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) (NMIBC) [2], and primary urethral carcinomas [3].

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

Guidelines are not mandates and do not purport to be a legal standard of care.

1.2.Panel Composition

The EAU Guidelines Panel consists of an international multidisciplinary group of clinicians, including urologists, 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/bladdercancermuscle-invasive-and-metastatic/?type=panel.

1.3.Available publications

A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version.

Several scientific publications are available (the most recent paper dating back to 2017 [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 2018 document presents a limited update of the 2017 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 2018 EAU MIBC Guidelines.

Key changes in the 2018 print are:

Section 5.2 – Imaging for staging of MIBC. This section has been aligned with the EAU Guidelines on Urothelial Carcinoma of the Upper Urinary Tract (UTUC) [1].

5.2.6 Summary of evidence and guidelines for staging in muscle-invasive bladder cancer

Section 7.4.3.1 – Pelvic organ preservation techniques in men. The systematic review (SR) this section is based on has been published [5].

Section 7.4.3.2 – Pelvic organ preservation techniques in women. The SR this section is based on has been published [6].

Section 7.6.4 – Multimodality bladder-preserving treatment. This section was revised, to include new data, however, the recommendations did not change.

Section 7.8.10 – Role of immunotherapy. Two additional subsections have been added and new recommendations have been included.

7.8.11 Summary of evidence and guidelines for metastatic disease

Figure 7.2 - Flow chart for the management of metastatic urothelial cancer, was completely revised.

Chapter 8 – Follow-up, has been completely revised.

2.METHODS

2.1.Data identification

For the 2018 MIBC Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature.

A broad and comprehensive literature search, covering all sections of the MIBC Guideline was performed. The search was limited to English language publications. Databases searched included Medline, EMBASE and the Cochrane Libraries, covering a time frame between April 5th 2016 and June 2nd 2017. A total of 5,961 records were identified, retrieved and screened for relevance. Forty-one new publications have been included in the 2018 print. A detailed search strategy is available online: http://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/?type=appendices-publications.

For the 2018 edition of the EAU Guidelines the Guidelines Office have transitioned to a modified GRADE methodology across all 20 guidelines [7,8]. For each recommendation within the guidelines there is an accompanying online strength rating form which addresses a number of key elements namely:

1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [9];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [10]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. The strength rating forms will be available online.

Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/.

A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2.Peer-review

No separate peer-review was done for the 2018 print of the MIBC Guidelines.

2.3.Future goals

Topics considered for inclusion in the 2019 update of the MIBC Guidelines:

• a systematic review on the impact of variant histology on bladder cancer outcomes;
• a systematic review on hospital volume and outcome of surgery in muscle-invasive bladder cancer;
• differential diagnosis for haematuria.

3.EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1.Epidemiology

Bladder cancer (BC) is the 7th most commonly diagnosed cancer in the male population worldwide, whilst it drops to 11th when both genders are considered [11]. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.0 for men and 2.2 for women [11]. In the European Union, the age-standardised incidence rate is 19.1 for men and 4.0 for women [12]. In Europe, the highest age-standardised incidence rate has been reported in Belgium (31 in men and 6.2 in women) and the lowest in Finland (18.1 in men and 4.3 in women) [11,12].

Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) was 3.2 for men vs. 0.9 for women in 2012 [11,12]. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and availability of treatments. The variations are, however, also partly caused by the different methodologies used in the studies and the quality of data collection [13,14].

The incidence and mortality of BC has decreased in some registries, possibly reflecting the decreased impact of causative agents [14,15].

Approximately 75% of patients with BC present with disease confined to the mucosa (stage Ta, carcinoma in situ [CIS]) or submucosa (stage T1). In younger patients (< 40 years) this percentage is even higher [16]. Patients with TaT1 and CIS have a high prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality compared to T2-4 tumours [12,13,17].

3.2.Aetiology

3.2.1.Tobacco smoking

Tobacco smoking is the most well-established risk factor for BC, causing 50-65% of male cases and 20-30% of female cases [18]. A causal relationship has been established between exposure to tobacco and cancer in studies in which chance, bias and confounding can be discounted with reasonable confidence [19].

The incidence of BC is directly related to the duration of smoking and the number of cigarettes smoked per day [20]. A meta-analysis looked at 216 observational studies on cigarette smoking and cancer published between 1961 and 2003, and the pooled risk estimates for BC demonstrated a significant association for both current and former smokers [21]. Recently, an increase in risk estimates for current smokers relative to never smokers has been described suggesting this could be due to changes in cigarette composition [18]. An immediate decrease in the risk of BC was observed in those who stopped smoking. The reduction was about 40% within one to four years of quitting smoking and 60% after 25 years of cessation [20]. Encouraging people to stop smoking would result in the incidence of BC decreasing equally in men and women.

3.2.2.Occupational exposure to chemicals

Occupational exposure is the second most important risk factor for BC. Work-related cases accounted for 20-25% of all BC cases in several series and it is likely to occur in occupations in which dyes, rubbers, textiles, paints, leathers, and chemicals are used [22]. The risk of BC due to occupational exposure to carcinogenic aromatic amines is significantly greater after ten years or more of exposure; the mean latency period usually exceeds 30 years [23,24]. Population-based studies established the occupational attribution for BC in men to be 7.1%, while no such attribution was discernible for women [13,25].

3.2.3.Radiotherapy

Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy (EBRT) for gynaecological malignancies, with relative risks (RR) of 2-4 [26]. In a population-based cohort study, the standardised incidence ratios for BC developing after radical prostatectomy (RP), EBRT, brachytherapy (BT), and EBRT-BT were 0.99, 1.42, 1.10, and 1.39, respectively, in comparison with the general U.S. population [27].

It has recently been proposed that patients who have received radiotherapy (RT) for prostate cancer with modern modalities such as intensity-modulated radiotherapy (IMRT) may have lower rates of in-field bladder- and rectal secondary malignancies [28]. Nevertheless, since longer follow-up data are not yet available, and as BC requires a long period to develop, patients treated with radiation and with a long life-expectancy are at a higher risk of developing BC [28].

3.2.4.Dietary factors

Several dietary factors have been considered to be related to BC; however, the links remain controversial. The European Prospective Investigation into Cancer and Nutrition (EPIC) study is an on-going multicentre cohort study designed to examine the association between diet, lifestyle, environmental factors and cancer. They found no links between BC and fluid intake, red meat, vegetable and fruit consumption, and only recently they have described an inverse association between dietary intake of flavonols and lignans and the risk of BC, in particular aggressive tumours [29].

3.2.5.Bladder schistosomiasis and chronic urinary tract infection

Bladder schistosomiasis (bilharzia) is the second most common parasitic infection after malaria, with about 600 million people exposed to infection in Africa, Asia, South America, and the Caribbean [30]. There is a well-established relationship between schistosomiasis and urothelial carcinoma (UC) of the bladder, which can progress to squamous cell carcinoma (SCC), however, a better control of the disease is decreasing the incidence of SCC of the bladder in endemic zones such as Egypt [31,32].

Similarly, invasive SCC has been linked to the presence of chronic urinary tract infection (UTI) distinct from schistosomiasis. A direct association between BC and UTIs has been observed in several case-control studies, which have reported a two-fold increased risk of BC in patients with recurrent UTIs in some series. However, some of these results may be attributed to recall bias [33].

3.2.6.Gender

Although men are more likely to develop BC than women, women present with more advanced disease and have worse survival rates. A meta-analysis including nearly 28,000 patients shows that female gender was associated with a worse survival outcome (hazard ratio [HR]: 1.20; 95% CI: 1.09-1.32) compared to male gender after radical cystectomy (RC) [34]. This finding had already been presented in a descriptive Nation-Wide Analysis based on 27,773 Austrian patients. After their analysis the authors found that cancer-specific-survival (CSS) was identical for pT1-tumours in both sexes, while women had a worse CSS in both age cohorts (< 70 years and ≥ 70 years) with higher tumour stages [35]. However this higher mortality is questionable once both genders receive the same therapy. In a population-based study from the Ontario Cancer Registry analysing all patients with BC treated with cystectomy or radical RT between 1994 and 2008, no differences in overall survival (OS), mortality and outcomes were found between males and females following radical therapy [36].

A population-based study from the MarketScan databases suggests that a possible reason for worse survival in the female population may be that women experienced longer delays in diagnosis than men, as the differential diagnosis in women includes diseases that are more prevalent than BC [37].

Furthermore, differences in the gender prevalence of BC may be due to other factors besides tobacco and chemical exposure. In a large prospective cohort study, post-menopausal status was associated with an increase in BC risk, even after adjustment for smoking status. This result suggests that the differences in oestrogen and androgen levels between men and women may be responsible for some of the difference in the gender prevalence of BC [38-40].

3.2.7.Genetic factors

There is growing evidence that genetic susceptibility factors and family association may influence the incidence of BC. The relationship between family history of cancer and risk of BC was examined in a Spanish BC study showing that family history of cancer in first-degree relatives was associated with an increased risk of BC; the association being stronger among younger patients. Shared environmental exposure was recognised as a potentially confounding factor [41]. Recent studies detected genetic susceptibility with independent loci, which are associated with BC risk [42].

Genome-wide association studies (GWAS) of BC identified several susceptibility loci associated with BC risk [43,44].

3.2.8.Summary of evidence and guidelines for epidemiology and risk factors

3.3.Pathology

3.3.1.Handling of transurethral resection and cystectomy specimens

In transurethral resection (TUR), a snap frozen specimen from the tumour and normal looking bladder wall should be taken, if possible. Separate specimens should be taken from the superficial and deep areas of the tumour and sent to the pathology laboratory separately, in case the outcome will impact on treatment decisions. If random biopsies of the flat mucosa are taken, each biopsy specimen of the flat mucosa should also be sent separately.

In RC, bladder fixation must be carried out as soon as possible. The pathologist must open the specimen from the urethra to the bladder dome and fix the specimen. In some circumstances this procedure can also be performed by the urologist. In a female cystectomy specimen, the length of the urethral segment removed en bloc with the specimen should be checked, preferably by the urological surgeon [45].

Specimen handling should follow the general rules as published by a collaborative group of pathologists and urologists [46,47]. It must be stressed that it may be very difficult to confirm the presence of a neoplastic lesion using gross examination of the cystectomy specimen after TUR or chemotherapy, so the entire retracted or ulcerated area should be included.

It is compulsory to study the urethra, the ureters, the prostate in men and the radial margins [48]. In urethra-sparing cystectomy; the level of urethral dissection, completeness of the prostate, specifically at the apex (in men), and the inclusion of the entire bladder neck and amount of adjacent urethra, uterus and vaginal top (in women) should be inked and documented.

All lymph node (LN) specimens should be provided in their totality, in clearly labelled containers. In case of doubt, or adipose differentiation of the LN, the entire specimen is to be included. Lymph nodes should be counted and measured on slides, capsular extension and percentage of LN invasion should be reported as well as vascular embols [49,50]. In the case of metastatic spread in the perivesical fat without real LN structures (capsule, subcapsular sinus), this localisation should nevertheless be considered as N+.

A meta-analysis indicated that LN density is an independent predictor of clinical outcome (HR OS: 1.45; 95%, confidence interval [CI]: 1.11-1.90) [51].

Positive margins in the peripelvic fat tissue (soft tissue margins), should be inked by the pathologist for evaluation. Positive margins decrease CSS in cases of pN0M0 UCs [52].

In rare cases, fresh frozen sections may be helpful to determine treatment strategy. A recent study confirmed the reliability of fresh frozen sections of obturator LNs, but further studies are warranted to confirm these results [53].

3.3.2.Pathology of muscle-invasive bladder cancer

In MIBC all cases are high-grade UCs. For this reason, no prognostic information can be provided by grading MIBC [54]. However, identification of some morphological subtypes may be important for prognostic reasons and treatment decisions [55,56]. Recently, an update of the World Health Organization (WHO) grading was published [57] however, the data presented in these guidelines are based on the 2004 WHO classification [58]. Currently the following differentiations are used:

1.urothelial carcinoma (more than 90% of all cases);

2.urothelial carcinomas with partial squamous and/or glandular differentiation [59,60];

3.micropapillary and microcystic UC;

4.nested variant [61] (including large nested variety);

5.lymphoepithelioma;

6.plasmocytoid, giant cell, signet ring, diffuse, undifferentiated;

7.some UCs with trophoblastic differentiation;

8.small-cell carcinomas [62];

9.sarcomatoid carcinomas.

3.3.3.Guidelines for the assessment of tumour specimens

4.STAGING AND CLASSIFICATION SYSTEMS

4.1.Pathological staging

For staging, the Tumour, Node, Metastasis (TNM) classification (2017, 8th edition) is recommended [63]. Blood and lymphatic vessel invasion and LN infiltration have an independent prognostic significance [64,65]. It seems that the pN category is closely related to the number of LNs studied by the pathologist [63]. New prognostic markers are under study (see Section 6.2.4 Prognostic Markers).

4.2.Tumour, node, metastasis classification

The TNM classification of malignant tumours is the method most widely used to classify the extent of cancer spread [55-57,63,66] (Table 4.1).

Table 4.1: TNM classification of urinary bladder cancer [63]

5.DIAGNOSTIC EVALUATION

5.1.Primary diagnosis

5.1.1.Symptoms

Painless haematuria is the most common presenting complaint. Other clinical signs include urgency, dysuria, increased frequency, and in more advanced tumours, pelvic pain and symptoms related to urinary tract obstruction.

5.1.2.Physical examination

Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be found in patients with locally advanced tumours. In addition, bimanual examination under anaesthesia should be carried out before and after transurethral resection of the bladder (TURB), to assess whether there is a palpable mass or if the tumour is fixed to the pelvic wall [67,68]. However, considering the discrepancy between bimanual examination and pT stage after cystectomy (11% clinical overstaging and 31% clinical understaging), some caution is suggested with the interpretation of bimanual examination [69].

5.1.3.Bladder imaging

Patients with a bladder mass identified by any diagnostic imaging technique should undergo cystoscopy, biopsy and/or resection for histopathological diagnosis and staging.

5.1.4.Urinary cytology and urinary markers

Examination of voided urine or bladder washings for exfoliated cancer cells has high sensitivity in high-grade tumours (LE: 3) and is a useful indicator in cases of high-grade malignancy or CIS.

However, positive urinary cytology may originate from a urothelial tumour located anywhere in the urinary tract. Evaluation of cytology specimens can be hampered by low cellular yield, UTIs, stones or intravesical instillations, but for experienced readers, specificity exceeds 90% [70,71] (LE: 2b). However, negative cytology does not exclude a tumour. There is no known urinary marker specific for the diagnosis of invasive BC [72].

A standardised reporting system redefining urinary cytology diagnostic categories was published in 2016 by the Paris Working Group [73]:

• Adequacy of urine specimens (Adequacy);
• Negative for high-grade UC (Negative);
• Atypical urothelial cells (AUC);
• Suspicious for high-grade UC (Suspicious);
• High-grade UC (HGUC);
• Low-grade urothelial neoplasia (LGUN).

5.1.5.Cystoscopy

Ultimately, the diagnosis of BC is made by cystoscopy and histological evaluation of resected tissue. If a bladder tumour has been visualised unequivocally by imaging studies, such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), diagnostic cystoscopy may be omitted and the patient can proceed directly to TURB for histological diagnosis and resection. Currently, there is no evidence for the role of photodynamic diagnosis (PDD) in the standard diagnosis of invasive BC.

A careful description of the cystoscopic findings is necessary. This should include documentation of the site, size, number, and appearance (papillary or solid) of the tumours, as well as a description of any mucosal abnormalities [29]. The use of a bladder diagram is recommended.

The use of PDD could be considered if a T1 high-grade tumour is present, to identify associated CIS. Presence of CIS may lead to a modified treatment plan (see Section 7.1). Photodynamic diagnosis is highly sensitive for the detection of CIS, but in experienced hands, the rate of false-positive results may be similar to that with regular white-light cystoscopy [65,74].

5.1.6.Transurethral resection of invasive bladder tumours

The goal of TURB is to enable histopathological diagnosis and staging, which requires the inclusion of bladder muscle in the resection biopsies.

The strategy of resection depends on the size of the lesion. Small tumours (< 1 cm in diameter) can be resected en bloc, where the specimen contains the complete tumour plus a part of the underlying bladder wall including muscle. Larger tumours need to be resected separately in parts, which includes the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle, and the edges of the resection area. At least the deeper part of the resection specimen must be referred to the pathologist in a separate labelled container to enable them to make a correct diagnosis. In cases in which RT is considered and CIS is to be excluded, PDD can be used [75].

The involvement of the prostatic urethra and ducts in men with bladder tumours has been reported. The exact risk is not known, but it seems to be higher if the tumour is located on the trigone or bladder neck, in the presence of bladder CIS, and in the case of multiple tumours [76,77] (LE: 3). Involvement of the prostatic urethra can be determined either at the time of primary TURB or by frozen section during the cystoprostatectomy procedure. A frozen section has a higher negative-predictive value and is more accurate [78-80].

5.1.7.Second resection

In the case of high-grade non-muscle-infiltrative tumour, residual disease is observed in 33-53% of patients [81-87]. In order to reduce the risk of understaging [82,83], a second TURB resection is often required to determine the future treatment strategy.

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 below the verumontanum bladder neck and on the inferior limits of the bladder neck for females.

5.1.8.Concomitant prostate cancer

Prostate cancer is found in 25-46% of patients undergoing cystectomy for BC [88,89]. The impact on survival is unknown but the impact on surgical treatment is limited.

5.1.9.Summary of evidence and guidelines for the primary assessment of presumably invasive bladder tumours
(For general information on the assessment of bladder tumours, see EAU Guidelines on Non-muscle-invasive Bladder Cancer [2]).

5.2.Imaging for staging of MIBC

The treatment and prognosis of MIBC is determined by tumour stage and grade [90,91]. In clinical practice, CT and MRI are the imaging techniques used. The purpose of using imaging for staging MIBC is to determine prognosis and provide information to assist treatment selection. Tumour staging must be accurate to ensure that the correct choice of treatment is made. Imaging parameters required for staging MIBC are:

• extent of local tumour invasion;
• tumour spread to LNs;
• tumour spread to the upper urinary tract (UUT) and other distant organs (e.g., liver, lungs, bones, peritoneum, pleura, and adrenal glands).

5.2.1.Local staging of MIBC

Both CT and MRI may be used for assessment of local invasion, but they are unable to accurately diagnose microscopic invasion of perivesical fat (T2 vs. T3a) [92]. The principal aim of CT and MRI is therefore to detect T3b disease, or higher.

5.2.1.1.MRI for local staging of invasive bladder cancer

Magnetic resonance imaging has superior soft tissue contrast resolution compared with CT, but poorer spatial resolution. In studies performed before the availability of multidetector CT, MRI was reported as more accurate in local assessment. The accuracy of MRI for primary tumour staging varies from 73% to 96% (mean 85%). These values were 10-33% (mean 19%) higher than those obtained with CT [93]. Dynamic contrast-enhanced (DCE) MRI may help to differentiate bladder tumour from surrounding tissues or evaluate post-biopsy reaction, because enhancement of the tumour occurs earlier than that of the normal bladder wall, due to neovascularisation [94-96].

In 2006, a link was established between the use of gadolinium-based contrast agents and nephrogenic systemic fibrosis (NSF), which may result in fatal or severely debilitating systemic fibrosis. Patients with impaired renal function are at risk of developing NSF and non-ionic linear gadolinium-based contrast agents should be avoided (gadodiamide, gadopentetate dimeglumine and gadoversetamide). A stable macrocyclic contrast agent should be used (gadobutrol, gadoterate meglumine or gadoteridol). Contrast-enhanced CT using iodinated contrast media should be considered as an alternative [97] (LE: 4).

5.2.1.2.CT imaging for local staging of MIBC

The advantages of CT include high spatial resolution, shorter acquisition time, wider coverage in a single breath hold, and lower susceptibility to variable patient factors. Computed tomography is unable to differentiate between stages from Ta - T3a tumours, but it is useful for detecting invasion into the perivesical fat (T3b) and adjacent organs. The accuracy of CT in determining extravesical tumour extension varies from 55% to 92% [98] and increases with more advanced disease [99].

5.2.2.Imaging of lymph nodes in MIBC

Assessment of LN metastases based solely on size is limited by the inability of both CT and MRI to identify metastases in normal-sized or minimally enlarged nodes. The sensitivity for detection of LN metastases is low (48-87%). Specificity is also low because nodal enlargement may be due to benign disease. Overall, CT and MRI show similar results in the detection of LN metastases in a variety of primary pelvic tumours [100-105]. Pelvic nodes > 8 mm and abdominal nodes > 10 mm in maximum short-axis diameter, detected by CT or MRI, should be regarded as pathologically enlarged [106,107]. Currently, there is no evidence supporting the routine use of positron emission tomography (PET) in the nodal staging of BC, although the method has been evaluated with varying results in small prospective trials [108-111].

5.2.3.Upper urinary tract urothelial carcinoma

5.2.3.1.Computed tomography urography

Computed tomography urography has the highest diagnostic accuracy of the available imaging techniques [112]. The sensitivity of CT urography for UTUC is 0.67–1.0 and specificity is 0.93–0.99 [113].

Rapid acquisition of thin sections allows high-resolution isotropic images that can be viewed in multiple planes to assist with diagnosis without loss of resolution. Epithelial “flat lesions” without mass effect or urothelial thickening are generally not visible with CT.

The secondary sign of hydronephrosis is associated with advanced disease and poor oncological outcome [114,115]. The presence of enlarged LNs is highly predictive of metastases in UTUC [116].

5.2.3.2.Magnetic resonance urography

Magnetic resonance urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated [117]. The sensitivity of MR urography is 0.75 after contrast injection for tumours < 2 cm [117]. The use of MR urography with gadolinium-based contrast media should be limited in patients with severe renal impairment (< 30 mL/min creatinine clearance), due to the risk of NSF. Computed tomography urography is generally preferred to MR urography for diagnosing and staging UTUC.

5.2.4.Distant metastases at sites other than lymph nodes

Prior to any curative treatment, it is essential to evaluate the presence of distant metastases. Computed tomography and MRI are the diagnostic techniques of choice to detect lung [118] and liver metastases [119], respectively. Bone and brain metastases are rare at the time of presentation of invasive BC. A bone scan and additional brain imaging are therefore not routinely indicated unless the patient has specific symptoms or signs to suggest bone or brain metastases [120,121]. Magnetic resonance imaging is more sensitive and specific for diagnosing bone metastases than bone scintigraphy [122,123] (LE: 2b).

