Committee I

Committee V

Bladder Cancer

Prof. Dr. Hassan Abol-Enein Professor of Urology, Mansoura University

Prof. Dr. Mohamed Adel Atta Professor of Urology, Alexandria University

Prof. Dr. Adel Elbakry Professor of Urology, Swiss Canal University

Ass. Prof. Ahmed Moeen Assistant Professor of Urology, Assuit University

Dr. Amr A. Elsawy Lecturer of Urology, Mansoura University

Contents
V.1 Abbreviations:
  • BCG - Bacillus Calmette-Guérin
  • BC - Bladder cancer
  • CIS - Carcinoma in Situ
  • CT - Computed tomography
  • CT-IVU - Computed Tomography-Intravenous Urography
  • FGFR - Fibroblast Growth Factor Receptor
  • G-CSF - Granulocyte Colony-Stimulating Factor
  • HD - High-Dose
  • HG - High-Grade
  • IVU - Intravenous Urography
  • LG - Low-Grade
  • MRI - Magnetic Resonance Imaging
  • MVAC - Methotrexate, Vinblastine, Adriamycin plus Cisplatin
  • MMT - Multimodality Treatments
  • MIBC - Muscle invasive bladder cancer
  • NAC - Neoadjuvant Chemotherapy
  • NMIBC - Non-muscle invasive bladder cancer
  • NMP - Nuclear Matrix Protein
  • PUNLMP - Papillary Urothelial Neoplasm of Low Malignant Potential
  • QoL - Quality of Life
  • RC - Radical Cystectomy
  • RT - Radiotherapy
  • SREs - Skeletal-Related Events
  • TERT - Telomerase Reverse Transcriptase
  • US - Ultrasound
  • UUT - Upper Urinary Tract
  • ZA - Zoledronic Acid

V.2 Introduction:

This overview represents the updated recommendations for bladder cancer diagnosis and management. The aim is to provide practical advice on the clinical work-up and treatment of different patterns of bladder cancer presentation (Non muscle invasive, muscle invasive and metastatic).
It must be emphasized that guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions and considering the personal values and preferences/individual circumstances of patients into account.
V.2.1 Methods:
A comprehensive scoping effort covering all guidelines (American, European and Canadian) and panels (National Comprehensive Cancer Network and International Bladder Cancer Database Consortium) as regard to different patterns of bladder cancer was performed.
For each recommendation and advice in this overview, all of the following elements were highly considered:

• Quality of evidence for this recommendation.
• Impact of this practice on patient and oncological outcomes.
• The balance between this practice and the different aspects of health service in our locality.
V.2.2 Results
These guidelines represent the best clinical evidence-based medicine available. These guidelines are not solely based upon the level of evidence of the international publications but also include expertise of the treating doctor and expectations of every patient.
V.2.3 Conclusions.
These guidelines provide practical evidence-based guidance on the clinical aspect of Urinary bladder cancer. The main target is entirely focused on assessment and treatment, reflecting the recommended clinical practice. This can provide the basis for thinking through patient’s management and also for planning and designing clinical services.
V.3 Epidemiology, Etiology and Pathology:
V.3.1 Epidemiology
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in the male population worldwide, while it drops to eleventh when both genders are considered. In Egypt, it is the most commonly diagnosed cancer in males (1).
Approximately 75% of patients with BC present with a disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1) (2).
V.3.2 Etiology
Tobacco smoking is the most important risk factor for BC, accounting for approximately 50% of cases (3). Tobacco smoke contains aromatic amines and polycyclic aromatic hydrocarbons, which are renally excreted. Occupational exposure to aromatic amines and chlorinated hydrocarbons is the second most important risk factor for BC, accounting for about 10% of all cases (4). This type of occupational exposure occurs mainly in industrial plants, which process paint, dye, metal and petroleum products (5).
Schistosomiasis, a chronic endemic cystitis based on recurrent infection with a parasitic trematode, is also a cause of BC. Exposure to ionizing radiation is connected with increased risk; weak association was also suggested for cyclophosphamide and pioglitazone (6). The impact of metabolic factors (body mass index, blood pressure, plasma glucose, cholesterol and triglycerides) is uncertain (7).
V.3.3 Pathology
V.3.3.1 Staging:
TNM classification is the standard tool for staging of BC (8) (Table V:1).

