Dementia
	Chronic lung disease
	Connective tissue disease
	Ulcer disease
	Mild liver disease
	Diabetes
2 points	61-70 years
	Hemiplegia
	Moderate to severe kidney disease
	Diabetes with organ damage
	Tumours of all origins
3 points	71-80 years
3 points	Moderate to severe liver disease
4 points	81-90 years
5 points	> 90 years
6 points	Metastatic solid tumours
6 points	AIDS

Summary of evidence	LE
Worldwide, bladder cancer is the 11th most commonly diagnosed cancer.	2a
Several risk factors connected with the risk of bladder cancer diagnosis have been identified.	3
Active and passive tobacco smoking continues to be the main risk factor, while the exposure-related incidence is decreasing.	2a
The increased risk of developing bladder cancer in patients undergoing external-beam radiotherapy (EBRT), brachytherapy (BT), or a combination of EBRT and BT, must be taken into account during patient follow-up. As bladder cancer requires time to develop, patients treated with radiation at a young age are at the greatest risk and should be followed up closely.	3

Recommendations	GR
The principal preventable risk factor for MIBC is active and passive smoking.	B
Notwithstanding stricter regulations, workers should be informed about the potential carcinogenic effects of a number of recognised substances, duration of exposure, and latency periods. Protective measures should be recommended.	A

Summary of evidence	LE
Currently, treatment decisions cannot be based on molecular markers.	3

Summary of evidence	LE
Imaging as part of staging in muscle-invasive bladder cancer (MIBC) provides information about prognosis and assists in selection of the most appropriate treatment.	2b
There are currently insufficient data on the use of diffusion-weighted imaging (DWI) and fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) in MIBC to allow a recommendation to be made.

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	GR
Base the decision on bladder-sparing treatment or radical cystectomy in elderly/geriatric patients with invasive bladder cancer on tumour stage and comorbidity.	B
Assess comorbidity by a validated score, such as the Charlson Comorbidity Index. The American Society of Anesthesiologists (ASA) score should not be used in this setting (see section 7.4.4.1).	B

Site of recurrence	Summary of evidence	LE	Recommendation	GR
Local recurrence	Poor prognosis. Treatment should be individualised depending on the local extent of tumour.	2b	Offer radiotherapy, chemotherapy and possibly surgery as options for treatment, either alone or in combination.	C
Distant recurrence	Poor prognosis.	2b	Offer chemotherapy as the first option, and consider metastasectomy in case of unique metastasis site.	C
Upper urinary tract recurrence	Multifocal disease (non-muscle-invasive bladder cancer/carcinoma in situ or positive ureteral margins).		See EAU guidelines on Upper Urinary Tract Urothelial Carcinomas.
Secondary urethral tumour	Staging and treatment should be done as for primary urethral tumour.	3	Use local conservative treatment for non-invasive tumour.	C
			Offer urethrectomy in isolated invasive disease.	B
			Do not use urethral washes and cytology.	A

1.INTRODUCTION

1.1.Aims and scope

1.2.Panel Composition

1.3.Available publications

1.4.Publication history and summary of changes

1.4.1.Publication history

1.4.2.Summary of changes

1.4.2.1.Change in summary of evidence

2.METHODS

2.1.Data identification

2.2.Review

2.3.Future goals

3.EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1.Epidemiology

3.2.Aetiology

3.2.1.Tobacco smoking

3.2.2.Occupational exposure to chemicals

3.2.3.Radiotherapy

3.2.4.Dietary factors

3.2.5.Bladder schistosomiasis and chronic urinary tract infection

3.2.6.Gender

3.2.7.Genetic factors

3.3.Pathology

3.3.1.Handling of transurethral resection and cystectomy specimens

3.3.2.Pathology of muscle-invasive bladder cancer

4.STAGING AND CLASSIFICATION SYSTEMS

4.1.Pathological staging

4.2.Tumour, node, metastasis classification

5.DIAGNOSTIC EVALUATION

5.1.Primary diagnosis

5.1.1.Symptoms

5.1.2.Physical examination

5.1.3.Bladder imaging

5.1.4.Urinary cytology and urinary markers

5.1.5.Cystoscopy

5.1.6.Transurethral resection of invasive bladder tumours

5.1.7.Second resection

5.1.8.Concomitant prostate cancer

5.1.9.Summary of evidence and specific recommendations for the primary assessment of presumably invasive bladder tumours

5.2.Imaging for staging of MIBC

5.2.1.Local staging of MIBC

5.2.1.1.MRI for local staging of invasive bladder cancer

5.2.1.2.CT imaging for local staging of MIBC

5.2.2.Imaging of lymph nodes in MIBC

5.2.3.Upper urinary tract urothelial carcinoma

5.2.4.Distant metastases at sites other than lymph nodes

5.2.5.Future developments

6.PROGNOSIS

6.1.Introduction

6.2.MIBC and comorbidity

6.2.1.Evaluation of comorbidity

6.2.2.Comorbidity scales, anaesthetic risk classification and geriatric assessment

6.2.4.Prognostic markers

6.2.4.1.Tumour location

6.2.4.2.Molecular markers