5.2.5.Future developments

Evidence is accruing in the literature suggesting that fluorodeoxyglucose (FDG)-PET/CT might have potential clinical use for staging metastatic BC [124,125], but there is no consensus as yet. The results of further trials are awaited before a recommendation can be made. Recently, the first study was published showing the superior feasibility of diffusion-weighted imaging (DWI) over T2-weighted and DCE MRI for assessing the therapeutic response to induction chemotherapy against MIBC [126]. The high specificity of DWI indicates that it is useful for accurate prediction of a complete histopathological response, allowing better patient selection for bladder-sparing protocols. Results from prospective studies are awaited.

5.2.6.Summary of evidence and guidelines for staging in muscle-invasive bladder cancer

6.PROGNOSIS

6.1.Introduction

The treatment and prognosis for MIBC is mainly determined by tumour and nodal stage [91].The pathological report will inform on histological type, lymphovascular invasion, presence of CIS, positive margins and extranodal extension. In clinical practice, CT and MRI are the imaging techniques used.

6.2.MIBC and comorbidity

Complications related to RC may be directly related to pre-existing comorbidity as well as the surgical procedure, bowel anastomosis, or urinary diversion. A significant body of literature has evaluated the usefulness of age as a prognostic factor for RC [127-129].

Advanced age has been identified as a risk factor for complications of RC, although chronological age is less important than biological age. Other risk factors for morbidity include prior abdominal surgery, extravesical disease, and prior RT [130]. Female gender, an increased body mass index (BMI) and lower pre-operative albumin levels are associated with a higher rate of parastomal hernias [131].

Low pre-operative serum albumin is also associated with impaired wound healing, gastrointestinal complications and a decrease of recurrence-free and OS after RC [132,133]. Therefore, it could be used as a prognostic biomarker for patients undergoing RC.

6.2.1.Evaluation of comorbidity

Rochon et al. have shown that evaluation of comorbidity provides a better indicator of life expectancy in MIBC than patient age [134]. The evaluation helps to identify the medical conditions likely to interfere with, or have an impact on, treatment and the evolution and prognosis of MIBC [135].

The value of assessing overall health before recommending and proceeding with surgery was emphasised by Zietman et al., who have demonstrated an association between comorbidity and adverse pathological and survival outcomes following RC [136]. Similar results were found for the impact of comorbidity on cancer-specific and other-cause mortality in a population-based competing risk analysis of > 11,260 patients from the Surveillance, Epidemiology, and End Results (SEER) registries. Age carried the highest risk for other-cause mortality but not for increased cancer-specific death, while the stage of locally advanced tumour was the strongest predictor for decreased CSS [137]. Stratifying elderly patients according to their risk-benefit profile using a multidisciplinary approach will help to select patients most likely to benefit from radical surgery and to optimise treatment outcomes [138]. Unfortunately, most series evaluating RC do not include indices of comorbidity in the patient evaluation.

6.2.2.Comorbidity scales, anaesthetic risk classification and geriatric assessment

A range of comorbidity scales has been developed [139]; six of which have been validated [140-145]
(LE: 3). The Charlson Comorbidity Index (CCI) ranges from 0 to 30 according to the importance of comorbidity described at four levels and is calculated by healthcare practitioners based on patients’ medical records. The score has been widely studied in patients with BC and found to be an independent prognostic factor for peri-operative mortality [146,147], overall mortality [148], and cancer-specific mortality [149-152]. Only the age-adjusted version of the CCI was correlated with both cancer-specific and other-cause mortality [153]. The age-adjusted CCI (Table 6.1) is the most widely used comorbidity index in cancer for estimating long-term survival and is easily calculated [154].

Table 6.1: Calculation of the Charlson Comorbidity Index

Interpretation

1.Calculate Charlson Comorbidity Score or Index=i
a. Add comorbidity score to age score
b. Total denoted as ‘i’ in the Charlson Probability calculation (see below). i=sum of comorbidity score to age score

2.Calculate Charlson Probability (10-year mortality=Y)
a. Calculate Y=10^{(i x 0.9)}
b. Calculate Ƶ=0.983Y (where Ƶ is the 10-year survival)

Health assessment of oncology patients must be supplemented by measuring their activity level. Extermann et al. have shown that there is no correlation between morbidity and competitive activity level [155]. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores and Karnofsky index have been validated to measure patient activity [156] (LE: 3). Performance score is correlated with patient OS after RC [151] and palliative chemotherapy [157-159].

According to a consensus conference of the National Institutes of Health, the aim of the Standardized Geriatric Assessment (SGA) is to discover, describe and explain the many problems of elderly people, to catalogue their resources and strengths, to assess individual service needs, and to develop a coordinated plan of care. The SGA can be carried out by means of several protocols. These protocols differ in the completeness of diagnostic research. The most complete protocol is the Comprehensive Geriatric Assessment (CGA) [160] which is tailored to the care of cancer patients [161]. In BC, the CGA has been used to adapt gemcitabine chemotherapy in previously untreated elderly patients with advanced BC [162].

6.2.3.Summary of evidence and guidelines for comorbidity scales

6.2.4.Prognostic markers

6.2.4.1.Tumour location

Location of the tumour at the bladder trigone has shown to be associated with an increased likelihood of nodal metastasis (OR 1.83 95% CI: 1.11-2.99) and decreased survival (OR 1.68; 95% CI: 1.11-2.55) [90].

6.2.4.2.Molecular markers

The performance of current commercially available pathological prognostic markers points to the relevance of including molecular prognostic markers in clinical practice [163], but so far very few studies have addressed this topic. At present, insufficient evidence exists to recommend the standard use of prognostic marker p53 in high-risk muscle-invasive disease, as it will not yield sufficient data upon which to base treatment in an individual patient [164].

Recent publications demonstrated four main molecular groups of BC:

• basal BC with the basal and claudin low-type group;
• luminal BC with luminal and p53-like subtype.

The basal group, which can have sarcomatoid aspects and shows an over-expression of epidermal growth factor receptor 3 (EGFR3), is chemosensitive, the luminal type displays an over-expression of fibroblast growth factor receptor 3 (FGFR3), epidermal growth factor receptor (ERBB2↑ and ERBB3), and is chemotherapy resistant [55,56,165].

In 2014, The Cancer Genome Atlas (TCGA) project in BC reported on the integrated genomic analysis of the first 131 MIBC patients, identifying genes that are mutated in a significant proportion of BCs, several of which were not previously reported [166]. Profiling studies have also reported on validated biomarker panels that predict prognosis and can be used to identify patients who may benefit from more aggressive therapy [167]. In the coming years, expanding knowledge of BC carcinogenesis may change our management of the disease.

7.DISEASE MANAGEMENT

7.1.Treatment failure of non-muscle invasive bladder cancer

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

In 2015 the European Organisation for Research and Treatment of Cancer (EORTC) group presented new nomograms based on two large phase III trials with a median follow-up of 7.4 years. These showed that with one to three years of maintenance bacillus Calmette-Guérin (BCG), the risk for progression at five years was 19.3% for T1G3 tumours [168]. Meta-analyses have demonstrated that BCG-therapy prevents the risk of tumour recurrence [169] and the risk of tumour progression [170,171] but so far, no significant overall- or disease-specific survival advantages have been shown, as compared to no intravesical therapy [170-172]. 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 [173-175]. Second TURB identifies upstaging to > T2 tumours in 10-20% of patients [176,177].

Progression to MIBC has been shown to significantly decrease 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. Although all studies reflect these findings, a recent large retrospective Canadian study showed that even progressive patients had a slightly better outcome [178]. High-grade T1 disease remains a dangerous disease, which underlines the need to recommend early radical treatment, such as RC, in case of intravesical therapy failure [2,179].

According to the EAU NMIBC Guidelines, it is reasonable to propose immediate RC to patients with non-muscle-invasive tumours who are at highest risk of progression [180-182]. 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 present 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 UC;
• 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 [2,174,183,184] (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 [185];
• 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 [186] (LE: 3).

There are now several bladder-preservation strategies available; immunotherapy, chemotherapy, device- assisted therapy, and combination therapy [187]. However, experience is limited and treatments other than RC must be considered oncologically inferior at the present time [187].

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

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 [175,188-191]. To improve these results, neoadjuvant chemotherapy (NAC) has been used since the 1980s [192,193].

There are many advantages and disadvantages of administering chemotherapy before planned definitive

surgery to patients with resectable muscle-invasive UC of the bladder and cN0M0 disease:

• Chemotherapy is delivered at the earliest time-point, when the burden of micrometastatic disease is expected to be low.
• Potential reflection of in-vivo chemosensitivity.
• Tolerability of chemotherapy and patient compliance are expected to be better pre-cystectomy.
• Patients 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 [194,195], although published studies on the negative effect of delayed cystectomy only include chemonaive 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 [196]. 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 [197].
• Clinical staging using bimanual palpation, CT or MRI may often result in over- and understaging and have a staging accuracy of only 70% [198,199]. 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 [196,200-212].

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 [213-216]. 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 [217]. 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 [218,219] (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 [196,200-209,220-225]. 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 [210-212]. In a meta-analysis, published in 2005 [212], with updated patient data from eleven randomised trials (n=3,005), a significant survival benefit was shown in favour of NAC. Compared with the 2005 meta-analysis, the most recent meta-analysis published in 2016 incorporated four additional randomised trials and used updated results from three large randomised trials, the Nordic I, Nordic II, and BA06 30894 trial (n=427 new patients and updated information on 1,596 patients). The results of this analysis confirmed the previously published data and showed a 8% absolute improvement in survival at five years with a number needed to treat of 12.5 [226].

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 [195]. Only cisplatin combination chemotherapy with at least one additional chemotherapeutic agent resulted in a meaningful therapeutic benefit [210,212]; the regimens tested were methotrexate, vinblastine, adriamycin (epirubicin) 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 [200] 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 (DFS), 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 [197]. 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 [217].

7.2.4.Summary of evidence and guidelines for neoadjuvant chemotherapy

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

7.3.1.Post-operative radiotherapy

The only data on adjuvant RT after RC are very limited and old. 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 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

To date, six randomised studies have been published, investigating pre-operative RT, although all are from several decades ago. In the largest trial, pre-operative RT at a dose of 45 Gy was used in patients with muscle-invasive tumours resulting in a significant increase in pathological complete response (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 (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 the 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 guidelines for pre- and post-operative radiotherapy

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 [175,243]. 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 and life expenctancy influence the choice of primary management, as well as the type of urinary diversion, with cystectomy being reserved for patients with a longer life expectancy without concomitant disease and a better PS. The value of assessing overall health before proceeding with surgery was emphasised in a multivariate analysis [149]. The analysis found an association between comorbidity and adverse pathological- and survival outcomes 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

A recent analysis of the Netherlands Cancer Registry showed that a delay of RC > 3 months was not associated with a worse clinical outcome [246]. Previously, Ayres et al. also found that in the United Kingdom 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 2001 and 2011 and concluded that a delay of more than twelve weeks has a negative impact on outcome and should be avoided [247]. Moreover, the SEER analysis did not show any significant utilisation and timing differences between men and women.

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 non-muscle-invasive 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-UC (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 [248].

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 [249]. In women, standard RC includes removal of the bladder, entire urethra and adjacent vagina, uterus, distal ureters, and regional LNs [250]. 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 [251]. 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 [252]. 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 [253-257]. Mapping studies have also found that skipping lesions at locations above the bifurcation of the aorta, without more distally located LN metastases, is rare [257,258].

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 [259]. 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 [259-263]. A super-extended lymphadenectomy extends cranially to the level of the inferior mesenteric artery [264,265].

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 [266]. Out of 1,692 abstracts retrieved and assessed, nineteen studies fulfilled the review criteria [259-263,265,267-279]. All five studies comparing LND vs. no LND reported a better oncological outcome for the LND group. Seven out of twelve studies comparing (super-)extended with limited or standard LND reported a beneficial outcome for (super)extended LND in at least a subset of patients which is in concordance with several other recently performed meta-analyses [280,281]. No difference in outcome was reported between extended and super-extended LND in the two high-volume-centre studies identified [265,277]. 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, survival rates increase with the number of dissected LNs [282]. 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 [283-285]. Submitting separate nodal packets instead of en bloc, has shown significant increased total LN yield, but did not result in an increased number of positive LNs, making LN density an inaccurate prognosticator [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 [132].

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 the EAU MIBC Panel undertook a SR [6].

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 [249,287-296] and three single-arm case series [297-299]. 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 with a median follow-up longer than five years.

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

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

For 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 was incidental prostate cancer with Gleason score ≥ 8 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 from 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

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 [5]. 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 years, CSS was 70-100% and OS was 65-100%, respectively. 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

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). However, since there is now a continuous flow of reports on RARC, this section of the text and the recommendations contained therein will be subject to significant updates in the coming years. A number of new publications have recently become available on RARC; a SR [300], a consensus panel report [301], a RCT from the Memorial Sloan Kettering Cancer Center (MSKCC) group [302] a SR on oncologic and functional outcomes after RARC [303] and a retrospective review on recurrence patterns after open radical cystectomy (ORC) and RARC [304].

For the methodology of the SR we refer to the manuscript by Novara et al. [300]. 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 duration of the operation 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. Intra-operative, 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 [302] compared to a large series of ORC (n=1,054) 47% of included patients had a < pT2 tumour [175].

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 [301] 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 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 chemotherapy 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. Safety after radiotherapy was confirmed by a small (n=46) retrospective study [305]. In experienced hands the percentage of 90-day (major) complications after robotic cystectomy was independent of previous RT.

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-day grade 2-5 complications for RARC [302]. 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. Similar health-related QoL (HRQoL) was also reported in an initial report of a prospective RCT comparing ORC and RARC [306]. Similar functional and oncological outcomes with five years follow-up were reported by Yuh et al. [303]. Nguyen et al. reported that RARC was not an independent predictor of recurrence after surgery in a retrospective review of 383 consecutive patients [304].

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

Although an intracorporeal neobladder is a very complex robotic procedure [307], 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 [307]. 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 [307].

The CORAL study was a small single centre RCT comparing open (n=20) vs. robotic (n=20) vs. laparoscopic (n=19) cystectomy [308]. The 30-day complication rate was significantly higher in the open arm (70%) compared to the laparoscopic arm (26%). There was no difference between the 90-day Clavien-graded complication rates in the three arms. Limitations of this study include the small and below target sample size, three different, although experienced, surgeons, and cross over between arms.

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

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.Patient selection and 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]

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 [248].

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 [313].

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 [314]. Despite the necessary interruption and re-anastomosis of bowel, a formal bowel preparation may not be necessary [315]. Bowel recovery time can be reduced by the use of early mobilisation and early oralisation, gastrointestinal stimulation with metoclopramide and chewing gum [316]. 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 [317].

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 (Visual Analogue Scale 3.1 vs. 1.1, p < 0.001), but post-operative ileus decreased from 22% to 7.3% (p=0.003) [318].

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 [319]. 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 [320].

7.4.4.2.Different types of urinary diversion

Radical cystectomy and urinary diversion are the two steps of one operation. However, the literature uniformly reports complications of RC, while ignoring the fact that most complications are diversion related [321]. Age alone is not a criterion for offering continent diversion [320,322]. 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 [323-326]. 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) [327]. Only age and anastomotic 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 [328]. Therefore, in older, or otherwise compromised, patients who need a supravesical diversion, ureterocutaneostomy is the preferred procedure [329,330]. Quality of life, which was assessed using the BCI, showed equal urinary bother and function for patients treated with ileal conduit and ureterocutaneostomy [328].

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 [329].

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) [331].

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 [332].

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 [332]. 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% [333-335]. 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) [336]; 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 [337-339]. Different anti-reflux techniques can be used [340]. Most patients have a well-functioning reservoir with day-time and night-time continence approaching 93% [341]. 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 [341]. Stone formation in the pouch occurred in 10% of patients [340-342]. In a small series of previously irradiated female patients, incontinence and stomal stenosis was seen in 8/44 patients (18%) [343].

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) [344,345]. 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 [313,346]. 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 [188,243,320]. 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 [320,352], 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) [320,354]. 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 [355,356].

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 [340,351]. According to the long-term results, the UUT is protected sufficiently by either method.

A detailed investigation of the bladder neck prior to RC is important for women who are scheduled for an orthotopic bladder substitute [357]. In women undergoing RC the rate of concomitant urethral malignancy has been reported to range from 12-16% [358]. 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 [359].

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 [360,361]. 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 [188,321,323,362,363]. In a large single-centre series, early complications (within three months of surgery) were seen in 58% of patients [321]. Late morbidity was usually linked to the type of urinary diversion (see also above) [324,364]. 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 [365]. 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 [362,366-370].

Table 7.6: Management of neobladder morbidity (30-64%) [371]

1 A recent SR showed that peri-operative blood transfusion (PBT) in patients who undergo RC correlates with increased overall 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 [372]. Buchner and co-workers showed similar results in a retrospective study. The 5-year CSS decreased in cases where intra-operative blood transfusion (CSS decreased from 67% to 48%) or post-operative blood transfusion (CSS decreased from 63% to 48%) were given [373].

2 Intra-operative tranexamin acid infusion reduces peri-operative blood transfusion rates from 57.7% to 31.1%. There was no increase seen in peri-operative 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 cystectomy. 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 [175]. However, the five-year recurrence-free survival in node-positive patients who underwent cystectomy was considerably less at 34-43% [174,175,379]. 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 [175].

A trend analysis according to the five-year survival and mortality rates of BC in the U.S., 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 guidelines for radical cystectomy and urinary diversion

Figure 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.Guidelines for unresectable tumours

7.5.2.Supportive care

7.5.2.1.Obstruction of the upper urinary tract

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

7.5.2.2.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, approximately 50% of patients 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 refuses open surgery, or as part of a multimodality bladder-preserving approach [392].

7.6.1.1.Guideline for transurethral resection of bladder tumour

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 complete response (CR) rate 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 more recent retrospective study in 118 medically unfit patients, with a median age of 80 years, confirmed efficacy with a CR rate of 87% and 73% locoregional control after 3 years [397]. Toxicity was reported to be low with late grade ≥ 2 urinary and intestinal toxicity rates of 14 and 5%, respectively.

A 2002 Cochrane analysis demonstrated that RC has an OS benefit compared to RT [398], although this was not the case in a 2014 retrospective review using a propensity score analysis [399]. In conclusion, EBRT can be an alternative treatment in patients unfit for radical surgery.

7.6.2.1.Summary of evidence and guideline for external beam radiotherapy

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% [400,401]. Response to chemotherapy is a prognostic factor for treatment outcome and eventual survival [198], although 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 [196,225,402,403]. Neoadjuvant chemotherapy with 2-3 cycles of MVAC or CMV has led to a downstaging of the primary tumour in different prospective series [196,225,402]. Pathological CR 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 [196,225,402,404-411].

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 [198]. However, this approach cannot be recommended for routine use.

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

7.6.4.Multimodality bladder-preserving treatment

Multimodality treatment (MMT) or trimodality treatment combines TURB, chemotherapy and radiation. The rationale for combing TURB with RT is to achieve local tumour control in the bladder and adjacent nodes. The addition of systemic chemotherapy or other radiosensitisers (mentioned below) is aimed at the potentiation of RT. Micrometastases are targeted by platinum-based combination chemotherapy, a topic covered in the section on NAC (see Section 7.2). The aim of MMT is to preserve the bladder and QoL, without compromising oncological outcome. There are no completed RCTs comparing the outcome of MMT with RC, but MMT has been shown to be superior to RT alone [412,413]. Many of the reported series have differing characteristics as compared to the larger surgical series, which typically have median ages in the mid to late 60s compared to mid-70s for some large RT series (reviewed by James, et al. [412]). In the case of MMT, two distinct patterns of care emerge: 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]. Even in the case of an initial presumed complete resection, a second TUR reveals tumour in > 50% of patients and subsequently improves 5-year OS in case of MMT [415]. 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.

A recent collaborative review has described the principles of MMT [416]. For radiation, two schedules are in common use worldwide: a split-dose format with interim cystoscopy is used in the U.S. [413], whilst single-phase treatment is more commonly used elsewhere [412]. A standard radiation schedule includes EBRT to the bladder and limited pelvic LNs with an initial dose of 40 Gy, with a boost to the whole bladder of 54 Gy and a further tumour boost, with a total dose of 64 Gy. In a small RCT, however, it was reported that leaving out elective pelvic nodal irradiation did not compromise pelvic control rate, but significantly decreased the acute radiation toxicity [417].

Different chemotherapy regimens have been used, but most evidence exists for cisplatin [418] and mitomycin C plus 5-FU [412]. In addition to these agents, other schedules have also been used, such as hypoxic cell sensitisation with nicotinamide, carbogen and gemcitabine. To detect non-responders, which should be offered salvage cystectomy, bladder biopsies should be performed after MMT.

The 5-year CSS and OS rates vary between 50% to 82% and 36% to 74%, respectively, with salvage cystectomy rates of 10–30% [412,416,418,419]. The Boston group reported on their experience in 66 patients treated with MMT and variant histology and found similar CR, OS, DSS and salvage cystectomy rates as in UC [420]. The impact of MMT as compared to RC on long-term OS remains undefined. Seisen et al. found similar median OS comparing both treatment options in a large series, but after two years, OS after MMT was significantly worse (RR 1.4) [421]. In another large series, however, even ten year survival data were comparable [422].

There are data that major complication rates are similar for salvage and primary cystectomy [423]. The majority of recurrences post-MMT are non invasive and can be managed conservatively [412]. Indeed, a retrospective study showed QoL to be good after MMT and in most domains better than after cystectomy, although prospective validations are needed [424].

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 [416]. 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.

There are no definitive data to support the benefit of using neoadjuvant or adjuvant chemotherapy. Critical to good outcomes is patient selection [416].

A bladder-preserving multimodality strategy requires very close multidisciplinary cooperation and a high level of patient compliance. Even if a patient has shown a clinical response (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 [425]. After a median follow-up of 5.9 years 41/119 (35%) of these patients experienced a bladder recurrence, and fourteen required salvage cystectomy. There was no difference between complete and near-complete responders.