Table V:1 TNM classification of bladder cancer

T- Primary tumor

TX - Primary tumor cannot be assessed
T0 - No evidence of primary tumor
Ta - Non-invasive papillary carcinoma
Tis - Carcinoma in situ: ‘flat tumor’
T1 - Tumor invades subepithelial connective tissue
T2 - Tumor invades muscle
T2a - Tumor invades superficial muscle (inner half)
T2b - Tumor invades deep muscle (outer half)
T3 - Tumor invades perivesical tissue
T3a - Microscopically
T3b - Macroscopically (extravesical mass)
T4 - Tumor invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
T4a - Tumor invades prostate stroma, seminal vesicles, uterus or vagina
T4b - Tumor invades pelvic wall or abdominal wall

N- Lymph Nodes

NX - Regional lymph nodes cannot be assessed
N0 - No regional lymph node metastasis
N1 - Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac or presacral)
N2 - Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac or presacral)
N3 - Metastasis in common iliac lymph node(s)

M - Distant metastasis

MX - Distant metastasis cannot be assessed
M0 - No distant metastasis
M1a - Non-regional lymph nodes
M1b - Other distant metastases
V.3.3.2 Histological grading:
Histological grading of BC should be done using the available two systems of grading (WHO 1973 and WHO/ISUP 2004) (9) (Table V:2).

Table V:2 Grading systems of bladder cancer

1973 WHO grading

Grade 1: well differentiated
Grade 2: moderately differentiated
Grade 3: poorly differentiated

2004 WHO/ISUP grading system (papillary lesions)

Papillary urothelial neoplasm of low malignant potential (PUNLMP)
Low-grade (LG) papillary urothelial carcinoma
High-grade (HG) papillary urothelial carcinoma
V.3.3.3 Carcinoma in situ and its classification
Carcinoma in situ (CIS) is a flat, high-grade, non-invasive urothelial carcinoma. Carcinoma in situ is often multifocal and can occur in the bladder, but also in the upper urinary tract (UUT), prostatic ducts, and prostatic urethra (10).
V.3.3.4 Classification of CIS according to clinical type:

o Primary: isolated CIS with no previous or concurrent papillary tumors and no previous CIS.
o Secondary: CIS detected during follow-up of patients with a previous tumor that was not CIS.
o Concurrent: CIS in the presence of any other urothelial tumor in the bladder.
V.3.3.5 Variants of urothelial carcinoma and lymphovascular invasion
Currently the following differentiations are used (11):
1. Urothelial carcinoma (more than 90% of all cases)
2. Urothelial carcinomas with partial squamous and/or glandular or trophoblastic differentiation
3. Micropapillary urothelial carcinoma
4. Nested variant (including large nested variant) and microcystic urothelial carcinoma
5. Plasmocytoid, giant cell, signet ring, diffuse, undifferentiated
6. Lymphoepithelioma-like
7. Small-cell carcinomas
8. Sarcomatoid urothelial carcinoma
In these pathological variants, the decision of optimal treatment is individualized. Early cystectomy with or without neo-adjuvant or adjuvant therapy is considered according to the decision of multidisciplinary team agreement.
The presence of an element of these variants together with TCC tumors is considered as nonurothelial and should be treated as tumor cell variant.
Revision of the histopathology may be needed by another expert to support the diagnosis

V.4 Non-muscle invasive bladder cancer (NMIBC)