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

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 [423,426] and is infrequently used [192].

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 [427].

There is limited evidence from adequately conducted and accrued randomised phase III trials in favour of the routine use of adjuvant chemotherapy [426,428-433]. An individual patient data meta-analysis [428] of survival data from six RCTs of adjuvant chemotherapy [419,434-437] included 491 patients (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 [426]. 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 [438], and one trial used cisplatin monotherapy [436]. These data were not convincing enough to give an unequivocal recommendation for the use of adjuvant chemotherapy.

In 2014, this meta-analysis [429] was updated with an additional three studies [430-432] resulting in the total inclusion of 945 patients from nine trials. None of the trials were fully accrued and no individual patient data were used in the analysis [429]. For one trial, only an abstract was available at the time of the meta-analysis [431], 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) [430,431]. 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.

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) [439]. A 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 [440].

Furthermore, a large observational study including 5,653 patients with pathological T3-4 and/or pathological node-positive BC, treated between 2003 and 2006 compared the effectiveness of adjuvant chemotherapy vs. observation. Twenty-three percent of patients received adjuvant chemotherapy with a five-year OS of 37% for the adjuvant arm (HR: 0.70; 95% CI: 0.64-0.76), vs. 29.1% in the observation group [441].

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 [408,442,443]. 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 [429]. 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.Guideline for adjuvant chemotherapy

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 [444]. Before the development of effective chemotherapy, patients with metastatic UC rarely had a median survival that exceeded three to six months [445].

7.8.1.1.Prognostic factors and treatment decisions

Prognostic factors are crucial for assessing phase II study results and stratifying phase III trials [406,410]. In a multivariate analysis, Karnofsky PS of < 80% and presence of visceral metastases were independent prognostic factors of poor survival after treatment with MVAC [410]. These prognostic factors have also been validated for newer combination chemotherapy regimens [446-448].

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 [449]. 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 [450-453]. In one phase III trial, the GFR cut off for cisplatin eligibility was > 50 mL/min [454].

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 [455].

7.8.1.3.Not eligible for cisplatin (unfit)

The EORTC conducted the first randomised phase II/III trial for UC patients who were unfit for cisplatin chemotherapy [456]. The EORTC definitions were GFR < 60 mL/min and/or PS 2.

An international survey among BC experts [457] 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 [458].

More than 50% of patients with UC are not eligible for cisplatin-based chemotherapy [459-462]. Renal function assessment in UC is of utmost importance for treatment selection. Calculation of creatinine clearance (CrCl) (24-hour urine collection) with current formulae tend to underestimate clearance in patients aged > 65 years compared to measured CrCl [459,463].

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 [464,465]. 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 to 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 with stagnant long-term survival of twelve to fourteen months in all series (for a review see [466]). Methotrexate, vinblastine, adriamycin plus cisplatin 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 equivalence of the two regimens [442]. 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 [467]. Methotrexate, vinblastine, adriamycin plus cisplatin is better tolerated when combined with granulocyte colony-stimulating factor (G-CSF) [467,468].

High-dose intensity MVAC (HD-MVAC) combined with G-CSF is less toxic and more efficacious than standard MVAC in terms of dose density, CR, and two-year survival rate. However, there is no significant difference in median survival between the two regimens [469,470]. 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 [469]. The disease sites also have an impact on long-term survival. In LN-only disease, 20.9% of patients were alive at five years compared to only 6.8% of patients with visceral metastases [442].

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 [471]. 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 grade 4 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 [472].

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 RCTs, therefore, it is not recommended for first-line use in cisplatin-eligible patients [473-480].

7.8.6.Chemotherapy in patients unfit for cisplatin

Up to 50% of patients are ineligible for cisplatin-containing chemotherapy [458]. 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 [456]. The ORR and SAT were both 26% for the former group, and 20% and 24%, respectively, for the latter group [456]. Phase III data have confirmed these results [448].

A recently published randomised, multinational phase-II trial (JASINT1) assessed the efficacy and tolerability profile of two vinflunine-based regimens (vinflunine-gemcitabine vs. vinflunine-carboplatin). Both regimens showed equal ORR and OS with less haematologic toxicity for the combination vinflunine-gemcitabine [481].

7.8.7.Second-line treatment

Second-line chemotherapy data are highly variable and prognostic factors have been established only recently (see Section 7.8.1.1) [449]. A reasonable strategy has been to re-challenge former cisplatin-sensitive patients if progression occurred, at least six to twelve months after first-line cisplatin-based combination chemotherapy. Second-line response rates of paclitaxel (weekly), docetaxel, nab-paclitaxel [482] oxaliplatin, ifosfamide, topotecan, pemetrexed, lapatinib, gefitinib and bortezomib have ranged between 0% and 28% in small phase II trials [465,483,484]. Although gemcitabine had also shown excellent response rates in second-line use, most patients already received this drug as part of their first-line treatment [464].

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 [445,479,485].

Vinflunine, a novel third-generation vinca alkaloid, provided promising results in phase II trials [486]. 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 [487]. 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. Based on these findings, vinflunine was approved in Europe (not in the U.S.) as the only second-line treatment option for this indication. As immunotherapy with checkpoint inhibitors has recently been approved for second-line treatment in metastatic UC, vinflunine should only be offered as second-line treatment if checkpoint inhibitors or combination chemotherapy are not feasible. However, vinflunine may be considered as third-line treatment option, although no randomised data exist for this indication.

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 [442,470,488,489]. The role of surgery of residual LNs after chemotherapy is still unclear. Although some studies suggest a survival benefit and QoL improvement, the level of evidence supporting this practice is very limited [490-504]. Retrospective studies of post-chemotherapy surgery after a partial or CR have indicated that surgery may contribute to long-term DFS in selected patients [411,505-507].

Surgery for limited pulmonary metastases may also be considered in highly selected cases. In the absence of data from RCTs, patients should be evaluated on an individual basis [507].

7.8.9.Treatment of bone metastases

The prevalence of metastatic bone disease (MBD) in patients with advanced/metastatic UC is 30-40% [508]. Skeletal complications due to MBD have a detrimental effect on pain and QoL and are also associated with increased mortality [509]. 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 [510]. Denosumab is a fully human monoclonal antibody that binds to and neutralises RANKL (receptor activator of nuclear factor-κB 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 [511]. 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 [509].

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 [512]. 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, its ligand (PD-L1) or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-pathway have shown significant anti-tumour activity with tolerable safety profiles and durable responses in patients with locally advanced and metastatic UC. Trials currently investigate immunotherapy agents; either as monotherapy or in combination with other immune-enhancing agents in a first-line or subsequent management setting. Pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab have demonstrated similar efficacy in patients progressing during, or after, standard platinum-based chemotherapy.

7.8.10.1.First-line immunotherapy for patients not eligible for standard cisplatin chemotherapy

A phase-II trial assessed the PD-1 inhibitor pembrolizumab in 370 patients with advanced or metastatic UC ineligible for cisplatin, showing an ORR of 29% and CR in 7% of patients [513]. With the PD-L1 inhibitor atezolizumab, a second agent was evaluated in this patient population. A two-cohort phase-II trial (n=119) included patients unfit for cisplatin (cohort 1). The ORR was 29%; 9% of patients presented with a CR and median OS was 15.9 months [514].

The toxicity profile was favourable for pembrolizumab as well as for atezolizumab. Since 2017 both drugs are U.S. Food and Drug Administration (FDA) and EMA approved for first-line treatment in cisplatin-ineligible patients.

7.8.10.2.Second-line immunotherapy for platinum-pretreated patients

Atezolizumab was the first PD-L1 inhibitor approved by the FDA (May 2016) for patients progressing during, or after, previous platinum-based chemotherapy. In a phase-II 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 in patients with high expression, but responses occurred also in patients with no expression of PD-L1. The toxicity profile of atezolizumab was favourable [515,516]. The results of the phase III trial (IMvigor211)) comparing atezolizumab with second-line chemotherapy were recently reported but have not yet been published as a full paper [514]. The trial did not met its first endpoint OS.

Pembrolizumab, a PD-1 inhibitor, was the first agent that showed significant OS benefit in patients progressing during, or after, platinum-based first-line chemotherapy. Based on the results of a phase-III trial the agent was approved in 2017. In the trial, patients (n=542) were randomised to receive either pembrolizumab monotherapy, or chemotherapy (either paclitaxel, docetaxel or vinflunine). The median OS in the pembrolizumab arm was 10.3 months (95% CI: 8.0-11.8) vs. 7.4 months (95% CI: 6.1-8.3) for the chemotherapy arm (HR for death, 0.73; 95% CI: 0.59-0.91, p=0.002) independent of PD-L1 expression levels [517].

In 2017 Nivolumab, another PD-1/PD-L1 inhibitor was approved based on the results of a single-arm phase-II trial (CheckMate275), enrolling 270 patients. The first endpoint was ORR. Patients were stratified by their PD-L1 expression (> 5% vs. < 5%). Objective response rate was 19.6%, and OS was 8.74 months for the entire group [518].

Based on results of phase I/II and phase Ib trials, two additional agents, durvalumab and avelumab (PD-1/PD-L1 inhibitors) are currently only approved for this indication in the United States, but not in Europe [519-521].

Current data show that in responders, PD-1/PD-L1 inhibitors can not only produce durable responses but also offer a superior survival benefit as compared to standard chemotherapy regimens.

7.8.11.Summary of evidence and guidelines for metastatic disease

GC=gemcitabine plus cisplatin; G-CSF=granulocyte colony-stimulating factor; 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 biomarkers are associated with tumour angiogenesis [522]. Small studies, usually retrospective, have investigated microvessel density, altered p53 tumour expression [522], serum vascular endothelial growth factor [523], urinary and tissue basic fibroblast growth factor [524], urinary (wild-type and mutant) and tissue fibroblast growth factor receptor-3 [525], and more recently, thrombospondin-1 [526], circulating tumour cells [527,528], and multidrug resistance gene expression [529]. 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

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

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

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 [530], EORTC QLQ-C30 [531], EORTC QLQ-BLM (muscle-invasive BC module) [532], and SF (Short Form)-36 [533,534] and recently the BCI questionnaire specifically designed and validated for BC patients [535].

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 [536].

7.9.2.Radical cystectomy and urinary diversion

Two recent SRs focused on HRQoL after RC [537,538] and one SR, based on 18 studies (n=1,553), showed a slight, but not significant, improvement of QoL in patients with an orthotopic diversion [537]. However, analysing only the studies comparing exclusively ileal conduit vs. ileal orthotopic neobladder, the advantage in QoL of the latter group was significant. Another SR, based on 29 studies (n=3,754), showed no difference in overall QoL between continent and incontinent diversion [538]. Subgroup analysis demonstrated greater improvement in physical health for incontinent compared to continent diversions (p=0.002), but no differences in mental health (p=0.35) or social health (p=0.81). However, patients with a neobladder demonstrated superior emotional function and body image [538-540].

Clifford and co-workers prospectively evaluated continence outcomes in male patients undergoing orthotopic neobladder diversion [541]. Day-time continence increased from 59% at less than three months post-operatively to 92% after 12 to 18 months. Night-time continence increased from 28% at less than three months post-operatively to 51% after 18 to 36 months. Also of interest is the urinary bother in female neobladder. Bartsch and co-workers found in 56 female patients day-time and night-time continence rates of 70.4% and 64.8%, respectively. Thirty-five patients (62.5%) performed clean intermittent catheterisation, which is much worse when 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 outcomes on HRQoL scores [542].

All together, HRQoL outcomes are most likely a result of good patient selection. An older, more isolated, patient is probably better served with an ileal conduit, whereas a younger patient with a likely higher level of interest in body image and sexuality is better off with an orthotopic diversion. The patient’s choice is the key to the selection of reconstruction method [538].

7.9.3.Bladder sparing trimodality therapy

A cross-sectional bi-institutional study found in multivariable analysis that patients who received trimodality therapy (n=64) had higher physical-, social-, emotional- and cognitive functioning, better general QoL, sexual function and body image than patients after RC (n=109). However, urinary symptom scores were similar [424]. To draw valid conclusions, prospective studies are needed.

7.9.4.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 [543]. There is limited literature describing HRQoL in BC patients receiving palliative care [544], but there are reports of bladder-related symptoms relieved by palliative surgery [385], RT [545], and/or chemotherapy [546].

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

8.FOLLOW-UP

8.1.Follow-up in muscle invasive bladder cancer

An appropriate schedule for disease monitoring should be based on natural timing of recurrence; probability and site of recurrence; functional monitoring after urinary diversion and the potential available management options [547].

Nomograms on CSS following RC have been developed and externally validated, but their wider use cannot be recommended until further data become available [548,549].

Current surveillance protocols are based on patterns of recurrence drawn from retrospective series only. Combining this data is not possible since most retrospective studies use different follow-up regimens and imaging techniques. Additionally, reports of asymptomatic recurrences diagnosed during routine oncological follow-up, and results from retrospective studies are contradictory [550-552]. From the Volkmer B, et al. series of 1,270 RC patients, no differences in OS were observed between asymptomatic and symptomatic recurrences [551]. Conversely, in the Giannarini, et al. series of 479 patients; those with recurrences detected during routine follow-up investigations (especially in the lungs) and with secondary urothelial tumours as the site of recurrence, had a slightly higher survival probability [550]. Boorjian, et al. included 1,599 RC patients in their series, 77% of which had symptomatic recurrences. On multivariate analysis, patients who were symptomatic at recurrence had a 60% increased risk of death as compared to asymptomatic patients [552].

However, at this time, no data from prospective trials, demonstrating the potential benefit of early detection of recurrent disease, and its impact on OS, are available [553].

8.2.Site of recurrence

8.2.1.Local recurrence

Local recurrence takes place in the soft tissues of the original surgical site or in LNs. Contemporary cystectomy has a 5-15% probability of pelvic recurrence that usually occurs during the first 24 months, most often within six to eighteen months after surgery. However, late recurrences can occur up to five years after RC. Risk factors described are pathological stage, LNs, positive margins, extent of LND and peri-operative chemotherapy [554].

Patients generally have a poor prognosis after pelvic recurrence. Even with treatment, the median survival ranges from four to eight months following diagnosis. Definitive therapy can prolong survival, but mostly provides significant palliation of symptoms. Multimodality management generally involves a combination of chemotherapy, radiation and surgery [553].

8.2.2.Distant recurrence

Distant recurrence is seen in up to 50% of patients treated with RC for MIBC. As with local recurrence, pathological stage and nodal involvement are risk factors [555]. Systemic recurrence is more common in locally advanced disease (pT3/4), ranging from 32 to 62%, and in patients with LN involvement (range 52–70%) [556].

The most likely sites for distant recurrence are LNs, lungs, liver and bone. Nearly 90% of distant recurrence appears within the first three years after RC, mainly in the first two years, although late recurrence has been described after > 10 years. Median survival of patients with progressive disease treated with platinum-based chemotherapy is 9–26 months [557-559]. However, longer survival (28-33% at five years) has been reported in patients with minimal metastatic disease undergoing multimodality management, including metastasectomy [491,499].

8.2.3.Urothelial recurrences

The incidence of new urethral tumours after RC is 1.5-6.0% in men, with a mean recurrence-free interval of 13.5-39.0 months and median survival of 28–38 months, of which > 50% die from systemic disease. Secondary urethral tumours are likely to occur at one to three years after surgery. Independent predictors for urethral recurrence are: cystectomy for NMIBC, prostate involvement, and a history of recurrent NMIBC [553].

In women, the main risk factor is bladder neck disease. Many studies have demonstrated that the risk of urethral recurrence after orthotopic diversion (0.9-4.0%) is significantly less than after non-orthotopic diversion (6.4-11.1%) [554].

There is limited data, and agreement, about urethral follow-up, with some authors recommending routine surveillance with urethral wash and urine cytology and others doubting the need for routine urethral surveillance. However, there is a significant survival advantage in men with urethral recurrence diagnosed asymptomatically vs. symptomatically, so follow-up of the male urethra is indicated in patients at risk of urethral recurrence [553]. Treatment is influenced by local stage and grade of urethral occurrence; in urethral CIS, BCG instillations have success rates of 83% [560]. In invasive disease, urethrectomy should be performed if the urethra is the only site of disease and in distant disease, systemic chemotherapy is indicated [4].

Upper urinary tract urothelial carcinomas occur in 1.8-6.0% of cases and represent the most common sites of late recurrence (three-year disease-free survival following RC). Median OS is 10-55 months, and 60-67% of patients die of metastatic disease [553]. A recent meta-analysis found that 38% of UTUC recurrence was diagnosed by follow-up investigations, whereas in the remaining 62%, diagnosis was based on symptoms. When urine cytology was used during surveillance, the rate of primary detection was 7% vs. 29.6% with UUT imaging. This meta-analysis concluded that patients with non-invasive cancer are twice as likely to have UTUC as patients with invasive disease [561]. Multifocality increases the risk of recurrence by threefold, while positive ureteral or urethral margins increase the risk by sevenfold. Radical nephroureterectomy can prolong survival [562].

8.3.Time schedule for surveillance

Although, based on low level of evidence, some follow-up schedules have been suggested, guided by the principle that recurrences tend to occur within the first years following initial treatment. A schedule suggested by the EAU Guidelines Panel includes a CT scan (every 6 months) until the third year, followed by annual imaging thereafter [4]. Patients with multifocal disease, NMIBC with CIS or positive ureteral margins are at higher risk of developing UTUC, which can develop late (> three years). In those cases, monitoring of the UUT is mandatory during follow-up. Computed tomography is to be used for imaging of the UUT [561].

However, the exact time to stop follow-up is not well known and recently a risk-adapted schedule has been proposed, based on the interaction between recurrence risk and competing health factors that could lead to individualised recommendations and may increase recurrence detection. Elderly and very low-risk patients (those with NMIBC or pT0 disease at final cystectomy report) showed a higher competing risk of non-BC mortality when compared with their level of BC recurrence risk. On the other hand, patients with locally advanced disease or LN involvement are at a higher risk of recurrence, for more than 20 years [563]. However, this model has not been validated and does not incorporate several risk factors related to non-BC mortality. Furthermore, the prognostic implications of the different sites of recurrence should be considered. Local and systemic recurrences have a poor prognosis and early detection of the disease will not influence survival [554]. Despite this, the rationale for a risk-adapted schedule for BC surveillance appears to be promising and deserves further investigation.

8.4.Follow-up of functional outcomes and complications

Apart from oncological surveillance, patients submitted for urinary diversion deserve functional follow-up. Complications related to urinary diversion are detected in 45% of patients during the first five years of follow-up. This rate increases over time, and exceeds 54% after fifteen years follow-up. Therefore, long-term follow-up of functional outcomes is desirable [553].

The functional complications are diverse and include: vitamin B12 deficiency, metabolic acidosis, worsening of renal function, urinary infections, urolithiasis, stenosis of uretero-intestinal anastomosis, stoma complications in patients with ileal conduit, neobladder continence problems, and emptying dysfunction [553]. Especially in women approximately two-thirds need to catheterise their neobladder, while almost 45% do not void spontaneously at all [542]. Recently also a 21% increased risk of fractures was described as compared to no RC, due to chronic metabolic acidosis and subsequent long-term bone loss [564].

8.5.Summary of evidence and recommendations for specific recurrence sites

9.REFERENCES

1.Rouprêt, M., et al. Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma. EAU Guidelines 2018. Edn presented at the 33nd EAU Annual Congress Copenhagen 2018.

http://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/

2.Babjuk, M., et al. Guidelines on Non-muscle-invasive bladder cancer (Ta, T1 and CIS). 2018. Edn presented at the 33nd EAU Annual Congress Copenhagen 2018.

http://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/

3.Gakis, G., et al. Guidelines on Primary Urethral Carcinoma EAU Guidelines 2018. Edn presented at the 33nd EAU Annual Congress Copenhagen 2018.

http://uroweb.org/guideline/primary-urethral-carcinoma/

4.Witjes, AJ., 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.Veskimae, E., et al. Systematic review of the oncological and functional outcomes of pelvic organ-preserving radical cystectomy (RC) compared with standard RC in women who undergo curative surgery and orthotopic neobladder substitution for bladder cancer. BJU Int, 2017. 120: 12.

https://www.ncbi.nlm.nih.gov/pubmed/28220653

6.Hernandez, V., et al. Oncological and functional outcomes of sexual function-preserving cystectomy compared with standard radical cystectomy in men: A systematic review. Urol Oncol, 2017. 35: 539.e17.

https://www.ncbi.nlm.nih.gov/pubmed/28495555

7.Guyatt, G.H., et al. What is “quality of evidence” and why is it important to clinicians? BMJ, 2008. 336: 995.

https://www.ncbi.nlm.nih.gov/pubmed/18456631

8.Guyatt, G.H., et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 2008. 336: 924.

https://www.ncbi.nlm.nih.gov/pubmed/18436948

9.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/

10.Guyatt, G.H., et al. Going from evidence to recommendations. BMJ, 2008. 336: 1049.

https://www.ncbi.nlm.nih.gov/pubmed/18467413

11.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

12.GLOBOCAN 2012 v1.0: Estimated cancer incidence, mortality and prevalence worldwide in 2012. 2016.

http://globocan.iarc.fr/Default.aspx

13.Burger, M., et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol, 2013. 63: 234.

https://www.ncbi.nlm.nih.gov/pubmed/22877502

14.Bosetti, C., et al. Trends in mortality from urologic cancers in Europe, 1970-2008. Eur Urol, 2011. 60: 1.

https://www.ncbi.nlm.nih.gov/pubmed/21497988

15.Chavan, S., et al. International variations in bladder cancer incidence and mortality. Eur Urol, 2014. 66: 59.

https://www.ncbi.nlm.nih.gov/pubmed/24451595

16.Comperat, E., et al. Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old. Virchows Arch, 2015. 466: 589.

https://www.ncbi.nlm.nih.gov/pubmed/25697540

17.Steinmaus, C., et al. Increased lung and bladder cancer incidence in adults after in utero and early-life arsenic exposure. Cancer Epidemiol Biomarkers Prev, 2014. 23: 1529.

https://www.ncbi.nlm.nih.gov/pubmed/24859871

18.Freedman, N.D., et al. Association between smoking and risk of bladder cancer among men and women. JAMA, 2011. 306: 737.

https://www.ncbi.nlm.nih.gov/pubmed/21846855

19.Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum, 2004. 83: 1.

https://www.ncbi.nlm.nih.gov/pubmed/15285078

20.Brennan, P., et al. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies. Int J Cancer, 2000. 86: 289.

https://www.ncbi.nlm.nih.gov/pubmed/10738259

21.Gandini, S., et al. Tobacco smoking and cancer: a meta-analysis. Int J Cancer, 2008. 122: 155.

https://www.ncbi.nlm.nih.gov/pubmed/17893872

22.Pashos, C.L., et al. Bladder cancer: epidemiology, diagnosis, and management. Cancer Pract, 2002. 10: 311.

https://www.ncbi.nlm.nih.gov/pubmed/12406054

23.Harling, M., et al. Bladder cancer among hairdressers: a meta-analysis. Occup Environ Med, 2010. 67: 351.

https://www.ncbi.nlm.nih.gov/pubmed/20447989

24.Weistenhofer, W., et al. N-acetyltransferase-2 and medical history in bladder cancer cases with a suspected occupational disease (BK 1301) in Germany. J Toxicol Environ Health A, 2008. 71: 906.

https://www.ncbi.nlm.nih.gov/pubmed/18569594

25.Rushton, L., et al. Occupation and cancer in Britain. Br J Cancer, 2010. 102: 1428.

https://www.ncbi.nlm.nih.gov/pubmed/20424618

26.Chrouser, K., et al. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol, 2005. 174: 107.

https://www.ncbi.nlm.nih.gov/pubmed/15947588

27.Nieder, A.M., et al. Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol, 2008. 180: 2005.

https://www.ncbi.nlm.nih.gov/pubmed/18801517

28.Zelefsky, M.J., et al. Incidence of secondary cancer development after high-dose intensity-modulated radiotherapy and image-guided brachytherapy for the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys, 2012. 83: 953.

https://www.ncbi.nlm.nih.gov/pubmed/22172904

29.Mariappan, P., et al. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol, 2010. 57: 843.

https://www.ncbi.nlm.nih.gov/pubmed/19524354

30.Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum, 1994. 61: 1.

https://www.ncbi.nlm.nih.gov/pubmed/7715068

31.Gouda, I., et al. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. J Egypt Natl Canc Inst, 2007. 19: 158.

https://www.ncbi.nlm.nih.gov/pubmed/19034337

32.Salem, H.K., et al. Changing patterns (age, incidence, and pathologic types) of schistosoma-associated bladder cancer in Egypt in the past decade. Urology, 2012. 79: 379.

https://www.ncbi.nlm.nih.gov/pubmed/22112287

33.Pelucchi, C., et al. Mechanisms of disease: The epidemiology of bladder cancer. Nat Clin Pract Urol, 2006. 3: 327.

https://www.ncbi.nlm.nih.gov/pubmed/16763645

34.Liu, S., et al. The impact of female gender on bladder cancer-specific death risk after radical cystectomy: a meta-analysis of 27,912 patients. Int Urol Nephrol, 2015. 47: 951.

https://www.ncbi.nlm.nih.gov/pubmed/25894962

35.Waldhoer, T., et al. Sex Differences of >/=pT1 Bladder Cancer Survival in Austria: A Descriptive, Long-Term, Nation-Wide Analysis Based on 27,773 Patients. Urol Int, 2015. 94: 383.

https://www.ncbi.nlm.nih.gov/pubmed/25833466

36.Patafio, F.M., et al. Is there a gender effect in bladder cancer? A population-based study of practice and outcomes. Can Urol Assoc J, 2015. 9: 269.

https://www.ncbi.nlm.nih.gov/pubmed/26316913

37.Cohn, J.A., et al. Sex disparities in diagnosis of bladder cancer after initial presentation with hematuria: a nationwide claims-based investigation. Cancer, 2014. 120: 555.

https://www.ncbi.nlm.nih.gov/pubmed/24496869

38.Dietrich, K., et al. Parity, early menopause and the incidence of bladder cancer in women: a case-control study and meta-analysis. Eur J Cancer, 2011. 47: 592.

https://www.ncbi.nlm.nih.gov/pubmed/21067913

39.Scosyrev, E., et al. Sex and racial differences in bladder cancer presentation and mortality in the US. Cancer, 2009. 115: 68.

https://www.ncbi.nlm.nih.gov/pubmed/19072984

40.Stenzl, A. Words of wisdom. Re: sex and racial differences in bladder cancer presentation and mortality in the US. Eur Urol, 2010. 57: 729.

https://www.ncbi.nlm.nih.gov/pubmed/20965044

41.Murta-Nascimento, C., et al. Risk of bladder cancer associated with family history of cancer: do low-penetrance polymorphisms account for the increase in risk? Cancer Epidemiol Biomarkers Prev, 2007. 16: 1595.

https://www.ncbi.nlm.nih.gov/pubmed/17684133

42.Figueroa, J.D., et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet, 2014. 23: 1387.

https://www.ncbi.nlm.nih.gov/pubmed/24163127

43.Rothman, N., et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet, 2010. 42: 978.

https://www.ncbi.nlm.nih.gov/pubmed/20972438

44.Kiemeney, L.A., et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet, 2008. 40: 1307.

https://www.ncbi.nlm.nih.gov/pubmed/18794855

45.Stenzl, A. Current concepts for urinary diversion in women. Eur Urol (EAU Update series 1), 2003: 91.

http://www.eusupplements.europeanurology.com/article/S1570-9124(03)00018-7/fulltext

46.Varinot, J., et al. Full analysis of the prostatic urethra at the time of radical cystoprostatectomy for bladder cancer: impact on final disease stage. Virchows Arch, 2009. 455: 449.

https://www.ncbi.nlm.nih.gov/pubmed/19841937

47.Hansel, D.E., et al. A contemporary update on pathology standards for bladder cancer: transurethral resection and radical cystectomy specimens. Eur Urol, 2013. 63: 321.

https://www.ncbi.nlm.nih.gov/pubmed/23088996

48.Herr, H.W. Pathologic evaluation of radical cystectomy specimens. Cancer, 2002. 95: 668.

https://www.ncbi.nlm.nih.gov/pubmed/12209761

49.Fajkovic, H., et al. Extranodal extension is a powerful prognostic factor in bladder cancer patients with lymph node metastasis. Eur Urol, 2013. 64: 837.

https://www.ncbi.nlm.nih.gov/pubmed/22877503

50.Fritsche, H.M., et al. Prognostic value of perinodal lymphovascular invasion following radical cystectomy for lymph node-positive urothelial carcinoma. Eur Urol, 2013. 63: 739.

https://www.ncbi.nlm.nih.gov/pubmed/23079053

51.Ku, J.H., et al. Lymph node density as a prognostic variable in node-positive bladder cancer: a meta-analysis. BMC Cancer, 2015. 15: 447.

https://www.ncbi.nlm.nih.gov/pubmed/26027955

52.Neuzillet, Y., et al. Positive surgical margins and their locations in specimens are adverse prognosis features after radical cystectomy in non-metastatic carcinoma invading bladder muscle: results from a nationwide case-control study. BJU Int, 2013. 111: 1253.

https://www.ncbi.nlm.nih.gov/pubmed/23331375

53.Baltaci, S., et al. Reliability of frozen section examination of obturator lymph nodes and impact on lymph node dissection borders during radical cystectomy: results of a prospective multicentre study by the Turkish Society of Urooncology. BJU Int, 2011. 107: 547.

https://www.ncbi.nlm.nih.gov/pubmed/20633004

54.Jimenez, R.E., et al. Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival. Am J Surg Pathol, 2000. 24: 980.

https://www.ncbi.nlm.nih.gov/pubmed/10895820

55.Sjodahl, G., et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res, 2012. 18: 3377.

https://www.ncbi.nlm.nih.gov/pubmed/22553347

56.Choi, W., et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell, 2014. 25: 152.

https://www.ncbi.nlm.nih.gov/pubmed/24525232

57.WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. 2016, Lyon, France

https://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb7/BB7.pdf

58.Sauter G, et al., Tumours of the urinary system: non-invasive urothelial neoplasias., in WHO classification of tumors of the urinary system and male genital organs. 2004, IARCC Press: Lyon.

https://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb7/BB7.pdf

59.Kapur, P., et al. Primary adenocarcinoma of the urinary bladder: value of cell cycle biomarkers. Am
J Clin Pathol, 2011. 135: 822.

https://www.ncbi.nlm.nih.gov/pubmed/21571954

60.Ploeg, M., et al. Clinical epidemiology of nonurothelial bladder cancer: analysis of the Netherlands Cancer Registry. J Urol, 2010. 183: 915.

https://www.ncbi.nlm.nih.gov/pubmed/20083267

61.Beltran, A.L., et al. Clinicopathological characteristics and outcome of nested carcinoma of the urinary bladder. Virchows Arch, 2014. 465: 199.

https://www.ncbi.nlm.nih.gov/pubmed/24878757

62.Mukesh, M., et al. Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the Anglian Cancer Network. BJU Int, 2009. 103: 747.

https://www.ncbi.nlm.nih.gov/pubmed/19076139

63.Brierley JD, et al. TNM classification of malignant tumors. UICC International Union Against Cancer. 8th edn. 2017, Oxford.

http://www.uicc.org/resources/tnm/publications-resources

64.Jensen, J.B., et al. Incidence of occult lymph-node metastasis missed by standard pathological examination in patients with bladder cancer undergoing radical cystectomy. Scand J Urol Nephrol, 2011. 45: 419.

https://www.ncbi.nlm.nih.gov/pubmed/21767245

65.Mariappan, P., et al. Good quality white-light transurethral resection of bladder tumours (GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking. BJU Int, 2012. 109: 1666.

https://www.ncbi.nlm.nih.gov/pubmed/22044434

66.Leissner, J., et al. Prognostic significance of vascular and perineural invasion in urothelial bladder cancer treated with radical cystectomy. J Urol, 2003. 169: 955.

https://www.ncbi.nlm.nih.gov/pubmed/12576821

67.Fossa, S.D., et al. Clinical significance of the “palpable mass” in patients with muscle-infiltrating bladder cancer undergoing cystectomy after pre-operative radiotherapy. Br J Urol, 1991. 67: 54.

https://www.ncbi.nlm.nih.gov/pubmed/8653315

68.Wijkstrom, H., et al. Evaluation of clinical staging before cystectomy in transitional cell bladder carcinoma: a long-term follow-up of 276 consecutive patients. Br J Urol, 1998. 81: 686.

https://www.ncbi.nlm.nih.gov/pubmed/9634042

69.Ploeg, M., et al. Discrepancy between clinical staging through bimanual palpation and pathological staging after cystectomy. Urol Oncol, 2012. 30: 247.

https://www.ncbi.nlm.nih.gov/pubmed/20451418

70.Lokeshwar, V.B., et al. Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology, 2005. 66: 35.

https://www.ncbi.nlm.nih.gov/pubmed/16399415

71.Raitanen, M.P., et al. Differences between local and review urinary cytology in diagnosis of bladder cancer. An interobserver multicenter analysis. Eur Urol, 2002. 41: 284.

https://www.ncbi.nlm.nih.gov/pubmed/12180229

72.van Rhijn, B.W., et al. Urine markers for bladder cancer surveillance: a systematic review. Eur Urol, 2005. 47: 736.

https://www.ncbi.nlm.nih.gov/pubmed/15925067

73.Barkan, G.A., et al. The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology. Adv Anat Pathol, 2016. 23: 193.

https://www.ncbi.nlm.nih.gov/pubmed/27233050

74.Stenzl, A., et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol, 2010. 184: 1907.

https://www.ncbi.nlm.nih.gov/pubmed/20850152

75.Burger, M., et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol, 2013. 64: 846.

https://www.ncbi.nlm.nih.gov/pubmed/23602406

76.Matzkin, H., et al. Transitional cell carcinoma of the prostate. J Urol, 1991. 146: 1207.

https://www.ncbi.nlm.nih.gov/pubmed/1942262

77.Mungan, M.U., et al. Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder. Eur Urol, 2005. 48: 760.

https://www.ncbi.nlm.nih.gov/pubmed/16005563

78.Kassouf, W., et al. Prostatic urethral biopsy has limited usefulness in counseling patients regarding final urethral margin status during orthotopic neobladder reconstruction. J Urol, 2008. 180: 164.

https://www.ncbi.nlm.nih.gov/pubmed/18485384

79.Walsh, D.L., et al. Dilemmas in the treatment of urothelial cancers of the prostate. Urol Oncol, 2009. 27: 352.

https://www.ncbi.nlm.nih.gov/pubmed/18439852

80.Lebret, T., et al. Urethral recurrence of transitional cell carcinoma of the bladder. Predictive value of preoperative latero-montanal biopsies and urethral frozen sections during prostatocystectomy. Eur Urol, 1998. 33: 170.

https://www.ncbi.nlm.nih.gov/pubmed/9519359

81.Miladi, M., et al. The value of a second transurethral resection in evaluating patients with bladder tumours. Eur Urol, 2003. 43: 241.

https://www.ncbi.nlm.nih.gov/pubmed/12600426

82.Jakse, G., et al. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol, 2004. 45: 539.

https://www.ncbi.nlm.nih.gov/pubmed/15082193

83.Brauers, A., et al. Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol, 2001. 165: 808.

https://www.ncbi.nlm.nih.gov/pubmed/11176474

84.Schips, L., et al. Is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? Urology, 2002. 59: 220.

https://www.ncbi.nlm.nih.gov/pubmed/11834389

85.Grimm, M.O., et al. Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol, 2003. 170: 433.

https://www.ncbi.nlm.nih.gov/pubmed/12853793

86.Divrik, R.T., et al. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol, 2006. 175: 1641.

https://www.ncbi.nlm.nih.gov/pubmed/16600720

87.Jahnson, S., et al. Results of second-look resection after primary resection of T1 tumour of the urinary bladder. Scand J Urol Nephrol, 2005. 39: 206.

https://www.ncbi.nlm.nih.gov/pubmed/16127800

88.Damiano, R., et al. Clinicopathologic features of prostate adenocarcinoma incidentally discovered at the time of radical cystectomy: an evidence-based analysis. Eur Urol, 2007. 52: 648.

https://www.ncbi.nlm.nih.gov/pubmed/17600614

89.Gakis, G., et al. Incidental prostate cancer at radical cystoprostatectomy: implications for apex-sparing surgery. BJU Int, 2010. 105: 468.

https://www.ncbi.nlm.nih.gov/pubmed/20102366

90.Svatek, R.S., et al. Intravesical tumor involvement of the trigone is associated with nodal metastasis in patients undergoing radical cystectomy. Urology, 2014. 84: 1147.

https://www.ncbi.nlm.nih.gov/pubmed/25174656

91.Jewett, H.J. Proceedings: Cancer of the bladder. Diagnosis and staging. Cancer, 1973. 32: 1072.

https://www.ncbi.nlm.nih.gov/pubmed/4757902

92.Paik, M.L., et al. Limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. J Urol, 2000. 163: 1693.

https://www.ncbi.nlm.nih.gov/pubmed/10799162

93.Barentsz, J.O., et al. Primary staging of urinary bladder carcinoma: the role of MRI and a comparison with CT. Eur Radiol, 1996. 6: 129.

https://www.ncbi.nlm.nih.gov/pubmed/8797968

94.Barentsz, J.O., et al. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology, 1996. 201: 185.

https://www.ncbi.nlm.nih.gov/pubmed/8816542

95.Mallampati, G.K., et al. MR imaging of the bladder. Magn Reson Imaging Clin N Am, 2004. 12: 545.

https://www.ncbi.nlm.nih.gov/pubmed/15271370

96.Rajesh, A., et al. Bladder cancer: evaluation of staging accuracy using dynamic MRI. Clin Radiol, 2011. 66: 1140.

https://www.ncbi.nlm.nih.gov/pubmed/21924408

97.Thomsen, H.S. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am, 2009. 47: 827.

https://www.ncbi.nlm.nih.gov/pubmed/19744597

98.Kundra, V., et al. Imaging in oncology from the University of Texas M. D. Anderson Cancer Center. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder. AJR Am
J Roentgenol, 2003. 180: 1045.

https://www.ncbi.nlm.nih.gov/pubmed/12646453

99.Kim, B., et al. Bladder tumor staging: comparison of contrast-enhanced CT, T1- and T2-weighted MR imaging, dynamic gadolinium-enhanced imaging, and late gadolinium-enhanced imaging. Radiology, 1994. 193: 239.

https://www.ncbi.nlm.nih.gov/pubmed/8090898

100.Kim, J.K., et al. Bladder cancer: analysis of multi-detector row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging. Radiology, 2004. 231: 725.

https://www.ncbi.nlm.nih.gov/pubmed/15118111

101.Jager, G.J., et al. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared-rapid gradient-echo sequence. AJR Am
J Roentgenol, 1996. 167: 1503.

https://www.ncbi.nlm.nih.gov/pubmed/8956585

102.Yang, W.T., et al. Comparison of dynamic helical CT and dynamic MR imaging in the evaluation of pelvic lymph nodes in cervical carcinoma. AJR Am J Roentgenol, 2000. 175: 759.

https://www.ncbi.nlm.nih.gov/pubmed/10954463

103.Kim, S.H., et al. Uterine cervical carcinoma: evaluation of pelvic lymph node metastasis with MR imaging. Radiology, 1994. 190: 807.

https://www.ncbi.nlm.nih.gov/pubmed/8115631

104.Kim, S.H., et al. Uterine cervical carcinoma: comparison of CT and MR findings. Radiology, 1990. 175: 45.

https://www.ncbi.nlm.nih.gov/pubmed/2315503

105.Oyen, R.H., et al. Lymph node staging of localized prostatic carcinoma with CT and CT-guided fine-needle aspiration biopsy: prospective study of 285 patients. Radiology, 1994. 190: 315.

https://www.ncbi.nlm.nih.gov/pubmed/8284375

106.Barentsz, J.O., et al. MR imaging of the male pelvis. Eur Radiol, 1999. 9: 1722.

https://www.ncbi.nlm.nih.gov/pubmed/10602944

107.Dorfman, R.E., et al. Upper abdominal lymph nodes: criteria for normal size determined with CT. Radiology, 1991. 180: 319.

https://www.ncbi.nlm.nih.gov/pubmed/2068292

108.Swinnen, G., et al. FDG-PET/CT for the preoperative lymph node staging of invasive bladder cancer. Eur Urol, 2010. 57: 641.

https://www.ncbi.nlm.nih.gov/pubmed/19477579

109.Kibel, A.S., et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma. J Clin Oncol, 2009. 27: 4314.

https://www.ncbi.nlm.nih.gov/pubmed/19652070

110.Lu, Y.Y., et al. Clinical value of FDG PET or PET/CT in urinary bladder cancer: a systemic review and meta-analysis. Eur J Radiol, 2012. 81: 2411.

https://www.ncbi.nlm.nih.gov/pubmed/21899971

111.Vargas, H.A., et al. Prospective evaluation of MRI, (1)(1)C-acetate PET/CT and contrast-enhanced CT for staging of bladder cancer. Eur J Radiol, 2012. 81: 4131.

https://www.ncbi.nlm.nih.gov/pubmed/22858427

112.Ito, Y., et al. Preoperative hydronephrosis grade independently predicts worse pathological outcomes in patients undergoing nephroureterectomy for upper tract urothelial carcinoma. J Urol, 2011. 185: 1621.

https://www.ncbi.nlm.nih.gov/pubmed/21419429

113.Cowan, N.C., et al. Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. BJU Int, 2007. 99: 1363.

https://www.ncbi.nlm.nih.gov/pubmed/17428251

114.Messer, J.C., et al. Multi-institutional validation of the ability of preoperative hydronephrosis to predict advanced pathologic tumor stage in upper-tract urothelial carcinoma. Urol Oncol, 2013. 31: 904.

https://www.ncbi.nlm.nih.gov/pubmed/21906967

115.Hurel, S., et al. Influence of preoperative factors on the oncologic outcome for upper urinary tract urothelial carcinoma after radical nephroureterectomy. World J Urol, 2015. 33: 335.

https://www.ncbi.nlm.nih.gov/pubmed/24810657

116.Verhoest, G., et al. Predictive factors of recurrence and survival of upper tract urothelial carcinomas. World J Urol, 2011. 29: 495.

https://www.ncbi.nlm.nih.gov/pubmed/21681525

117.Takahashi, N., et al. Gadolinium enhanced magnetic resonance urography for upper urinary tract malignancy. J Urol, 2010. 183: 1330.

https://www.ncbi.nlm.nih.gov/pubmed/20171676

118.Girvin, F., et al. Pulmonary nodules: detection, assessment, and CAD. AJR Am J Roentgenol, 2008. 191: 1057.

https://www.ncbi.nlm.nih.gov/pubmed/18806142

119.Heidenreich, A., et al. Imaging studies in metastatic urogenital cancer patients undergoing systemic therapy: recommendations of a multidisciplinary consensus meeting of the Association of Urological Oncology of the German Cancer Society. Urol Int, 2010. 85: 1.

https://www.ncbi.nlm.nih.gov/pubmed/20693823

120.Braendengen, M., et al. Clinical significance of routine pre-cystectomy bone scans in patients with muscle-invasive bladder cancer. Br J Urol, 1996. 77: 36.

https://www.ncbi.nlm.nih.gov/pubmed/8653315

121.Brismar, J., et al. Bone scintigraphy in staging of bladder carcinoma. Acta Radiol, 1988. 29: 251.

https://www.ncbi.nlm.nih.gov/pubmed/2965914

122.Lauenstein, T.C., et al. Whole-body MR imaging: evaluation of patients for metastases. Radiology, 2004. 233: 139.

https://www.ncbi.nlm.nih.gov/pubmed/15317952

123.Schmidt, G.P., et al. Whole-body MR imaging of bone marrow. Eur J Radiol, 2005. 55: 33.

https://www.ncbi.nlm.nih.gov/pubmed/15950099

124.Yang, Z., et al. Is whole-body fluorine-18 fluorodeoxyglucose PET/CT plus additional pelvic images (oral hydration-voiding-refilling) useful for detecting recurrent bladder cancer? Ann Nucl Med, 2012. 26: 571.