V.4.1 Diagnosis
V.4.1.1 Patient history
A focused patient history is mandatory.
V.4.1.1.1 Signs and symptoms
Hematuria is the most common finding in NMIBC. Carcinoma in situ might be suspected in patients with lower urinary tract symptoms, especially irritative voiding. Sometimes, the bladder lesion is detected during routine sonographic survey especially those located in the bladder dome and anterior wall.
V.4.1.1.2 Physical examination
A focused urological examination is mandatory although it does not reveal NMIBC.
V.4.1.1.3 Imaging
V.4.1.1.3.1 Ultrasound
Ultrasound (US) may be performed as an adjunct to physical examination as it has moderate sensitivity to a wide range of abnormalities in the upper and lower urinary tract (12). It permits characterization of associated pathology, detection of hydronephrosis, and visualization of intraluminal masses in the bladder.
V.4.1.1.3.2 Computed tomography urography and intravenous urography
Computed tomography (CT) urography is used to detect papillary tumors in the urinary tract, indicated by filling defects and/or hydronephrosis (13).
Intravenous urography (IVU) is an alternative if CT is not available but particularly in muscle-invasive tumors of the bladder and in UTUCs, CT urography provides more information (including status of lymph nodes and surrounding organs) (14).
The incidence of UTUCs is low (1.8%), but increases to 7.5% in tumors located in the trigone. The risk of UTUC during follow up increases in patients with multiple- and high-risk tumors (15).
CTU or magnetic resonance imaging are an essential tool in the diagnosis, staging and Management
V.4.2 Urinary cytology
The examination of voided urine or bladder-washing specimens for exfoliated cancer cells has high sensitivity in G3 and high-grade tumors (84%), but low sensitivity in G1/LG tumors (16%). The sensitivity in CIS detection is 28-100% (16).
Positive voided urinary cytology can indicate an urothelial carcinoma anywhere in the urinary tract; negative cytology, however, does not exclude its presence (17).
Cytological interpretation is user-dependent. Evaluation can be hampered by low cellular yield, urinary tract infections, stones, or intravesical instillations; however, in experienced hands specificity exceeds 90% (18).
V.4.3 Urinary molecular marker tests
Driven by the low sensitivity of urine cytology, numerous urinary tests have been developed. None of these markers have been accepted for diagnosis or follow-up in routine practice or clinical guidelines (19).
The following conclusions can be drawn regarding the existing tests:
• Sensitivity is usually higher at the cost of lower specificity, compared to urine cytology.
• Benign conditions and previous BCG instillations may influence the results of many urinary marker tests.
• The wide range in performance of the markers and low reproducibility may be explained by patient selection and complicated laboratory methods required.
• Positive results of cytology, UroVysion (FISH), Nuclear Matrix Protein (NMP)22R, Fibroblast Growth Factor Receptor (FGFR)3/Telomerase Reverse Transcriptase (TERT) and microsatellite analysis in patients with negative cystoscopy and upper tract work-up, may identify patients more likely to experience disease recurrence and possibly progression.
• If main aim is to avoid unnecessary cystoscopies, rather than looking for markers with a high sensitivity and specificity

Table V:3 Recommendations for bladder cancer classification

Recommendation

strength rating
1. Use the 2017 TNM system for classification of the depth of tumour invasion (staging). Strong
2. Do not use the term “superficial bladder cancer”. Strong


V.4.4 Cystoscopy
The diagnosis of papillary BC ultimately depends on cystoscopic examination of the bladder and histological evaluation of sampled tissue by either cold-cup biopsy or resection (20).
Carcinoma in situ is diagnosed by a combination of cystoscopy, urine cytology, and histological evaluation of multiple bladder biopsies (21).
Cystoscopy is initially performed as an outpatient procedure. A flexible instrument with topical intraurethral anesthetic lubricant instillation results in better compliance compared to a rigid instrument, especially in men (22).
When flexible cystoscopy is not available, provided that the imaging is positive for bladder lesion; formal cystoscopy is required under anesthesia (23). The urologist should be ready to carry out resection or at least biopsy.