https://www.ncbi.nlm.nih.gov/pubmed/22763630

125.Maurer, T., et al. Diagnostic efficacy of [11C]choline positron emission tomography/computed tomography compared with conventional computed tomography in lymph node staging of patients with bladder cancer prior to radical cystectomy. Eur Urol, 2012. 61: 1031.

https://www.ncbi.nlm.nih.gov/pubmed/22196847

126.Yoshida, S., et al. Role of diffusion-weighted magnetic resonance imaging in predicting sensitivity to chemoradiotherapy in muscle-invasive bladder cancer. Int J Radiat Oncol Biol Phys, 2012. 83: e21.

https://www.ncbi.nlm.nih.gov/pubmed/22414281

127.Game, X., et al. Radical cystectomy in patients older than 75 years: assessment of morbidity and mortality. Eur Urol, 2001. 39: 525.

https://www.ncbi.nlm.nih.gov/pubmed/11464032

128.Clark, P.E., et al. Radical cystectomy in the elderly: comparison of clincal outcomes between younger and older patients. Cancer, 2005. 104: 36.

https://www.ncbi.nlm.nih.gov/pubmed/15912515

129.May, M., et al. Results from three municipal hospitals regarding radical cystectomy on elderly patients. Int Braz J Urol, 2007. 33: 764.

https://www.ncbi.nlm.nih.gov/pubmed/18199344

130.Lawrentschuk, N., et al. Prevention and management of complications following radical cystectomy for bladder cancer. Eur Urol, 2010. 57: 983.

https://www.ncbi.nlm.nih.gov/pubmed/20227172

131.Donahue, T.F., et al. Risk factors for the development of parastomal hernia after radical cystectomy. J Urol, 2014. 191: 1708.

https://www.ncbi.nlm.nih.gov/pubmed/24384155

132.Djaladat, H., et al. The association of preoperative serum albumin level and American Society of Anesthesiologists (ASA) score on early complications and survival of patients undergoing radical cystectomy for urothelial bladder cancer. BJU Int, 2014. 113: 887.

https://www.ncbi.nlm.nih.gov/pubmed/23906037

133.Garg, T., et al. Preoperative serum albumin is associated with mortality and complications after radical cystectomy. BJU Int, 2014. 113: 918.

https://www.ncbi.nlm.nih.gov/pubmed/24053616

134.Rochon, P.A., et al. Comorbid illness is associated with survival and length of hospital stay in patients with chronic disability. A prospective comparison of three comorbidity indices. Med Care, 1996. 34: 1093.

https://www.ncbi.nlm.nih.gov/pubmed/8911426

135.Feinstein, A.R. The pre-therapeutic classification of co-morbidity in chronic disease. J Chron Dis, 1970. 23: 455.

https://www.ncbi.nlm.nih.gov/pubmed/26309916

136.Zietman, A.L., et al. Organ-conserving approaches to muscle-invasive bladder cancer: future alternatives to radical cystectomy. Ann Med, 2000. 32: 34.

https://www.ncbi.nlm.nih.gov/pubmed/10711576

137.Lughezzani, G., et al. A population-based competing-risks analysis of the survival of patients treated with radical cystectomy for bladder cancer. Cancer, 2011. 117: 103.

https://www.ncbi.nlm.nih.gov/pubmed/20803606

138.Froehner, M., et al. Complications following radical cystectomy for bladder cancer in the elderly.
Eur Urol, 2009. 56: 443.

https://www.ncbi.nlm.nih.gov/pubmed/19481861

139.de Groot, V., et al. How to measure comorbidity. a critical review of available methods.
J Clin Epidemiol, 2003. 56: 221.

https://www.ncbi.nlm.nih.gov/pubmed/12725876

140.Linn, B.S., et al. Cumulative illness rating scale. J Am Geriatr Soc, 1968. 16: 622.

https://www.ncbi.nlm.nih.gov/pubmed/5646906

141.Kaplan, M.H., et al. The importance of classifying initial co-morbidity in evaluating the outcome of diabetes mellitus. J Chronic Dis, 1974. 27: 387.

https://www.ncbi.nlm.nih.gov/pubmed/4436428

142.Charlson, M.E., et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis, 1987. 40: 373.

https://www.ncbi.nlm.nih.gov/pubmed/3558716

143.Greenfield, S., et al. The importance of co-existent disease in the occurrence of postoperative complications and one-year recovery in patients undergoing total hip replacement. Comorbidity and outcomes after hip replacement. Med Care, 1993. 31: 141.

https://www.ncbi.nlm.nih.gov/pubmed/8433577

144.Paleri, V., et al. Applicability of the adult comorbidity evaluation - 27 and the Charlson indexes to assess comorbidity by notes extraction in a cohort of United Kingdom patients with head and neck cancer: a retrospective study. J Laryngol Otol, 2002. 116: 200.

https://www.ncbi.nlm.nih.gov/pubmed/11893262

145.Litwin, M.S., et al. Assessment of prognosis with the total illness burden index for prostate cancer: aiding clinicians in treatment choice. Cancer, 2007. 109: 1777.

https://www.ncbi.nlm.nih.gov/pubmed/17354226

146.Mayr, R., et al. Predictive capacity of four comorbidity indices estimating perioperative mortality after radical cystectomy for urothelial carcinoma of the bladder. BJU Int, 2012. 110: E222.

https://www.ncbi.nlm.nih.gov/pubmed/22314129

147.Morgan, T.M., et al. Predicting the probability of 90-day survival of elderly patients with bladder cancer treated with radical cystectomy. J Urol, 2011. 186: 829.

https://www.ncbi.nlm.nih.gov/pubmed/21788035

148.Abdollah, F., et al. Development and validation of a reference table for prediction of postoperative mortality rate in patients treated with radical cystectomy: a population-based study. Ann Surg Oncol, 2012. 19: 309.

https://www.ncbi.nlm.nih.gov/pubmed/21701925

149.Miller, D.C., et al. The impact of co-morbid disease on cancer control and survival following radical cystectomy. J Urol, 2003. 169: 105.

https://www.ncbi.nlm.nih.gov/pubmed/12478114

150.Koppie, T.M., et al. Age-adjusted Charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer. Cancer, 2008. 112: 2384.

https://www.ncbi.nlm.nih.gov/pubmed/18404699

151.Bolenz, C., et al. Management of elderly patients with urothelial carcinoma of the bladder: guideline concordance and predictors of overall survival. BJU Int, 2010. 106: 1324.

https://www.ncbi.nlm.nih.gov/pubmed/20500510

152.Yoo, S., et al. Does radical cystectomy improve overall survival in octogenarians with muscle-invasive bladder cancer? Korean J Urol, 2011. 52: 446.

https://www.ncbi.nlm.nih.gov/pubmed/21860763

153.Mayr, R., et al. Comorbidity and performance indices as predictors of cancer-independent mortality but not of cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder. Eur Urol, 2012. 62: 662.

https://www.ncbi.nlm.nih.gov/pubmed/22534059

154.Hall, W.H., et al. An electronic application for rapidly calculating Charlson comorbidity score.
BMC Cancer, 2004. 4: 94.

https://www.ncbi.nlm.nih.gov/pubmed/15610554

155.Extermann, M., et al. Comorbidity and functional status are independent in older cancer patients.
J Clin Oncol, 1998. 16: 1582.

https://www.ncbi.nlm.nih.gov/pubmed/9552069

156.Blagden, S.P., et al. Performance status score: do patients and their oncologists agree? Br J Cancer, 2003. 89: 1022.

https://www.ncbi.nlm.nih.gov/pubmed/12966419

157.Logothetis, C.J., et al. Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial. J Clin Oncol, 1995. 13: 2272.

https://www.ncbi.nlm.nih.gov/pubmed/7666085

158.von der Maase, H., et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol, 2000. 18: 3068.

https://www.ncbi.nlm.nih.gov/pubmed/11001674

159.Niegisch, G., et al. Prognostic factors in second-line treatment of urothelial cancers with gemcitabine and paclitaxel (German Association of Urological Oncology trial AB20/99). Eur Urol, 2011. 60: 1087.

https://www.ncbi.nlm.nih.gov/pubmed/21839579

160.Cohen, H.J., et al. A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med, 2002. 346: 905.

https://www.ncbi.nlm.nih.gov/pubmed/11907291

161.Balducci, L., et al. General guidelines for the management of older patients with cancer. Oncology (Williston Park), 2000. 14: 221.

https://www.ncbi.nlm.nih.gov/pubmed/11195414

162.Castagneto, B., et al. Single-agent gemcitabine in previously untreated elderly patients with advanced bladder carcinoma: response to treatment and correlation with the comprehensive geriatric assessment. Oncology, 2004. 67: 27.

https://www.ncbi.nlm.nih.gov/pubmed/15459492

163.van Rhijn, B.W., et al. Molecular markers for urothelial bladder cancer prognosis: toward implementation in clinical practice. Urol Oncol, 2014. 32: 1078.

https://www.ncbi.nlm.nih.gov/pubmed/25217465

164.Amin, M.B., et al. Best practices recommendations in the application of immunohistochemistry in the bladder lesions: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol, 2014. 38: e20.

https://www.ncbi.nlm.nih.gov/pubmed/25029121

165.Choi, W., et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol, 2014. 11: 400.

https://www.ncbi.nlm.nih.gov/pubmed/24960601

166.Comprehensive molecular characterization of urothelial bladder carcinoma. Nature, 2014. 507: 315.

http://www.nature.com/nature/journal/v507/n7492/full/nature12965.html

167.Mitra, A.P., et al. Potential role for targeted therapy in muscle-invasive bladder cancer: lessons from the cancer genome atlas and beyond. Urol Clin North Am, 2015. 42: 201.

https://www.ncbi.nlm.nih.gov/pubmed/25882562

168.Cambier, S., et al. EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guerin. Eur Urol, 2015.

https://www.ncbi.nlm.nih.gov/pubmed/26210894

169.Sylvester, R.J., et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol, 2010. 57: 766.

https://www.ncbi.nlm.nih.gov/pubmed/20034729

170.Sylvester, R.J., et al. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol, 2002. 168: 1964.

https://www.ncbi.nlm.nih.gov/pubmed/12394686

171.Bohle, A., et al. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology, 2004. 63: 682.

https://www.ncbi.nlm.nih.gov/pubmed/15072879

172.Malmstrom, P.U., et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol, 2009. 56: 247.

https://www.ncbi.nlm.nih.gov/pubmed/19409692

173.Hautmann, R.E., et al. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol, 2006. 176: 486.

https://www.ncbi.nlm.nih.gov/pubmed/16813874

174.Madersbacher, S., et al. Radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy. J Clin Oncol, 2003. 21: 690.

https://www.ncbi.nlm.nih.gov/pubmed/12586807

175.Stein, J.P., et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol, 2001. 19: 666.

https://www.ncbi.nlm.nih.gov/pubmed/15912515

176.Schwaibold, H.E., et al. The value of a second transurethral resection for T1 bladder cancer. BJU Int, 2006. 97: 1199.

https://www.ncbi.nlm.nih.gov/pubmed/16566814

177.Dalbagni, G., et al. Clinical outcome in a contemporary series of restaged patients with clinical T1 bladder cancer. Eur Urol, 2009. 56: 903.

https://www.ncbi.nlm.nih.gov/pubmed/19632765

178.Zakaria, A.S., et al. Survival after Radical Cystectomy for Bladder Cancer in Relation to Prior Non-Muscle Invasive Disease in Quebec. Urol Int, 2016. 97: 49.

https://www.ncbi.nlm.nih.gov/pubmed/26863611

179.van den Bosch, S., et al. Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol, 2011. 60: 493.

https://www.ncbi.nlm.nih.gov/pubmed/21664041

180.Kamat, A.M., et al. The case for early cystectomy in the treatment of nonmuscle invasive micropapillary bladder carcinoma. J Urol, 2006. 175: 881.

https://www.ncbi.nlm.nih.gov/pubmed/16469571

181.Palou, J., et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guerin. Eur Urol, 2012. 62: 118.

https://www.ncbi.nlm.nih.gov/pubmed/22101115

182.Fernandez-Gomez, J., et al. Predicting nonmuscle invasive bladder cancer recurrence and
progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model.
J Urol, 2009. 182: 2195.

https://www.ncbi.nlm.nih.gov/pubmed/19758621

183.Pansadoro, V., et al. Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intravesical bacille Calmette-Guerin: 18-year experience. Urology, 2002. 59: 227.

https://www.ncbi.nlm.nih.gov/pubmed/11834391

184.Margel, D., et al. Long-term follow-up of patients with Stage T1 high-grade transitional cell carcinoma managed by Bacille Calmette-Guerin immunotherapy. Urology, 2007. 69: 78.

https://www.ncbi.nlm.nih.gov/pubmed/17270621

185.Willis, D.L., et al. Clinical outcomes of cT1 micropapillary bladder cancer. J Urol, 2015. 193: 1129.

https://www.ncbi.nlm.nih.gov/pubmed/25254936

186.Raj, G.V., et al. Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer. J Urol, 2007. 177: 1283.

https://www.ncbi.nlm.nih.gov/pubmed/17382713

187.Yates, D.R., et al. Treatment options available for bacillus Calmette-Guerin failure in non-muscle-invasive bladder cancer. Eur Urol, 2012. 62: 1088.

https://www.ncbi.nlm.nih.gov/pubmed/22959049

188.Stein, J.P., et al. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol, 2006. 24: 296.

https://www.ncbi.nlm.nih.gov/pubmed/11157016

189.Dalbagni, G., et al. Cystectomy for bladder cancer: a contemporary series. J Urol, 2001. 165: 1111.

https://www.ncbi.nlm.nih.gov/pubmed/11257649

190.Bassi, P., et al. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol, 1999. 161: 1494.

https://www.ncbi.nlm.nih.gov/pubmed/10210380

191.Ghoneim, M.A., et al. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol, 1997. 158: 393.

https://www.ncbi.nlm.nih.gov/pubmed/18485392

192.David, K.A., et al. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. J Urol, 2007. 178: 451.

https://www.ncbi.nlm.nih.gov/pubmed/17561135

193.Porter, M.P., et al. Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol, 2011. 29: 252.

https://www.ncbi.nlm.nih.gov/pubmed/19450992

194.Sanchez-Ortiz, R.F., et al. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol, 2003. 169: 110.

https://www.ncbi.nlm.nih.gov/pubmed/12478115

195.Stein, J.P. Contemporary concepts of radical cystectomy and the treatment of bladder cancer.
J Urol, 2003. 169: 116.

https://www.ncbi.nlm.nih.gov/pubmed/12478116

196.Grossman, H.B., et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med, 2003. 349: 859.

https://www.ncbi.nlm.nih.gov/pubmed/12944571

197.Sherif, A., et al. Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol, 2004. 45: 297.

https://www.ncbi.nlm.nih.gov/pubmed/12623505

198.Sternberg, C.N., et al. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer, 2003. 97: 1644.

https://www.ncbi.nlm.nih.gov/pubmed/12655521

199.Herr, H.W., et al. Surgery of invasive bladder cancer: is pathologic staging necessary? Semin Oncol, 1990. 17: 590.

https://www.ncbi.nlm.nih.gov/pubmed/2218571

200.Griffiths, G., et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol, 2011. 29: 2171.

https://www.ncbi.nlm.nih.gov/pubmed/21502557

201.Bassi P., et al. Neoadjuvant M-VAC chemotherapy of invasive bladder cancer: The G.U.O.N.E. multicenter phase III trial. Eur Urol 1998. Suppl 33: 142. [No abstract available].

202.Sherif, A., et al. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer - Nordic cystectomy trial 2. Scand J Urol Nephrol, 2002. 36: 419.

https://www.ncbi.nlm.nih.gov/pubmed/12623505

203.Sengelov, L., et al. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol, 2002. 41: 447.

https://www.ncbi.nlm.nih.gov/pubmed/12442921

204.GISTV (Italian Bladder Tumor Study Group). Neoadjuvant treatment for locally advanced bladder cancer: a randomized prospective clinical trial. J Chemother 1996. 8: 345. [No abstract available].

205.Orsatti, M., et al. Alternating chemo-radiotherapy in bladder cancer: a conservative approach. Int
J Radiat Oncol Biol Phys, 1995. 33: 173.

https://www.ncbi.nlm.nih.gov/pubmed/7642415

206.Marcuello, E., et al. 1155 A phase III trial of neoadjuvant chemotherapy (NCT) in patients (PTS) with invasive bladder cancer (IBC). Preliminary results: NCT improves pathological complete response rate. Eur J Cancer 31: S241.

http://www.ejcancer.com/article/0959-8049(95)96401-X/abstract

207.Shipley, W.U., et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol, 1998. 16: 3576.

https://www.ncbi.nlm.nih.gov/pubmed/9817278

208.Cannobio L., et al. A randomized study between neoadjuvant chemoradiotherapy (CT-RT) before radical cystectomy and cystectomy alone in bladder cancer. A 6 year follow-up. Proc Am Soc Clin Oncol 1995. 14: abstr 654. [No abstract available].

209.Abol-Enein H., et al. Neo-adjuvant chemotherapy in the treatment of invasive transitional bladder cancer. A controlled prospective randomized study. J Urol 1997. 79 174.

https://www.ncbi.nlm.nih.gov/pubmed/279621730

210.Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet, 2003. 361: 1927.

https://www.ncbi.nlm.nih.gov/pubmed/14713760

211.Winquist, E., et al. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol, 2004. 171: 561.

https://www.ncbi.nlm.nih.gov/pubmed/14713760

212.Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration.
Eur Urol, 2005. 48: 202.

https://www.ncbi.nlm.nih.gov/pubmed/15939524

213.Letocha, H., et al. Positron emission tomography with L-methyl-11C-methionine in the monitoring of therapy response in muscle-invasive transitional cell carcinoma of the urinary bladder. Br J Urol, 1994. 74: 767.

https://www.ncbi.nlm.nih.gov/pubmed/7827849

214.Nishimura, K., et al. The effects of neoadjuvant chemotherapy and chemo-radiation therapy on MRI staging in invasive bladder cancer: comparative study based on the pathological examination of whole layer bladder wall. Int Urol Nephrol, 2009. 41: 869.

https://www.ncbi.nlm.nih.gov/pubmed/19396568

215.Barentsz, J.O., et al. Evaluation of chemotherapy in advanced urinary bladder cancer with fast dynamic contrast-enhanced MR imaging. Radiology, 1998. 207: 791.

https://www.ncbi.nlm.nih.gov/pubmed/9609906

216.Krajewski, K.M., et al. Optimisation of the size variation threshold for imaging evaluation of response in patients with platinum-refractory advanced transitional cell carcinoma of the urothelium treated with vinflunine. Eur J Cancer, 2012. 48: 1495.

https://www.ncbi.nlm.nih.gov/pubmed/22176867

217.Rosenblatt, R., et al. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol, 2012. 61: 1229.

https://www.ncbi.nlm.nih.gov/pubmed/22189383

218.Takata, R., et al. Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling. Clin Cancer Res, 2005. 11: 2625.

https://www.ncbi.nlm.nih.gov/pubmed/15814643

219.Takata, R., et al. Validation study of the prediction system for clinical response of M-VAC neoadjuvant chemotherapy. Cancer Sci, 2007. 98: 113.

https://www.ncbi.nlm.nih.gov/pubmed/17116130

220.Wallace, D.M., et al. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol, 1991. 67: 608.

https://www.ncbi.nlm.nih.gov/pubmed/2070206

221.Font A., et al. Improved survival with induction chemotherapy in bladder cancer: preliminary results of a randomized trial. Ann Oncol 1994. 5: Abstr #355. [No abstract available].

222.Martinez-Pineiro, J.A., et al. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol, 1995. 153: 964.

https://www.ncbi.nlm.nih.gov/pubmed/7853584

223.Rintala, E., et al. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scand J Urol Nephrol, 1993. 27: 355.

https://www.ncbi.nlm.nih.gov/pubmed/8290916

224.Malmstrom, P.U., et al. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol, 1996. 155: 1903.

https://www.ncbi.nlm.nih.gov/pubmed/8618283

225.Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet, 1999. 354: 533.

https://www.ncbi.nlm.nih.gov/pubmed/10470696

226.Yin, M., et al. Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis. Oncologist, 2016. 21: 708.

https://www.ncbi.nlm.nih.gov/pubmed/27053504

227.Yuh, B.E., et al. Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer. J Urol, 2013. 189: 1682.

https://www.ncbi.nlm.nih.gov/pubmed/23123547

228.Lee, F.C., et al. Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer. Adv Urol, 2013. 2013: 317190.

https://www.ncbi.nlm.nih.gov/pubmed/24382958

229.Dash, A., et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer, 2008. 113: 2471.

https://www.ncbi.nlm.nih.gov/pubmed/18823036

230.Weight, C.J., et al. Lack of pathologic down-staging with neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder: a contemporary series. Cancer, 2009. 115: 792.

https://www.ncbi.nlm.nih.gov/pubmed/19127557

231.Zaghloul, M.S. The need to revisit adjuvant and neoadjuvant radiotherapy in bladder cancer. Expert Rev Anticancer Ther, 2010. 10: 1527.

https://www.ncbi.nlm.nih.gov/pubmed/20942623

232.El-Monim, H.A., et al. A prospective randomized trial for postoperative vs. preoperative adjuvant radiotherapy for muscle-invasive bladder cancer. Urol Oncol, 2013. 31: 359.

https://www.ncbi.nlm.nih.gov/pubmed/21353794

233.Bayoumi, Y., et al. Survival benefit of adjuvant radiotherapy in stage III and IV bladder cancer: results of 170 patients. Cancer Manag Res, 2014. 6: 459.

https://www.ncbi.nlm.nih.gov/pubmed/25506244

234.Widmark, A., et al. A systematic overview of radiation therapy effects in urinary bladder cancer. Acta Oncol, 2003. 42: 567.

https://www.ncbi.nlm.nih.gov/pubmed/14596515

235.Diaz, D.A., et al. Neoadjuvant Radiotherapy Improves Survival in Patients With T2b/T3 Bladder Cancer: A Population-Based Analysis. Clin Genitourin Cancer, 2015. 13: 378.

https://www.ncbi.nlm.nih.gov/pubmed/25907230

236.Granfors, T., et al. Downstaging and survival benefits of neoadjuvant radiotherapy before cystectomy for patients with invasive bladder carcinoma. Scand J Urol Nephrol, 2009. 43: 293.

https://www.ncbi.nlm.nih.gov/pubmed/19363744

237.Slack, N.H., et al. Five-year follow-up results of a collaborative study of therapies for carcinoma of the bladder. J Surg Oncol, 1977. 9: 393.

https://www.ncbi.nlm.nih.gov/pubmed/330958

238.Smith, J.A., Jr., et al. Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study. J Urol, 1997. 157: 805.

https://www.ncbi.nlm.nih.gov/pubmed/9072571

239.Ghoneim, M.A., et al. Randomized trial of cystectomy with or without preoperative radiotherapy for carcinoma of the bilharzial bladder. J Urol, 1985. 134: 266.

https://www.ncbi.nlm.nih.gov/pubmed/3894693

240.Anderstrom, C., et al. A prospective randomized study of preoperative irradiation with cystectomy or cystectomy alone for invasive bladder carcinoma. Eur Urol, 1983. 9: 142.

https://www.ncbi.nlm.nih.gov/pubmed/6861819

241.Blackard, C.E., et al. Results of a clinical trial of surgery and radiation in stages II and 3 carcinoma of the bladder. J Urol, 1972. 108: 875.

https://www.ncbi.nlm.nih.gov/pubmed/5082739

242.Huncharek, M., et al. Planned preoperative radiation therapy in muscle invasive bladder cancer; results of a meta-analysis. Anticancer Res, 1998. 18: 1931.

https://www.ncbi.nlm.nih.gov/pubmed/9677446

243.Hautmann, R.E., et al. Urinary diversion. Urology, 2007. 69: 17.

https://www.ncbi.nlm.nih.gov/pubmed/17280907

244.Figueroa, A.J., et al. Radical cystectomy for elderly patients with bladder carcinoma: an updated experience with 404 patients. Cancer, 1998. 83: 141.

https://www.ncbi.nlm.nih.gov/pubmed/9655304

245.Geriatric Assessment Methods for Clinical Decision making. NIH Consens Statement 1987. 6: 1. U.S. Department of Health & Human Services.

https://consensus.nih.gov/1987/1987geriatricassessment065html.htm

246.Bruins, H.M., et al. The effect of the time interval between diagnosis of muscle-invasive bladder cancer and radical cystectomy on staging and survival: A Netherlands Cancer Registry analysis. Urol Oncol, 2016. 34: 166.e1.

https://www.ncbi.nlm.nih.gov/pubmed/26705102

247.Williams, S.B., et al. Discerning the survival advantage among patients with prostate cancer who undergo radical prostatectomy or radiotherapy: The limitations of cancer registry data. Cancer, 2017. 123: 1617.

https://www.ncbi.nlm.nih.gov/pubmed/28099688

248.Lebret, T., et al. After cystectomy, is it justified to perform a bladder replacement for patients with lymph node positive bladder cancer? Eur Urol, 2002. 42: 344.

https://www.ncbi.nlm.nih.gov/pubmed/12361899

249.Mertens, L.S., et al. Prostate sparing cystectomy for bladder cancer: 20-year single center experience. J Urol, 2014. 191: 1250.

https://www.ncbi.nlm.nih.gov/pubmed/24286830

250.Stenzl, A., et al. Cystectomy – Technical Considerations in Male and Female Patients. EAU Update Series, 2005. 3: 138.

https://www.sciencedirect.com/science/article/pii/S1570912405000310

251.Wallmeroth, A., et al. Patterns of metastasis in muscle-invasive bladder cancer (pT2-4): An autopsy study on 367 patients. Urol Int, 1999. 62: 69.

https://www.ncbi.nlm.nih.gov/pubmed/10461106

252.Davies, J.D., et al. Anatomic basis for lymph node counts as measure of lymph node dissection extent: a cadaveric study. Urology, 2013. 81: 358.

https://www.ncbi.nlm.nih.gov/pubmed/23374802

253.Jensen, J.B., et al. Lymph node mapping in patients with bladder cancer undergoing radical cystectomy and lymph node dissection to the level of the inferior mesenteric artery. BJU Int, 2010. 106: 199.

https://www.ncbi.nlm.nih.gov/pubmed/20002670

254.Vazina, A., et al. Stage specific lymph node metastasis mapping in radical cystectomy specimens.
J Urol, 2004. 171: 1830.

https://www.ncbi.nlm.nih.gov/pubmed/15076287

255.Leissner, J., et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol, 2004. 171: 139.

https://www.ncbi.nlm.nih.gov/pubmed/14665862

256.Roth, B., et al. A new multimodality technique accurately maps the primary lymphatic landing sites of the bladder. Eur Urol, 2010. 57: 205.

https://www.ncbi.nlm.nih.gov/pubmed/19879039

257.Dorin, R.P., et al. Lymph node dissection technique is more important than lymph node count in identifying nodal metastases in radical cystectomy patients: a comparative mapping study. Eur Urol, 2011. 60: 946.

https://www.ncbi.nlm.nih.gov/pubmed/21802833

258.Wiesner, C., et al. Cancer-specific survival after radical cystectomy and standardized extended lymphadenectomy for node-positive bladder cancer: prediction by lymph node positivity and density. BJU Int, 2009. 104: 331.

https://www.ncbi.nlm.nih.gov/pubmed/19220265

259.Simone, G., et al. Stage-specific impact of extended versus standard pelvic lymph node dissection in radical cystectomy. Int J Urol, 2013. 20: 390.

https://www.ncbi.nlm.nih.gov/pubmed/22970939

260.Holmer, M., et al. Extended lymph node dissection in patients with urothelial cell carcinoma of the bladder: can it make a difference? World J Urol, 2009. 27: 521.

https://www.ncbi.nlm.nih.gov/pubmed/19145436

261.Poulsen, A.L., et al. Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol, 1998. 160: 2015.

https://www.ncbi.nlm.nih.gov/pubmed/9817313

262.Jensen, J.B., et al. Extended versus limited lymph node dissection in radical cystectomy: impact on recurrence pattern and survival. Int J Urol, 2012. 19: 39.

https://www.ncbi.nlm.nih.gov/pubmed/22050425

263.Dhar, N.B., et al. Outcome after radical cystectomy with limited or extended pelvic lymph node dissection. J Urol, 2008. 179: 873.

https://www.ncbi.nlm.nih.gov/pubmed/18221953

264.Zlotta, A.R. Limited, extended, superextended, megaextended pelvic lymph node dissection at the time of radical cystectomy: what should we perform? Eur Urol, 2012. 61: 243.

https://www.ncbi.nlm.nih.gov/pubmed/22119158

265.Zehnder, P., et al. Super extended versus extended pelvic lymph node dissection in patients undergoing radical cystectomy for bladder cancer: a comparative study. J Urol, 2011. 186: 1261.

https://www.ncbi.nlm.nih.gov/pubmed/21849183

266.Bruins, H.M., et al. The impact of the extent of lymphadenectomy on oncologic outcomes in patients undergoing radical cystectomy for bladder cancer: a systematic review. Eur Urol, 2014. 66: 1065.

https://www.ncbi.nlm.nih.gov/pubmed/25074764

267.Brossner, C., et al. Does extended lymphadenectomy increase the morbidity of radical cystectomy? BJU Int, 2004. 93: 64.

https://www.ncbi.nlm.nih.gov/pubmed/14678370

268.Finelli, A., et al. Laparoscopic extended pelvic lymphadenectomy for bladder cancer: technique and initial outcomes. J Urol, 2004. 172: 1809.

https://www.ncbi.nlm.nih.gov/pubmed/15540725

269.Abd El Latif, A., et al. 1752 Impact of extended versus standard lymph node dissection on overall survival among patients with urothelial cancer of bladder. J Urol. 187: e707.

http://www.jurology.com/article/S0022-5347(12)02130-1/abstract

270.Abd El Latif, A., et al. 1896. Impact of extended versus standard lymph node dissection (SLND) on post-cystectomy survival (PCS) among patients with LN-negative urothelial bladder cancer (UBC). J Urol. 185: e759.

http://www.jurology.com/article/S0022-5347(11)02268-3/abstract

271.Abol-Enein, H., et al. Does the extent of lymphadenectomy in radical cystectomy for bladder cancer influence disease-free survival? A prospective single-center study. Eur Urol, 2011. 60: 572.

https://www.ncbi.nlm.nih.gov/pubmed/21684070

272.Dharaskar, A., et al. Does extended lymph node dissection affect the lymph node density and survival after radical cystectomy? Indian J Cancer, 2011. 48: 230.

https://www.ncbi.nlm.nih.gov/pubmed/21768672

273.Abdollah, F., et al. Stage-specific impact of pelvic lymph node dissection on survival in patients with non-metastatic bladder cancer treated with radical cystectomy. BJU Int, 2012. 109: 1147.

https://www.ncbi.nlm.nih.gov/pubmed/21883849

274.Liu, J.-J., et al. 1404. Practice patterns of pelvic lymph node dissection for radical cystectomy from the Veterans Affairs Central Cancer Registry (VACCR). J Urol. 185: e562.

http://www.jurology.com/article/S0022-5347(11)01543-6/abstract

275.Isaka, S., et al. [Pelvic lymph node dissection for invasive bladder cancer]. Nihon Hinyokika Gakkai Zasshi, 1989. 80: 402.

https://www.ncbi.nlm.nih.gov/pubmed/2733302

276.Miyakawa, M., et al. [Results of the multidisciplinary treatment of invasive bladder cancer]. Hinyokika Kiyo, 1986. 32: 1931.

https://www.ncbi.nlm.nih.gov/pubmed/3825830

277.Simone, G., et al. 1755. Extended versus super-extended PLND during radical cystectomy: comparison of two prospective series. J Urol. 187: e708.

http://www.jurology.com/article/S0022-5347(12)02133-7/abstract

278.Bostrom, P.J., et al. 1595. Extended lymphadenectomy and chemotherapy and chemotherapy offer survival advantage in muscle-invasive bladder cancer. J Urol. 185: e640.

http://www.jurology.com/article/S0022-5347(11)01893-3/abstract

279.Yuasa, M., et al. [Clinical evaluation of total cystectomy for bladder carcinoma: a ten-year experience]. Hinyokika Kiyo, 1988. 34: 975.

https://www.ncbi.nlm.nih.gov/pubmed/3223462

280.Mandel, P., et al. Extent of lymph node dissection and recurrence-free survival after radical cystectomy: a meta-analysis. Urol Oncol, 2014. 32: 1184.

https://www.ncbi.nlm.nih.gov/pubmed/25027683

281.Bi, L., et al. Extended vs non-extended pelvic lymph node dissection and their influence on recurrence-free survival in patients undergoing radical cystectomy for bladder cancer: a systematic review and meta-analysis of comparative studies. BJU Int, 2014. 113: E39.

https://www.ncbi.nlm.nih.gov/pubmed/24053715

282.Koppie, T.M., et al. Standardization of pelvic lymphadenectomy performed at radical cystectomy: can we establish a minimum number of lymph nodes that should be removed? Cancer, 2006. 107: 2368.

https://www.ncbi.nlm.nih.gov/pubmed/17041887

283.Fleischmann, A., et al. Extracapsular extension of pelvic lymph node metastases from urothelial carcinoma of the bladder is an independent prognostic factor. J Clin Oncol, 2005. 23: 2358.

https://www.ncbi.nlm.nih.gov/pubmed/15800327

284.Wright, J.L., et al. The association between extent of lymphadenectomy and survival among patients with lymph node metastases undergoing radical cystectomy. Cancer, 2008. 112: 2401.

https://www.ncbi.nlm.nih.gov/pubmed/18383515

285.Studer, U.E., et al. Morbidity from pelvic lymphadenectomy in men undergoing radical prostatectomy. Eur Urol, 2006. 50: 887.

https://www.ncbi.nlm.nih.gov/pubmed/16956714

286.Zehnder, P., et al. Radical cystectomy with super-extended lymphadenectomy: impact of separate vs en bloc lymph node submission on analysis and outcomes. BJU Int, 2016. 117: 253.

https://www.ncbi.nlm.nih.gov/pubmed/25307941

287.Kessler, T.M., et al. Attempted nerve sparing surgery and age have a significant effect on urinary continence and erectile function after radical cystoprostatectomy and ileal orthotopic bladder substitution. J Urol, 2004. 172: 1323.

https://www.ncbi.nlm.nih.gov/pubmed/15371833

288.de Vries, R.R., et al. Prostate-sparing cystectomy: long-term oncological results. BJU Int, 2009. 104: 1239.

https://www.ncbi.nlm.nih.gov/pubmed/24286830

289.Basiri, A., et al. Overall survival and functional results of prostate-sparing cystectomy: a matched case-control study. Urol J, 2012. 9: 678.

https://www.ncbi.nlm.nih.gov/pubmed/23235973

290.Wang, X.H., et al. [Impact of preservation of distal prostatic capsula and seminal vesicle on functions of orthotopic ideal neobladder and erectile function of bladder cancer patients]. Ai Zheng, 2008. 27: 62.

https://www.ncbi.nlm.nih.gov/pubmed/18184466

291.Moon, H., et al. Nerve and Seminal Sparing Cystectomy for Bladder Cancer. Korean J Urol 2005: 555.

https://www.researchgate.net/publication/291150065_Nerve_and_seminal_sparing_cystectomy_for_bladder_cancer

292.Vilaseca, A., et al. Erectile function after cystectomy with neurovascular preservation. Actas Urol Esp, 2013. 37: 554.

https://www.ncbi.nlm.nih.gov/pubmed/23790714

293.el-Bahnasawy, M.S., et al. Urethral pressure profile following orthotopic neobladder: differences between nerve sparing and standard radical cystectomy techniques. J Urol, 2006. 175: 1759.

https://www.ncbi.nlm.nih.gov/pubmed/16600753

294.Hekal, I.A., et al. Recoverability of erectile function in post-radical cystectomy patients: subjective and objective evaluations. Eur Urol, 2009. 55: 275.

https://www.ncbi.nlm.nih.gov/pubmed/18603350

295.Jacobs, B.L., et al. Prostate capsule sparing versus nerve sparing radical cystectomy for bladder cancer: results of a randomized, controlled trial. J Urol, 2015. 193: 64.

https://www.ncbi.nlm.nih.gov/pubmed/25066875

296.Colombo, R., et al. Fifteen-year single-centre experience with three different surgical procedures of nerve-sparing cystectomy in selected organ-confined bladder cancer patients. World J Urol, 2015. 33: 1389.

https://www.ncbi.nlm.nih.gov/pubmed/25577131

297.Gotsadze, D.T., et al. [Why and how to modify standard cystectomy]. Urologiia, 2008: 22.

https://www.ncbi.nlm.nih.gov/pubmed/18572764

298.Rozet F., et al. Oncological evaluation of prostate sparing cystectomy: the Montsouris long-term results. J Urol. , 2008. 179.

https://www.ncbi.nlm.nih.gov/pubmed/18423740

299.Muto, G., et al. Seminal-sparing cystectomy: technical evolution and results over a 20-year period. Urology, 2014. 83: 856.

https://www.ncbi.nlm.nih.gov/pubmed/24485363

300.Novara, G., et al. Systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. Eur Urol, 2015. 67: 376.

https://www.ncbi.nlm.nih.gov/pubmed/18423740

301.Wilson, T.G., et al. Best practices in robot-assisted radical cystectomy and urinary reconstruction: recommendations of the Pasadena Consensus Panel. Eur Urol, 2015. 67: 363.

https://www.ncbi.nlm.nih.gov/pubmed/25582930

302.Bochner, B.H., et al. Comparing Open Radical Cystectomy and Robot-assisted Laparoscopic Radical Cystectomy: A Randomized Clinical Trial. Eur Urol, 2015. 67: 1042.

https://www.ncbi.nlm.nih.gov/pubmed/25496767

303.Yuh, B., et al. Systematic review and cumulative analysis of oncologic and functional outcomes after robot-assisted radical cystectomy. Eur Urol, 2015. 67: 402.

https://www.ncbi.nlm.nih.gov/pubmed/25560797

304.Nguyen, D.P., et al. Recurrence patterns after open and robot-assisted radical cystectomy for bladder cancer. Eur Urol, 2015. 68: 399.

https://www.ncbi.nlm.nih.gov/pubmed/25709026

305.Al Hussein Al Awamlh, B., et al. The safety of robot-assisted cystectomy in patients with previous history of pelvic irradiation. BJU Int, 2016. 118: 437.

https://www.ncbi.nlm.nih.gov/pubmed/26935481

306.Fahmy, O., et al. Current status of robotic assisted radical cystectomy with intracorporeal ileal neobladder for bladder cancer. J Surg Oncol, 2015. 112: 427.

https://www.ncbi.nlm.nih.gov/pubmed/26265262

307.Tang, K., et al. Laparoscopic versus open radical cystectomy in bladder cancer: a systematic review and meta-analysis of comparative studies. PLoS One, 2014. 9: e95667.

https://www.ncbi.nlm.nih.gov/pubmed/24835573

308.Khan, M.S., et al. A Single-centre Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol, 2016. 69: 613.

https://www.ncbi.nlm.nih.gov/pubmed/26272237

309.Stenzl, A. Bladder substitution. Curr Opin Urol, 1999. 9: 241.

https://www.ncbi.nlm.nih.gov/pubmed/10726098

310.de Vries, R.R., et al. Short-term outcome after cystectomy: comparison of two different perioperative protocols. Urol Int, 2012. 88: 383.

https://www.ncbi.nlm.nih.gov/pubmed/22433508

311.Malavaud, B., et al. Complications for radical cystectomy. Impact of the American Society of Anesthesiologists score. Eur Urol, 2001. 39: 79.

https://www.ncbi.nlm.nih.gov/pubmed/11173943

312.Haynes, S.R., et al. An assessment of the consistency of ASA physical status classification allocation. Anaesthesia, 1995. 50: 195.

https://www.ncbi.nlm.nih.gov/pubmed/7717481

313.Gerharz, E.W., et al. Metabolic and functional consequences of urinary reconstruction with bowel. BJU Int, 2003. 91: 143.

https://www.ncbi.nlm.nih.gov/pubmed/12519116

314.Madersbacher, S., et al. Contemporary cystectomy and urinary diversion. World J Urol, 2002. 20: 151.

https://www.ncbi.nlm.nih.gov/pubmed/12196898

315.Pruthi, R.S., et al. Fast track program in patients undergoing radical cystectomy: results in 362 consecutive patients. J Am Coll Surg, 2010. 210: 93.

https://www.ncbi.nlm.nih.gov/pubmed/20123338

316.Kouba, E.J., et al. Gum chewing stimulates bowel motility in patients undergoing radical cystectomy with urinary diversion. Urology, 2007. 70: 1053.

https://www.ncbi.nlm.nih.gov/pubmed/18158012

317.Karl, A., et al. A new concept for early recovery after surgery for patients undergoing radical cystectomy for bladder cancer: results of a prospective randomized study. J Urol, 2014. 191: 335.

https://www.ncbi.nlm.nih.gov/pubmed/23968966

318.Xu, W., et al. Postoperative Pain Management after Radical Cystectomy: Comparing Traditional versus Enhanced Recovery Protocol Pathway. J Urol, 2015. 194: 1209.

https://www.ncbi.nlm.nih.gov/pubmed/26021824

319.Lee, C.T., et al. Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial. Eur Urol, 2014. 66: 265.

https://www.ncbi.nlm.nih.gov/pubmed/24630419

320.Hautmann, R.E., et al. Long-term results of standard procedures in urology: the ileal neobladder. World J Urol, 2006. 24: 305.

https://www.ncbi.nlm.nih.gov/pubmed/20643429

321.Hautmann, R.E., et al. Lessons learned from 1,000 neobladders: the 90-day complication rate.
J Urol, 2010. 184: 990.

https://www.ncbi.nlm.nih.gov/pubmed/20643429

322.Stein, J.P., et al. Indications and technique of the orthotopic neobladder in women. Urol Clin North Am, 2002. 29: 725.

https://www.ncbi.nlm.nih.gov/pubmed/12476536

323.Hautmann, R.E., et al. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol, 2012. 61: 1039.

https://www.ncbi.nlm.nih.gov/pubmed/22381169

324.Jentzmik, F., et al. The ileal neobladder in female patients with bladder cancer: long-term clinical, functional, and oncological outcome. World J Urol, 2012. 30: 733.

https://www.ncbi.nlm.nih.gov/pubmed/22322390

325.Ahmadi, H., et al. Urinary functional outcome following radical cystoprostatectomy and ileal neobladder reconstruction in male patients. J Urol, 2013. 189: 1782.

https://www.ncbi.nlm.nih.gov/pubmed/23159582

326.Neuzillet, Y., et al. The Z-shaped ileal neobladder after radical cystectomy: an 18 years experience with 329 patients. BJU Int, 2011. 108: 596.

https://www.ncbi.nlm.nih.gov/pubmed/21223470

327.Gershman, B., et al. Comparative impact of continent and incontinent urinary diversion on long-term renal function after radical cystectomy in patients with preoperative chronic kidney disease 2 and chronic kidney disease 3a. Int J Urol, 2015. 22: 651.

https://www.ncbi.nlm.nih.gov/pubmed/25881721

328.Longo, N., et al. Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. BJU Int, 2016. 118: 521.

https://www.ncbi.nlm.nih.gov/pubmed/26935245

329.Deliveliotis, C., et al. Urinary diversion in high-risk elderly patients: modified cutaneous ureterostomy or ileal conduit? Urology, 2005. 66: 299.

https://www.ncbi.nlm.nih.gov/pubmed/16040096

330.Kilciler, M., et al. Comparison of ileal conduit and transureteroureterostomy with ureterocutaneostomy urinary diversion. Urol Int, 2006. 77: 245.

https://www.ncbi.nlm.nih.gov/pubmed/17033213

331.Berger, I., et al. Impact of the use of bowel for urinary diversion on perioperative complications and 90-day mortality in patients aged 75 years or older. Urol Int, 2015. 94: 394.

https://www.ncbi.nlm.nih.gov/pubmed/25612612

332.Nieuwenhuijzen, J.A., et al. Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. Eur Urol, 2008. 53: 834.

https://www.ncbi.nlm.nih.gov/pubmed/17904276

333.Madersbacher, S., et al. Long-term outcome of ileal conduit diversion. J Urol, 2003. 169: 985.

https://www.ncbi.nlm.nih.gov/pubmed/12576827

334.Wood, D.N., et al. Stomal complications of ileal conduits are significantly higher when formed in women with intractable urinary incontinence. J Urol, 2004. 172: 2300.

https://www.ncbi.nlm.nih.gov/pubmed/15538253

335.Neal, D.E. Complications of ileal conduit diversion in adults with cancer followed up for at least five years. Br Med J (Clin Res Ed), 1985. 290: 1695.

https://www.ncbi.nlm.nih.gov/pubmed/3924218

336.Mues, A.C., et al. Contemporary experience in the management of angiomyolipoma. J Endourol, 2010. 24: 1883.

https://www.ncbi.nlm.nih.gov/pubmed/20919915

337.Benson, M.C., et al. Continent urinary diversion. Urol Clin North Am, 1999. 26: 125.

https://www.ncbi.nlm.nih.gov/pubmed/10086055

338.Gerharz, E.W., et al. Ten years’ experience with the submucosally embedded in situ appendix in continent cutaneous diversion. Eur Urol, 2001. 40: 625.

https://www.ncbi.nlm.nih.gov/pubmed/11805408

339.Jonsson, O., et al. Long-time experience with the Kock ileal reservoir for continent urinary diversion. Eur Urol, 2001. 40: 632.

https://www.ncbi.nlm.nih.gov/pubmed/11805409

340.Thoeny, H.C., et al. Is ileal orthotopic bladder substitution with an afferent tubular segment detrimental to the upper urinary tract in the long term? J Urol, 2002. 168: 2030.

https://www.ncbi.nlm.nih.gov/pubmed/11834389

341.Wiesner, C., et al. Continent cutaneous urinary diversion: long-term follow-up of more than 800 patients with ileocecal reservoirs. World J Urol, 2006. 24: 315.

https://www.ncbi.nlm.nih.gov/pubmed/16676186

342.Wiesner, C., et al. Long-term followup of the intussuscepted ileal nipple and the in situ, submucosally embedded appendix as continence mechanisms of continent urinary diversion with the cutaneous ileocecal pouch (Mainz pouch I). J Urol, 2006. 176: 155.

https://www.ncbi.nlm.nih.gov/pubmed/16753391

343.Leissner, J., et al. Colon pouch (Mainz pouch III) for continent urinary diversion after pelvic irradiation. Urology, 2000. 56: 798.

https://www.ncbi.nlm.nih.gov/pubmed/11068305

344.Simon, J. Ectopia Vesicae (Absence of the anterior walls of the Bladder and the pubic abdominal parietes) Operation for directing the orifices of the ureteres into the rectum, temporary success) JAMA 1911: 398. [No abstract available].