V.4.5 Transurethral resection of TaT1 bladder tumors

V.4.5.1 Strategy of the procedure
Transurethral resection of the bladder should be performed systematically in individual steps.
The operative steps necessary to achieve a successful TURB include identifying the factors required to determine the disease risk (number of tumors, size, multifocality, characteristics, concern for the presence of CIS, recurrent vs. primary tumor), clinical stage (bimanual examination under anesthesia, assignment of clinical tumor stage), adequacy of the resection (visually complete resection, visualization of muscle at the resection base), and presence of complications (assessment for perforation) (24).
V.4.5.2 Surgical and technical aspects of tumor resection
A complete resection, performed by either fractioned or en-bloc technique, is essential to achieve a good prognosis.
• Piecemeal resection in fractions (separate resection of the exophytic part of the tumor, the underlying bladder wall and the edges of the resection area) provides good information about the vertical and horizontal extent of the tumor (24).
• En-bloc resection using monopolar or bipolar current, Thulium-YAG or Holmium-YAG laser is feasible in selected exophytic tumors. It provides high quality resected specimens with the presence of detrusor muscle in 96-100% of cases (25).
The technique selected is dependent on the size and location of th tumor, experience of the surgeon and the availability of the facilities as well.
V.4.5.3 Evaluation of resection quality
The absence of detrusor muscle in the specimen is associated with a significantly higher risk of residual disease, early recurrence and tumor understaging. The presence of detrusor muscle in the specimen is considered as the surrogate criterion of the resection quality and is required (except in TaG1/LG tumors) (26).
The resected tissues should be identified in specific well labelled containers (tumor, base, random biopsies) (27)
V.4.5.3.1 Bladder biopsies
Carcinoma in situ can present as a velvet-like, reddish area, indistinguishable from inflammation, or it may not be visible at all. For this reason, biopsies from suspicious urothelium should be taken. However, in patients with positive urine cytology, or with a history of HG/G3 NMIBC and in tumors with non-papillary appearance, mapping biopsies from normal-looking mucosa is recommended (27).
V.4.5.3.2 Prostatic urethral biopsies
The risk of prostatic urethra or duct involvement is higher if the tumor is located at the trigone or bladder neck, in the presence of bladder CIS and multiple tumors (28). Based on this observation, a biopsy from the prostatic urethra is necessary in some cases.
It is preferable to obtain biopsy from the prostatic urethra if the patient would receive orthotopic diversion (29).
V.4.5.3.2.1 Second resection
A second TURB can increase recurrence-free survival, improve outcomes after BCG treatment and provide prognostic information (30). It is recommended in selected cases two-six weeks after initial resection.
Second TURB is indicated in the following situations (31):
After incomplete initial TURB, or in case of doubt about completeness of a TURB)
If there is no muscle in the specimen after initial resection, with the exception of Ta LG/G1 tumors and primary CIS in T1 tumors
V.4.6 Predicting disease recurrence and progression
Treatment of NMIBC should be based on a patient’s prognosis (32). In order to predict, both the short- and long-term risks of disease recurrence and progression in individual patients, the EORTC GenitoUrinary Cancer Group has developed a scoring system and risk tables (33).
The scoring system is based on the six most significant clinical and pathological factors which are shown in Table-4. It also illustrates the weights applied to various factors for calculating the total scores for recurrence and progression. Table V:4 Calculation of NMIBC recurrence and progression scores

Factor

Recurrence

Progression

Number of tumors

Single 0 0
2-7 3 3
>8 6 3

Tumor diameter

< 3 cm 0 0
> 3 cm 3 3

Prior recurrence rate

Primary 0 0
< 1 recurrence/year 2 2
> 1 recurrence/year 4 2

Category

Ta 0 0
T1 1 4

Concurrent CIS

No 0 0
Yes 1 6

Grade

G1 0 0
G2 1 0
G3 3 5

Total Score

 10-17

0-23
V.4.6.1 Prognosis of Carcinoma in situ
Without any treatment, approximately 54% of patients with CIS progress to muscle-invasive disease. There are no reliable prognostic factors, some studies, however, have reported a worse prognosis in concurrent CIS and T1 tumors compared to primary CIS multifocal disease and in CIS in the prostatic urethra (34).
The response to intravesical treatment with BCG or chemotherapy is an important prognostic factor for subsequent progression and death caused by BC. Approximately 10-20% of complete responders eventually progress to muscle-invasive disease, compared with 66% of non-responders (35).
V.4.6.2 Patient stratification into risk groups
Three major risk groups are considered which takes into account the EORTC risk tables’ probabilities of recurrence and, especially, progression (36) (Table 5).

Table V:5 Risk group stratification

Risk group stratification

Characteristics

Low-risk tumors Primary, solitary, TaG1 (PUNLMP, LG), < 3 cm, no CIS.
Intermediate-risk tumors All tumors not defined in the two adjacent categories (between the category of low- and high risk).
High-risk tumors Any of the following:
• T1 tumor • G3 (HG) tumor
• carcinoma in situ (CIS)
• Multiple, recurrent and large (> 3 cm) TaG1G2/LG tumors (all features must be present)


Table V:6 Recommendations for primary Management of non-muscle invasive bladder cancer

Recommendation

strength rating
1. Take a patient history, focusing on urinary tract symptoms and haematuria. Strong
2. Use renal and bladder ultrasound and/or computed tomography (CT)intravenous urography during the initial work-up in patients with haematuria. Strong
3. Perform cystoscopy in patients with symptoms suggestive of bladder cancer or during surveillance. It cannot be replaced by cytology or by any other noninvasive test. Strong
4. Take biopsies from abnormal-looking urothelium. Biopsies from normallooking mucosa (mapping biopsies from the trigone, bladder dome, right, left, anterior and posterior bladder wall) are recommended when cytology is positive, in case of a history of HG/G3 tumours and in tumours with nonpapillary appearance. Strong
5. Take a biopsy of the prostatic urethra in cases of bladder neck tumour, if bladder carcinoma in situ is present or suspected, if there is positive cytology without evidence of tumour in the bladder, or if abnormalities of the prostatic urethra are visible. If biopsy is not performed during the initial procedure, it should be completed at the time of the second resection. Strong
6. The TURB protocol must describe tumour location, appearance, size and multifocality, all steps of the procedure, as well as extent and completeness of resection. Strong
7. In patients with positive cytology, but negative cystoscopy, exclude an upper tract urothelial carcinoma, CIS in the bladder (by mapping biopsies or PDDguided biopsies) and tumour in the prostatic urethra (by prostatic urethra biopsy). Strong
8. Perform a 2nd TURB in the following situations: Strong
9. After incomplete initial TURB, or in case of doubt about completeness of a TURB) Strong
10. If there is no muscle in the specimen after initial resection, with the exception of TaG1 tumours and primary CIS; Strong
11. In T1 tumours. Strong
12. If indicated, perform a 2nd TURB within two to six weeks after initial resection. This 2nd TURB should include resection of the primary tumour site. Strong
13. Stratify patients into three risk groups Strong
14. Apply the EORTC risk tables and calculator for the prediction of the risk of tumour recurrence and progression in different intervals after transurethral resection of the bladder, in individual patients. Strong

V.5 Disease management

V.5.1 Adjuvant treatment
Although TURB by itself can eradicate a TaT1 tumor completely, these tumors commonly recur and can progress to MIBC. It is therefore necessary to consider adjuvant therapy in all patients.
V.5.1.1 Intravesical chemotherapy
V.5.1.1.1 A single, immediate, post-operative intravesical instillation of chemotherapy
 Immediate single instillation has been shown to act by destroying circulating tumor cells after TURB, and by an ablative effect on residual tumor cells at the resection site and on small overlooked tumors (37). Some reports did not demonstrate the efficacy of immediate single instillation in intermediate and high risk patients (38).
V.5.1.1.2 Additional adjuvant intravesical chemotherapy instillations
 The need for further adjuvant intravesical therapy depends on prognosis. In low-risk patients, a single instillation reduces the risk of recurrence and is considered to be the standard and complete treatment (39).