345.Coffey, R.C., Physiologic implantation of the severed ureter or common bile-duct into the intestine. JAMA, 1911. LVI: 397.

https://jamanetwork.com/journals/jama/article-abstract/435854?redirect=true

346.Azimuddin, K., et al. Neoplasia after ureterosigmoidostomy. Dis Colon Rectum, 1999. 42: 1632.

https://www.ncbi.nlm.nih.gov/pubmed/10613486

347.Kalble, T., et al. Tumor induction and prophylaxis following different forms of intestinal urinary diversion in a rat model. Urol Res, 1995. 23: 365.

https://www.ncbi.nlm.nih.gov/pubmed/8788273

348.Donat, S.M., et al. Radical cystectomy in octogenarians--does morbidity outweigh the potential survival benefits? J Urol, 2010. 183: 2171.

https://www.ncbi.nlm.nih.gov/pubmed/20399461

349.Hautmann, R.E., et al. 25 years of experience with 1,000 neobladders: long-term complications.
J Urol, 2011. 185: 2207.

https://www.ncbi.nlm.nih.gov/pubmed/21497841

350.Stein, J.P., et al. The orthotopic T pouch ileal neobladder: experience with 209 patients. J Urol, 2004. 172: 584.

https://www.ncbi.nlm.nih.gov/pubmed/15247737

351.Abol-Enein, H., et al. Functional results of orthotopic ileal neobladder with serous-lined extramural ureteral reimplantation: experience with 450 patients. J Urol, 2001. 165: 1427.

https://www.ncbi.nlm.nih.gov/pubmed/11342891

352.Stein, J.P., et al. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU Int, 2003. 92: 12.

https://www.ncbi.nlm.nih.gov/pubmed/12823375

353.Yossepowitch, O., et al. Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence. J Urol, 2003. 169: 177.

https://www.ncbi.nlm.nih.gov/pubmed/12478130

354.Stein, J.P., et al. Urethral tumor recurrence following cystectomy and urinary diversion: clinical and pathological characteristics in 768 male patients. J Urol, 2005. 173: 1163.

https://www.ncbi.nlm.nih.gov/pubmed/15758728

355.Gerharz, E.W., et al. Quality of life after cystectomy and urinary diversion: an evidence based analysis. J Urol, 2005. 174: 1729.

https://www.ncbi.nlm.nih.gov/pubmed/16217273

356.Porter, M.P., et al. Health related quality of life after radical cystectomy and urinary diversion for bladder cancer: a systematic review and critical analysis of the literature. J Urol, 2005. 173: 1318.

https://www.ncbi.nlm.nih.gov/pubmed/15758789

357.Gakis, G., et al. [Benefits and risks of orthotopic neobladder reconstruction in female patients]. Aktuelle Urol, 2011. 42: 109.

https://www.ncbi.nlm.nih.gov/pubmed/21437834

358.Stein, J.P., et al. Pathological guidelines for orthotopic urinary diversion in women with bladder cancer: a review of the literature. J Urol, 2007. 178: 756.

https://www.ncbi.nlm.nih.gov/pubmed/17631333

359.Stein, J.P., et al. Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens. J Urol, 1995. 154: 1329.

https://www.ncbi.nlm.nih.gov/pubmed/7658531

360.Vallancien, G., et al. Cystectomy with prostate sparing for bladder cancer in 100 patients: 10-year experience. J Urol, 2002. 168: 2413.

https://www.ncbi.nlm.nih.gov/pubmed/12441929

361.Stenzl, A., et al. Radical cystectomy with orthotopic neobladder for invasive bladder cancer: a critical analysis of long term oncological, functional and quality of life results. Int Braz J Urol, 2010. 36: 537.

https://www.ncbi.nlm.nih.gov/pubmed/21044370

362.Nielsen, M.E., et al. Association of hospital volume with conditional 90-day mortality after cystectomy: an analysis of the National Cancer Data Base. BJU Int, 2014. 114: 46.

https://www.ncbi.nlm.nih.gov/pubmed/24219110

363.Porter, M.P., et al. Hospital volume and 90-day mortality risk after radical cystectomy: a population-based cohort study. World J Urol, 2011. 29: 73.

https://www.ncbi.nlm.nih.gov/pubmed/21132553

364.Hautmann, R.E., et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Urinary diversion. Eur Urol, 2013. 63: 67.

https://www.ncbi.nlm.nih.gov/pubmed/22995974

365.Cookson, M.S., et al. Complications of radical cystectomy for nonmuscle invasive disease: comparison with muscle invasive disease. J Urol, 2003. 169: 101.

https://www.ncbi.nlm.nih.gov/pubmed/12478113

366.Sabir, E.F., et al. Impact of hospital volume on local recurrence and distant metastasis in bladder cancer patients treated with radical cystectomy in Sweden. Scand J Urol, 2013. 47: 483.

https://www.ncbi.nlm.nih.gov/pubmed/23590830

367.Morgan, T.M., et al. Volume outcomes of cystectomy--is it the surgeon or the setting? J Urol, 2012. 188: 2139.

https://www.ncbi.nlm.nih.gov/pubmed/23083864

368.Finks, J.F., et al. Trends in hospital volume and operative mortality for high-risk surgery. N Engl
J Med, 2011. 364: 2128.

https://www.ncbi.nlm.nih.gov/pubmed/23083864

369.Corcoran, A.T., et al. Variation in performance of candidate surgical quality measures for muscle-invasive bladder cancer by hospital type. BJU Int, 2015. 115: 230.

https://www.ncbi.nlm.nih.gov/pubmed/24447637

370.Ravi, P., et al. Benefit in regionalisation of care for patients treated with radical cystectomy: a nationwide inpatient sample analysis. BJU Int, 2014. 113: 733.

https://www.ncbi.nlm.nih.gov/pubmed/24007240

371.Shabsigh, A., et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol, 2009. 55: 164.

https://www.ncbi.nlm.nih.gov/pubmed/18675501

372.Wang, Y.L., et al. Perioperative Blood Transfusion Promotes Worse Outcomes of Bladder Cancer after Radical Cystectomy: A Systematic Review and Meta-Analysis. PLoS One, 2015. 10: e0130122.

https://www.ncbi.nlm.nih.gov/pubmed/26080092

373.Buchner, A., et al. Dramatic impact of blood transfusion on cancer-specific survival after radical cystectomy irrespective of tumor stage. Scand J Urol, 2017. 51: 130.

https://www.ncbi.nlm.nih.gov/pubmed/28332428

374.Zaid, H.B., et al. Efficacy and Safety of Intraoperative Tranexamic Acid Infusion for Reducing Blood Transfusion During Open Radical Cystectomy. Urology, 2016. 92: 57.

https://www.ncbi.nlm.nih.gov/pubmed/26968489

375.Hammond, J., et al. Rates of venous thromboembolism among patients with major surgery for cancer. Ann Surg Oncol, 2011. 18: 3240.

https://www.ncbi.nlm.nih.gov/pubmed/21584837

376.Potretzke, A.M., et al. Highest risk of symptomatic venous thromboembolic events after radical cystectomy occurs in patients with obesity or nonurothelial cancers. Urol Ann, 2015. 7: 355.

https://www.ncbi.nlm.nih.gov/pubmed/26229325

377.Shariat, S.F., et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol, 2006. 176: 2414.

https://www.ncbi.nlm.nih.gov/pubmed/17085118

378.Nuhn, P., et al. External validation of postoperative nomograms for prediction of all-cause mortality, cancer-specific mortality, and recurrence in patients with urothelial carcinoma of the bladder.
Eur Urol, 2012. 61: 58.

https://www.ncbi.nlm.nih.gov/pubmed/21840642

379.Bruins, H.M., et al. Clinical outcomes and recurrence predictors of lymph node positive urothelial cancer after cystectomy. J Urol, 2009. 182: 2182.

https://www.ncbi.nlm.nih.gov/pubmed/19758623

380.Abdollah, F., et al. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol, 2013. 37: 219.

https://www.ncbi.nlm.nih.gov/pubmed/23485480

381.Ok, J.H., et al. Medical and surgical palliative care of patients with urological malignancies. J Urol, 2005. 174: 1177.

https://www.ncbi.nlm.nih.gov/pubmed/16145365

382.Ubrig, B., et al. Extraperitoneal bilateral cutaneous ureterostomy with midline stoma for palliation of pelvic cancer. Urology, 2004. 63: 973.

https://www.ncbi.nlm.nih.gov/pubmed/15134993

383.Zebic, N., et al. Radical cystectomy in patients aged > or=75 years: an updated review of patients treated with curative and palliative intent. BJU Int, 2005. 95: 1211.

https://www.ncbi.nlm.nih.gov/pubmed/15892803

384.El-Tabey, N.A., et al. Bladder cancer with obstructive uremia: oncologic outcome after definitive surgical management. Urology, 2005. 66: 531.

https://www.ncbi.nlm.nih.gov/pubmed/16140072

385.Nagele, U., et al. The rationale for radical cystectomy as primary therapy for T4 bladder cancer. World J Urol, 2007. 25: 401.

https://www.ncbi.nlm.nih.gov/pubmed/17525849

386.Ghahestani, S.M., et al. Palliative treatment of intractable hematuria in context of advanced bladder cancer: a systematic review. Urol J, 2009. 6: 149.

https://www.ncbi.nlm.nih.gov/pubmed/19711266

387.Srinivasan, V., et al. A comparison of two radiotherapy regimens for the treatment of symptoms from advanced bladder cancer. Clin Oncol (R Coll Radiol), 1994. 6: 11.

https://www.ncbi.nlm.nih.gov/pubmed/7513538

388.Herr, H.W. Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol, 1987. 138: 1162.

https://www.ncbi.nlm.nih.gov/pubmed/3669160

389.Herr, H.W. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome.
J Clin Oncol, 2001. 19: 89.

https://www.ncbi.nlm.nih.gov/pubmed/11134199

390.Holmang, S., et al. Long-term followup of all patients with muscle invasive (stages T2, T3 and T4) bladder carcinoma in a geographical region. J Urol, 1997. 158: 389.

https://www.ncbi.nlm.nih.gov/pubmed/9224309

391.Solsona, E., et al. Feasibility of radical transurethral resection as monotherapy for selected patients with muscle invasive bladder cancer. J Urol, 2010. 184: 475.

https://www.ncbi.nlm.nih.gov/pubmed/20620402

392.Whitmore, W.F., Jr., et al. Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J Urol, 1977. 118: 184.

https://www.ncbi.nlm.nih.gov/pubmed/875217

393.Milosevic, M., et al. Radiotherapy for bladder cancer. Urology, 2007. 69: 80.

https://www.ncbi.nlm.nih.gov/pubmed/17280910

394.Sondergaard, J., et al. A comparison of morbidity following conformal versus intensity-modulated radiotherapy for urinary bladder cancer. Acta Oncol, 2014. 53: 1321.

https://www.ncbi.nlm.nih.gov/pubmed/24980045

395.Tonoli, S., et al. Radical radiotherapy for bladder cancer: retrospective analysis of a series of 459 patients treated in an Italian institution. Clin Oncol (R Coll Radiol), 2006. 18: 52.

https://www.ncbi.nlm.nih.gov/pubmed/16477920

396.Chung, P.W., et al. Long-term outcome of radiation-based conservation therapy for invasive bladder cancer. Urol Oncol, 2007. 25: 303.

https://www.ncbi.nlm.nih.gov/pubmed/17628296

397.Lutkenhaus, L.J., et al. Clinical results of conformal versus intensity-modulated radiotherapy using a focal simultaneous boost for muscle-invasive bladder cancer in elderly or medically unfit patients. Radiat Oncol, 2016. 11: 45.

https://www.ncbi.nlm.nih.gov/pubmed/26993980

398.Shelley, M.D., et al. Surgery versus radiotherapy for muscle invasive bladder cancer. Cochrane Database Syst Rev, 2002: CD002079.

https://www.ncbi.nlm.nih.gov/pubmed/11869621

399.Booth, C.M., et al. Curative therapy for bladder cancer in routine clinical practice: a population-based outcomes study. Clin Oncol (R Coll Radiol), 2014. 26: 506.

https://www.ncbi.nlm.nih.gov/pubmed/24954284

400.Scher, H.I., et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) effect on the primary bladder lesion. J Urol, 1988. 139: 470.

https://www.ncbi.nlm.nih.gov/pubmed/3343728

401.Herr, H.W., et al. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol, 1998. 16: 1298.

https://www.ncbi.nlm.nih.gov/pubmed/9552029

402.Kachnic, L.A., et al. Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol, 1997. 15: 1022.

https://www.ncbi.nlm.nih.gov/pubmed/9060542

403.Als, A.B., et al. Long-term survival after gemcitabine and cisplatin in patients with locally advanced transitional cell carcinoma of the bladder: focus on supplementary treatment strategies. Eur Urol, 2007. 52: 478.

https://www.ncbi.nlm.nih.gov/pubmed/17383078

404.Sternberg, C.N., et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol, 1988. 139: 461.

https://www.ncbi.nlm.nih.gov/pubmed/3343727

405.Logothetis, C.J., et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol, 1990. 8: 1050.

https://www.ncbi.nlm.nih.gov/pubmed/2189954

406.Loehrer, P.J., Sr., et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol, 1992. 10: 1066.

https://www.ncbi.nlm.nih.gov/pubmed/1607913

407.Kaufman, D., et al. Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol, 2000. 18: 1921.

https://www.ncbi.nlm.nih.gov/pubmed/10784633

408.Stadler, W.M., et al. Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer. Urol Oncol, 2002. 7: 153.

https://www.ncbi.nlm.nih.gov/pubmed/12474531

409.Moore, M.J., et al. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 1999. 17: 2876.

https://www.ncbi.nlm.nih.gov/pubmed/11001674

410.Bajorin, D.F., et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol, 1999. 17: 3173.

https://www.ncbi.nlm.nih.gov/pubmed/10506615

411.Herr, H.W., et al. Post-chemotherapy surgery in patients with unresectable or regionally metastatic bladder cancer. J Urol, 2001. 165: 811.

https://www.ncbi.nlm.nih.gov/pubmed/11176475

412.James, N.D., et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. New Engl J Med, 2012. 366: 1477.

https://www.ncbi.nlm.nih.gov/pubmed/22512481

413.Efstathiou, J.A., et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol, 2012. 61: 705.

https://www.ncbi.nlm.nih.gov/pubmed/22101114

414.Giacalone, N.J., et al. Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience. Eur Urol, 2017. 71: 952.

https://www.ncbi.nlm.nih.gov/pubmed/28081860

415.Suer, E., et al. Significance of second transurethral resection on patient outcomes in muscle-invasive bladder cancer patients treated with bladder-preserving multimodal therapy. World J Urol, 2016. 34: 847.

https://www.ncbi.nlm.nih.gov/pubmed/26462931

416.Ploussard, G., et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur Urol, 2014. 66: 120.

https://www.ncbi.nlm.nih.gov/pubmed/24613684

417.Arafat, W., et al. Comparison between standard and reduced volume radiotherapy in bladder preservation trimodality protocol for muscle-invasive bladder cancer patients. Ecancermedicalscience, 2016. 10: 682.

https://www.ncbi.nlm.nih.gov/pubmed/27899955

418.Hoskin, P.J., et al. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.
J Clin Oncol, 2010. 28: 4912.

https://www.ncbi.nlm.nih.gov/pubmed/20956620

419.Ramani, V.A., et al. Differential complication rates following radical cystectomy in the irradiated and nonirradiated pelvis. Eur Urol, 2010. 57: 1058.

https://www.ncbi.nlm.nih.gov/pubmed/20022162

420.Krasnow, R.E., et al. Clinical Outcomes of Patients with Histologic Variants of Urothelial Cancer Treated with Trimodality Bladder-sparing Therapy. Eur Urol, 2017. 72: 54.

https://www.ncbi.nlm.nih.gov/pubmed/28040351

421.Seisen, T., et al. Comparative Effectiveness of Trimodal Therapy Versus Radical Cystectomy for Localized Muscle-invasive Urothelial Carcinoma of the Bladder. Eur Urol, 2017.

https://www.ncbi.nlm.nih.gov/pubmed/28412065

422.Vashistha, V., et al. Radical Cystectomy Compared to Combined Modality Treatment for Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. Int J Radiat Oncol Biol Phys, 2017. 97: 1002.

https://www.ncbi.nlm.nih.gov/pubmed/28332983

423.Cohen, S.M., et al. The role of perioperative chemotherapy in the treatment of urothelial cancer. Oncologist, 2006. 11: 630.

https://www.ncbi.nlm.nih.gov/pubmed/16794242

424.Mak, K.S., et al. Quality of Life in Long-term Survivors of Muscle-Invasive Bladder Cancer. Int
J Radiat Oncol Biol Phys, 2016. 96: 1028.

https://www.ncbi.nlm.nih.gov/pubmed/27727064

425.Mitin, T., et al. Long-Term Outcomes Among Patients Who Achieve Complete or Near-Complete Responses After the Induction Phase of Bladder-Preserving Combined-Modality Therapy for Muscle-Invasive Bladder Cancer: A Pooled Analysis of NRG Oncology/RTOG 9906 and 0233. Int
J Radiat Oncol Biol Phys, 2016. 94: 67.

https://www.ncbi.nlm.nih.gov/pubmed/26700703

426.Sylvester, R., et al. The role of adjuvant combination chemotherapy after cystectomy in locally advanced bladder cancer: what we do not know and why. Ann Oncol, 2000. 11: 851.

https://www.ncbi.nlm.nih.gov/pubmed/10997813

427.Donat, S.M., et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol, 2009. 55: 177.

https://www.ncbi.nlm.nih.gov/pubmed/18640770

428.ABC Meta-analysis Coll. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol, 2005. 48: 189.

https://www.ncbi.nlm.nih.gov/pubmed/15939530

429.Leow, J.J., et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol, 2014. 66: 42.

https://www.ncbi.nlm.nih.gov/pubmed/24018020

430.Cognetti, F., et al. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol, 2012. 23: 695.

https://www.ncbi.nlm.nih.gov/pubmed/21859900

431.Paz-Ares, L.G., et al. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. J Clin Oncol, 2010. vol. 28 no. 18_suppl.

http://ascopubs.org/doi/abs/10.1200/jco.2010.28.18_suppl.lba4518

432.Stadler, W.M., et al. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol, 2011. 29: 3443.

https://www.ncbi.nlm.nih.gov/pubmed/21810677

433.Lehmann, J., et al. Complete long-term survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer. BJU Int, 2006. 97: 42.

https://www.ncbi.nlm.nih.gov/pubmed/16336326

434.Freiha, F., et al. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol, 1996. 155: 495.

https://www.ncbi.nlm.nih.gov/pubmed/8558644

435.Stockle, M., et al. Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. J Urol, 1995. 153: 47.

https://www.ncbi.nlm.nih.gov/pubmed/7966789

436.Studer, U.E., et al. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol, 1994. 152: 81.

https://www.ncbi.nlm.nih.gov/pubmed/8201695

437.Skinner, D.G., et al. Adjuvant chemotherapy following cystectomy benefits patients with deeply invasive bladder cancer. Semin Urol, 1990. 8: 279.

https://www.ncbi.nlm.nih.gov/pubmed/2284533

438.Lehmann, J., et al. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol, 2005. 23: 4963.

https://www.ncbi.nlm.nih.gov/pubmed/15939920

439.Svatek, R.S., et al. The effectiveness of off-protocol adjuvant chemotherapy for patients with urothelial carcinoma of the urinary bladder. Clin Cancer Res, 2010. 16: 4461.