Additional adjuvant chemotherapy instillation is indicated in intermediate risk patients with no history of allergy to the utilized agent. The most widely utilized chemotherapeutic agents are mitomycin C, pararubicin and doxorubicin (40). The length and frequency of repeat chemotherapy instillations is still controversial; however, Initial induction regimen (six weekly instillations) followed by maintenance regimen (monthly instillation for at least one year) is advocated (39). 4
V.5.1.1.3 Intravesical bacillus Calmette-Guérin (BCG) immunotherapy
 BCG therapy delays and potentially lowers the risk of tumor progression, most studies showed a reduction in the risk of progression in high- and intermediate-risk tumors (41).
Induction BCG instillations are given according to the empirical 6-weekly schedule. For optimal efficacy, BCG must be given in a maintenance schedule. Many different maintenance schedules have been used, ranging from a total of ten instillations given in eighteen weeks to 27 over three years (42).
BCG intravesical treatment is associated with more side effects compared to intravesical chemotherapy (43). However, serious side effects are encountered in < 5% of patients and can be treated effectively in almost all cases (44). The patient should be counseled about the possible adverse events of BCG instillations up to severe form of contracted bladder which may obligate cystectomy and urinary diversion.
To reduce BCG toxicity, instillation of a reduced dose was proposed. However, it has been suggested that a full dose of BCG is more effective in multifocal tumors (45).

Table V:7 Treatment recommendations in TaT1 tumours and carcinoma in situ according to risk stratification

Risk Category

Criteria

Treatment Recommendation
Low-risk tumors Primary, solitary, TaG1 (PUNLMP, Low Grade), < 3 cm, no CIS One immediate instillation of intravesical chemotherapy after TURB
Intermediate risk tumors All tumors not defined in the two adjacent categories between the category of low and high risk). In patients, with previous low recurrence rate (≤ one recurrence per year) and expected EORTC recurrence score < 5, one immediate instillation of intra-vesical chemotherapy after TURB. In all patients; either 1-year fulldose BCG treatment (induction plus 3-weekly instillations at 3, 6 and 12 months), or instillations of chemotherapy (the optimal schedule is not known) for a maximum of one year.
High-risk Tumors Any of the following:
• T1 tumours;
• G3 (High Grade) tumour;
• CIS;
• Multiple, recurrent and large (> 3 cm) TaG1G2/Low Grade tumours (all features must be present). 		Intravesical full-dose BCG instillations for one to three years or radical cystectomy (in highest-risk tumours in selected patients)


Table V:8 Recommendation for intravesical therapy

Recommendation

strength rating
1. Intravesical therapy after TURBT should be based on the risk groups Strong
2. In patients with tumors presumed to be at low risk and in those presumed to be at intermediate risk with previous low recurrence rate one immediate chemotherapy instillation is recommended. . Strong
3. In patients with intermediate-risk tumours one-year full-dose bacillus Calmette- Guérin (BCG) treatment (induction plus 3-weekly instillations at 3, 6 and 12 months) Strong
4. In patients with high-risk tumors, full-dose intravesical BCG for one to three years (induction plus 3-weekly instillations at 3, 6, 12, 18, 24, 30 and 36 months), is indicated. The additional beneficial effect of the second and third years of maintenance should be weighed against its added costs, side-effects and problems connected with BCG shortages. Strong
5. Offer transurethral resection of the prostate, followed by intravesical instillation of BCG to patients with CIS in the epithelial lining of the prostatic urethra. Weak Discuss immediate radical cystectomy (RC) with patients at highest risk of tumor progression. Strong
6. If given, administer a single immediate instillation of chemotherapy within 24 hours Weak
7. Absolute contraindications of BCG intravesical instillation are:
• During the first two weeks after TURB;
• In patients with visible haematuria;
• After traumatic catheterisation;
• In patients with symptomatic urinary tract infection. 		Strong