https://www.ncbi.nlm.nih.gov/pubmed/20651056

440.Sternberg, C.N., et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol, 2015. 16: 76.

https://www.ncbi.nlm.nih.gov/pubmed/25498218

441.Galsky, M.D., et al. Effectiveness of Adjuvant Chemotherapy for Locally Advanced Bladder Cancer.
J Clin Oncol, 2016. 34: 825.

http://ascopubs.org/doi/abs/10.1200/jco.2015.64.1076

442.von der Maase, H., et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol, 2005. 23: 4602.

https://www.ncbi.nlm.nih.gov/pubmed/17383078

443.Sternberg, C.N. Perioperative chemotherapy in muscle-invasive bladder cancer to enhance survival and/or as a strategy for bladder preservation. Semin Oncol, 2007. 34: 122.

https://www.ncbi.nlm.nih.gov/pubmed/17382795

444.Rosenberg, J.E., et al. Update on chemotherapy for advanced bladder cancer. J Urol, 2005. 174: 14.

https://www.ncbi.nlm.nih.gov/pubmed/15947569

445.Sternberg, C.N., et al. Gemcitabine, paclitaxel, pemetrexed and other newer agents in urothelial and kidney cancers. Crit Rev Oncol Hematol, 2003. 46 Suppl: S105.

https://www.ncbi.nlm.nih.gov/pubmed/12850531

446.Bellmunt, J., et al. Pretreatment prognostic factors for survival in patients with advanced urothelial tumors treated in a phase I/II trial with paclitaxel, cisplatin, and gemcitabine. Cancer, 2002. 95: 751.

https://www.ncbi.nlm.nih.gov/pubmed/12209718

447.Sengelov, L., et al. Metastatic urothelial cancer: evaluation of prognostic factors and change in prognosis during the last twenty years. Eur Urol, 2001. 39: 634.

https://www.ncbi.nlm.nih.gov/pubmed/11464051

448.De Santis, M., et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol, 2012. 30: 191.

https://www.ncbi.nlm.nih.gov/pubmed/22162575

449.Bellmunt, J., et al. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol, 2010. 28: 1850.

https://www.ncbi.nlm.nih.gov/pubmed/20231682

450.Carles, J., et al. Feasiblity study of gemcitabine and cisplatin administered every two weeks in patients with advanced urothelial tumors and impaired renal function. Clin Transl Oncol, 2006. 8: 755.

https://www.ncbi.nlm.nih.gov/pubmed/17074675

451.Hussain, S.A., et al. A study of split-dose cisplatin-based neo-adjuvant chemotherapy in muscle-invasive bladder cancer. Oncol Lett, 2012. 3: 855.

https://www.ncbi.nlm.nih.gov/pubmed/22741006

452.Hussain, S.A., et al. A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer.
Br J Cancer, 2004. 91: 844.

https://www.ncbi.nlm.nih.gov/pubmed/15292922

453.Morales-Barrera, R., et al. Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function. Eur J Cancer, 2012. 48: 1816.

https://www.ncbi.nlm.nih.gov/pubmed/22595043

454.Bamias, A., et al. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol, 2013. 24: 1011.

https://www.ncbi.nlm.nih.gov/pubmed/23136231

455.Galsky, M.D., et al. Cisplatin-based combination chemotherapy in septuagenarians with metastatic urothelial cancer. Urol Oncol, 2014. 32: 30.e15.

https://www.ncbi.nlm.nih.gov/pubmed/23428534

456.De Santis, M., et al. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol, 2009. 27: 5634.

https://www.ncbi.nlm.nih.gov/pubmed/19786668

457.Galsky, M.D., et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol, 2011. 12: 211.

https://www.ncbi.nlm.nih.gov/pubmed/21376284

458.Galsky, M.D., et al. Treatment of patients with metastatic urothelial cancer “unfit” for Cisplatin-based chemotherapy. J Clin Oncol, 2011. 29: 2432.

https://www.ncbi.nlm.nih.gov/pubmed/21555688

459.Dash, A., et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer, 2006. 107: 506.

https://www.ncbi.nlm.nih.gov/pubmed/16773629

460.Nogue-Aliguer, M., et al. Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: an alternative therapy. Cancer, 2003. 97: 2180.

https://www.ncbi.nlm.nih.gov/pubmed/12712469

461.Balducci, L., et al. Management of cancer in the older person: a practical approach. Oncologist, 2000. 5: 224.

https://www.ncbi.nlm.nih.gov/pubmed/10884501

462.De Santis, M., et al. New developments in first- and second-line chemotherapy for transitional cell, squamous cell and adenocarcinoma of the bladder. Curr Opin Urol, 2007. 17: 363.

https://www.ncbi.nlm.nih.gov/pubmed/17762632

463.Raj, G.V., et al. Formulas calculating creatinine clearance are inadequate for determining eligibility for Cisplatin-based chemotherapy in bladder cancer. J Clin Oncol, 2006. 24: 3095.

https://www.ncbi.nlm.nih.gov/pubmed/16809735

464.von der Maase, H. Gemcitabine in transitional cell carcinoma of the urothelium. Expert Rev Anticancer Ther, 2003. 3: 11.

https://www.ncbi.nlm.nih.gov/pubmed/12597345

465.Yafi, F.A., et al. First- and second-line therapy for metastatic urothelial carcinoma of the bladder. Curr Oncol, 2011. 18: e25.

https://www.ncbi.nlm.nih.gov/pubmed/21331269

466.Bellmunt, J., et al. New therapeutic challenges in advanced bladder cancer. Semin Oncol, 2012. 39: 598.

https://www.ncbi.nlm.nih.gov/pubmed/23040256

467.Gabrilove, J.L., et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med, 1988. 318: 1414.

https://www.ncbi.nlm.nih.gov/pubmed/2452983

468.Bamias, A., et al. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol, 2004. 22: 220.

https://www.ncbi.nlm.nih.gov/pubmed/14665607

469.Sternberg, C.N., et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol, 2001. 19: 2638.

https://www.ncbi.nlm.nih.gov/pubmed/11352955

470.Sternberg, C.N., et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer, 2006. 42: 50.

https://www.ncbi.nlm.nih.gov/pubmed/16330205

471.Bellmunt, J., et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol, 2012. 30: 1107.

https://www.ncbi.nlm.nih.gov/pubmed/22370319

472.Galsky, M.D., et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol, 2012. 23: 406.

https://www.ncbi.nlm.nih.gov/pubmed/21543626

473.Albers, P., et al. Gemcitabine monotherapy as second-line treatment in cisplatin-refractory transitional cell carcinoma - prognostic factors for response and improvement of quality of life. Onkologie, 2002. 25: 47.

https://www.ncbi.nlm.nih.gov/pubmed/11893883

474.Sternberg, C.N., et al. Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer, 2001. 92: 2993.

https://www.ncbi.nlm.nih.gov/pubmed/11753976

475.Meluch, A.A., et al. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network.
J Clin Oncol, 2001. 19: 3018.

https://www.ncbi.nlm.nih.gov/pubmed/11408496

476.Parameswaran R, et al. GU98-2 - A Hoosier Oncology Group phase II study of weekly paclitaxel and gemcitabine in advanced transitional cell (TCC) carcinoma of the bladder. Proc Am Soc Clin Oncol, 2001. 200.

https://hoosiercancer.org/clinical-trials/trial/gu98-2/

477.Guardino AE, Gemcitabine and paclitaxel as second line chemotherapy for advanced urothelial malignancies. Proc Am Soc Clin Oncol 2002. 21. [No abstract available].

478.Fechner, G., et al. Randomised phase II trial of gemcitabine and paclitaxel second-line chemotherapy in patients with transitional cell carcinoma (AUO Trial AB 20/99). Int J Clin Pract, 2006. 60: 27.

https://www.ncbi.nlm.nih.gov/pubmed/16409425

479.Kaufman D.S., et al. Gemcitabine (G) and paclitaxel (P) every two weeks (GP2w):a completed multicenter phase II trial in locally advanced or metastatic urothelial cancer (UC). Proc Am Soc Clin Oncol 2002. 21. [No abstract available].

480.Calabro, F., et al. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer, 2009. 115: 2652.

https://www.ncbi.nlm.nih.gov/pubmed/19396817

481.De Santis, M., et al. Vinflunine-gemcitabine versus vinflunine-carboplatin as first-line chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma: results of an international randomized phase II trial (JASINT1). Ann Oncol, 2016. 27: 449.

https://www.ncbi.nlm.nih.gov/pubmed/26673352

482.Ko, Y.J., et al. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol, 2013. 14: 769.

https://www.ncbi.nlm.nih.gov/pubmed/23706985

483.Oing, C., et al. Second Line Chemotherapy for Advanced and Metastatic Urothelial Carcinoma: Vinflunine and Beyond-A Comprehensive Review of the Current Literature. J Urol, 2016. 195: 254.

https://www.ncbi.nlm.nih.gov/pubmed/26410730

484.Raggi, D., et al. Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. Ann Oncol, 2016. 27: 49.

https://www.ncbi.nlm.nih.gov/pubmed/26487582

485.Albers, P., et al. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol, 2011. 22: 288.

https://www.ncbi.nlm.nih.gov/pubmed/20682548

486.Culine, S., et al. A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen. Br J Cancer, 2006. 94: 1395.

https://www.ncbi.nlm.nih.gov/pubmed/16622447

487.Bellmunt, J., et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol, 2009. 27: 4454.

https://www.ncbi.nlm.nih.gov/pubmed/19687335

488.Stadler, W.M. Gemcitabine doublets in advanced urothelial cancer. Semin Oncol, 2002. 29: 15.

https://www.ncbi.nlm.nih.gov/pubmed/11894003

489.Hussain, M., et al. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol, 2001. 19: 2527.

https://www.ncbi.nlm.nih.gov/pubmed/11331332

490.Abe, T., et al. Impact of multimodal treatment on survival in patients with metastatic urothelial cancer. Eur Urol, 2007. 52: 1106.

https://www.ncbi.nlm.nih.gov/pubmed/17367917

491.Bekku, K., et al. Could salvage surgery after chemotherapy have clinical impact on cancer survival of patients with metastatic urothelial carcinoma? Int J Clin Oncol, 2013. 18: 110.

https://www.ncbi.nlm.nih.gov/pubmed/22095246

492.Cowles, R.S., et al. Long-term results following thoracotomy for metastatic bladder cancer. Urology, 1982. 20: 390.

https://www.ncbi.nlm.nih.gov/pubmed/7147508

493.de Vries, R.R., et al. Long-term survival after combined modality treatment in metastatic bladder cancer patients presenting with supra-regional tumor positive lymph nodes only. Eur J Surg Oncol, 2009. 35: 352.

https://www.ncbi.nlm.nih.gov/pubmed/18722076

494.Dodd, P.M., et al. Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol, 1999. 17: 2546.

https://www.ncbi.nlm.nih.gov/pubmed/10561321

495.Donat, S.M., et al. Methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and cystectomy for unresectable bladder cancer. J Urol, 1996. 156: 368.

https://www.ncbi.nlm.nih.gov/pubmed/8683681

496.Gowardhan, B., et al. Twenty-three years of disease-free survival following cutaneous metastasis from a primary bladder transitional cell carcinoma. Int J Urol, 2004. 11: 1031.

https://www.ncbi.nlm.nih.gov/pubmed/15509212

497.Kanzaki, R., et al. Outcome of surgical resection of pulmonary metastasis from urinary tract transitional cell carcinoma. Interact Cardiovasc Thorac Surg, 2010. 11: 60.

https://www.ncbi.nlm.nih.gov/pubmed/20395251

498.Ku, J.H., et al. Metastasis of transitional cell carcinoma to the lower abdominal wall 20 years after cystectomy. Yonsei Med J, 2005. 46: 181.

https://www.ncbi.nlm.nih.gov/pubmed/15744826

499.Lehmann, J., et al. Surgery for metastatic urothelial carcinoma with curative intent: the German experience (AUO AB 30/05). Eur Urol, 2009. 55: 1293.

https://www.ncbi.nlm.nih.gov/pubmed/19058907

500.Matsuguma, H., et al. Is there a role for pulmonary metastasectomy with a curative intent in patients with metastatic urinary transitional cell carcinoma? Ann Thorac Surg, 2011. 92: 449.

https://www.ncbi.nlm.nih.gov/pubmed/21801905

501.Miller, R.S., et al. Cisplatin, methotrexate and vinblastine plus surgical restaging for patients with advanced transitional cell carcinoma of the urothelium. J Urol, 1993. 150: 65.

https://www.ncbi.nlm.nih.gov/pubmed/8510277

502.Otto, T., et al. Impact of surgical resection of bladder cancer metastases refractory to systemic therapy on performance score: a phase II trial. Urology, 2001. 57: 55.

https://www.ncbi.nlm.nih.gov/pubmed/11164143

503.Sarmiento, J.M., et al. Solitary cerebral metastasis from transitional cell carcinoma after a 14-year remission of urinary bladder cancer treated with gemcitabine: Case report and literature review. Surg Neurol Int, 2012. 3: 82.

https://www.ncbi.nlm.nih.gov/pubmed/22937482

504.Tanis, P.J., et al. Surgery for isolated lung metastasis in two patients with bladder cancer. Urology, 2005. 66: 881.

https://www.ncbi.nlm.nih.gov/pubmed/16230169

505.Sweeney, P., et al. Is there a therapeutic role for post-chemotherapy retroperitoneal lymph node dissection in metastatic transitional cell carcinoma of the bladder? J Urol, 2003. 169: 2113.

https://www.ncbi.nlm.nih.gov/pubmed/12771730

506.Siefker-Radtke, A.O., et al. Is there a role for surgery in the management of metastatic urothelial cancer? The M. D. Anderson experience. J Urol, 2004. 171: 145.

https://www.ncbi.nlm.nih.gov/pubmed/14665863

507.Abufaraj, M., et al. The Role of Surgery in Metastatic Bladder Cancer: A Systematic Review.
Eur Urol, 2017. S0302: 30840. [Epub ahead of print].

https://www.ncbi.nlm.nih.gov/pubmed/29122377

508.Coleman, R.E. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev, 2001. 27: 165.

https://www.ncbi.nlm.nih.gov/pubmed/11417967

509.Aapro, M., et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol, 2008. 19: 420.

https://www.ncbi.nlm.nih.gov/pubmed/17906299

510.Zaghloul, M.S., et al. A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol, 2010. 15: 382.

https://www.ncbi.nlm.nih.gov/pubmed/20354750

511.Henry, D.H., et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol, 2011. 29: 1125.

https://www.ncbi.nlm.nih.gov/pubmed/21343556

512.Rosen, L.S., et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer, 2004. 100: 2613.

https://www.ncbi.nlm.nih.gov/pubmed/15197804

513.O’Donnell, P.H., et al. Pembrolizumab (Pembro; MK-3475) for advanced urothelial cancer: Results of a phase IB study. J Clin Oncol 2015. 33: 296.

http://ascopubs.org/doi/abs/10.1200/jco.2015.33.7_suppl.296

514.Balar, A.V., et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet, 2017. 389: 67.

https://www.ncbi.nlm.nih.gov/pubmed/27939400

515.Powles, T., et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature, 2014. 515: 558.

https://www.ncbi.nlm.nih.gov/pubmed/25428503

516.Rosenberg, J.E., et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet, 2016. 387: 1909.

https://www.ncbi.nlm.nih.gov/pubmed/26952546

517.Bellmunt, J., et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.
N Engl J Med, 2017. 376: 1015.

https://www.ncbi.nlm.nih.gov/pubmed/28212060

518.Sharma, P., et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol, 2017. 18: 312.

https://www.ncbi.nlm.nih.gov/pubmed/28131785

519.Farina, M.S., et al. Immunotherapy in Urothelial Cancer: Recent Results and Future Perspectives. Drugs, 2017. 77: 1077.

https://www.ncbi.nlm.nih.gov/pubmed/28493171

520.Apolo, A.B., et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study.
J Clin Oncol, 2017. 35: 2117.

https://www.ncbi.nlm.nih.gov/pubmed/28375787

521.Powles, T., et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol, 2017. 3: e172411.

https://www.ncbi.nlm.nih.gov/pubmed/28817753

522.Youssef, R.F., et al. Molecular targets and targeted therapies in bladder cancer management.
World J Urol, 2009. 27: 9.

https://www.ncbi.nlm.nih.gov/pubmed/19039591

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

https://www.ncbi.nlm.nih.gov/pubmed/20299037

524.Song, S., et al. Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs. Proc Natl Acad Sci U S A, 2000. 97: 8658.

https://www.ncbi.nlm.nih.gov/pubmed/10890892

525.Gomez-Roman, J.J., et al. Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res, 2005. 11: 459.

https://www.ncbi.nlm.nih.gov/pubmed/15701828

526.Ioachim, E., et al. Thrombospondin-1 expression in urothelial carcinoma: prognostic significance and association with p53 alterations, tumour angiogenesis and extracellular matrix components. BMC Cancer, 2006. 6: 140.

https://www.ncbi.nlm.nih.gov/pubmed/16732887

527.Gallagher, D.J., et al. Detection of circulating tumor cells in patients with urothelial cancer.
Ann Oncol, 2009. 20: 305.

https://www.ncbi.nlm.nih.gov/pubmed/18836088

528.Flaig, T.W., et al. Detection of circulating tumor cells in metastatic and clinically localized urothelial carcinoma. Urology, 2011. 78: 863.

https://www.ncbi.nlm.nih.gov/pubmed/21813167

529.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.

https://www.ncbi.nlm.nih.gov/pubmed/20689757

530.Cella, D.F., et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol, 1993. 11: 570.

https://www.ncbi.nlm.nih.gov/pubmed/8445433

531.Aaronson, N.K., et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst, 1993. 85: 365.

https://www.ncbi.nlm.nih.gov/pubmed/8433390

532.Sogni, F., et al. Morbidity and quality of life in elderly patients receiving ileal conduit or orthotopic neobladder after radical cystectomy for invasive bladder cancer. Urology, 2008. 71: 919.

https://www.ncbi.nlm.nih.gov/pubmed/18355900

533.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.

https://www.ncbi.nlm.nih.gov/pubmed/1593914

534.Ware, J.E., Jr., et al. Evaluating translations of health status questionnaires. Methods from the IQOLA project. International Quality of Life Assessment. Int J Technol Assess Health Care, 1995. 11: 525.

https://www.ncbi.nlm.nih.gov/pubmed/7591551

535.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.
J Urol, 2010. 183: 1764.

https://www.ncbi.nlm.nih.gov/pubmed/20299056

536.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.

https://www.ncbi.nlm.nih.gov/pubmed/15777491

537.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.

https://www.ncbi.nlm.nih.gov/pubmed/26620844

538.Yang, L.S., et al. A systematic review and meta-analysis of quality of life outcomes after radical cystectomy for bladder cancer. Surg Oncol, 2016. 25: 281.

https://www.ncbi.nlm.nih.gov/pubmed/27566035

539.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.

https://www.ncbi.nlm.nih.gov/pubmed/24053658

540.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.

https://www.ncbi.nlm.nih.gov/pubmed/20451964

541.Clifford, T.G., et al. Prospective Evaluation of Continence Following Radical Cystectomy and Orthotopic Urinary Diversion Using a Validated Questionnaire. J Urol, 2016. 196: 1685.

https://www.ncbi.nlm.nih.gov/pubmed/27256205

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

https://www.ncbi.nlm.nih.gov/pubmed/24317553

543.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.

https://www.ncbi.nlm.nih.gov/pubmed/2476317

544.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.

https://www.ncbi.nlm.nih.gov/pubmed/2699072

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

https://www.ncbi.nlm.nih.gov/pubmed/16445379

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

https://www.ncbi.nlm.nih.gov/pubmed/12118019

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

https://www.ncbi.nlm.nih.gov/pubmed/17280906

548.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.

https://www.ncbi.nlm.nih.gov/pubmed/16952631

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

https://www.ncbi.nlm.nih.gov/pubmed/20002664

550.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.

https://www.ncbi.nlm.nih.gov/pubmed/20541311

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

https://www.ncbi.nlm.nih.gov/pubmed/19233433

552.Boorjian, S.A., et al. Detection of asymptomatic recurrence during routine oncological followup after radical cystectomy is associated with improved patient survival. J Urol, 2011. 186: 1796.

https://www.ncbi.nlm.nih.gov/pubmed/21944088

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

https://www.ncbi.nlm.nih.gov/pubmed/22609313

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

https://www.ncbi.nlm.nih.gov/pubmed/23611464

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

https://www.ncbi.nlm.nih.gov/pubmed/18485392

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

https://www.ncbi.nlm.nih.gov/pubmed/17009050

557.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.

https://www.ncbi.nlm.nih.gov/pubmed/18421461

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

https://www.ncbi.nlm.nih.gov/pubmed/20657286

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

https://www.ncbi.nlm.nih.gov/pubmed/20019993

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

https://www.ncbi.nlm.nih.gov/pubmed/15311003

561.Picozzi, S., et al. Upper urinary tract recurrence following radical cystectomy for bladder cancer: a meta-analysis on 13,185 patients. J Urol, 2012. 188: 2046.

https://www.ncbi.nlm.nih.gov/pubmed/23083867

562.Sanderson, K.M., et al. Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year followup. J Urol, 2007. 177: 2088.

https://www.ncbi.nlm.nih.gov/pubmed/17509294

563.Stewart-Merrill, S.B., et al. Evaluation of current surveillance guidelines following radical cystectomy and proposal of a novel risk-based approach. Urol Oncol, 2015. 33: 339 e1.

https://www.ncbi.nlm.nih.gov/pubmed/26031371

564.Gupta, A., et al. Risk of fracture after radical cystectomy and urinary diversion for bladder cancer.
J Clin Oncol, 2014. 32: 3291.

https://www.ncbi.nlm.nih.gov/pubmed/25185104

10.CONFLICT OF INTEREST

All members of the Muscle-invasive and Metastatic Bladder Cancer Guidelines Working Group have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publicly accessible through the European Association of Urology website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.

This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

11.CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:

EAU Guidelines. Edn. presented at the EAU Annual Congress Copenhagen 2018. ISBN 978-94-92671-01-1.

If a publisher and/or location is required, include:

EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/

References to individual guidelines should be structured in the following way:

Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.