V.5.1.2 Treatment of carcinoma in situ
The detection of concurrent CIS increases the risk of recurrence and progression of TaT1 tumors, in this case further treatment according to the risk categorization and previous treatment is mandatory. Carcinoma in situ cannot be cured by an endoscopic procedure alone. Histological diagnosis of CIS must be followed by further treatment, either intravesical BCG instillations or radical cystectomy (46).
V.5.1.3 Treatment of failure of intravesical therapy
V.5.1.3.1 Failure of intravesical chemotherapy
Patients with NMIBC recurrence after a chemotherapy regimen can benefit from BCG instillations. Prior intravesical chemotherapy has no impact on the effect of BCG instillation (47).
V.5.1.3.2 Recurrence and failure after intravesical BCG immunotherapy
Several categories of BCG failures, broadly defined as any disease occurrence following therapy, have been proposed.
Non-muscle-invasive BC presenting after BCG can be categorized into BCG refractory, BCG unresponsive and BCG relapse (48).
V.5.1.3.3 Treatment of BCG failure
Patients with BCG unresponsive disease are unlikely to respond to further BCG therapy; radical cystectomy is therefore the preferred option. Additionally, several bladder preservation strategies are under different stages of investigation such as cytotoxic intravesical therapies, device assisted instillations, intravesical immunotherapy, systemic immunotherapy or gene therapy (48).
V.5.1.3.4 Radical cystectomy for non-muscle-invasive bladder cancer
Early radical cystectomy (RC) is strongly recommended in patients with BCG unresponsive tumors, as mentioned above. A delay in RC may lead to decreased disease-specific survival (49).

Table V:9 Recommendations for Treatment of BCG Failure

Treatment options

strength rating
BCG unresponsive Radical cystectomy (RC). Weak

Late BCG relapsing: T1Ta/High Grade Recurrence > 6 months or CIS > 12 months of last BCG exposure

 Radical cystectomy or repeat BCG course according to individual Situation. Weak

Low Grade recurrence after BCG for primary intermediate risk tumour

Repeat BCG or Intravesical Chemotherapy. Strong

V.5.2 Critical consideration in management of NMIBC

External beam radiation therapy and / or systemic chemotherapy are not useful modalities in patients with NMIBC

V.5.3 Follow up of patients with NMIBC

As a result of the risk of recurrence and progression, patients with NMIBC need surveillance, following therapy. However, the frequency and duration of cystoscopy and imaging follow-up should reflect the individual patient’s degree of risk (50).
Patients with low-risk Ta tumors should undergo cystoscopy at three months. If negative, subsequent cystoscopy is advised nine months later, and then yearly for five years (51). Patients with high-risk tumors should undergo cystoscopy and urinary cytology at three months. If negative, subsequent cystoscopy and cytology should be repeated every three months for a period of two years, and every six months thereafter until five years, and then yearly (52). Patients with intermediate-risk Ta tumors should have an in-between (individualized) follow-up scheme using cystoscopy. Regular (yearly) upper tract imaging (computed tomography-intravenous urography [CT-IVU] or IVU) is recommended for high-risk tumors.
Endoscopy under anesthesia and bladder biopsies should be performed when office cystoscopy shows suspicious findings or if urinary cytology is positive.

Table V:10 Recommendations for Follow up of Patients with NMIBC

Recommendation

strength rating
1. Base follow-up of TaT1 tumours and carcinoma in situ (CIS) on regular Cystoscopy. Strong
2. Patients with low-risk Ta tumours should undergo cystoscopy at three months. If negative, subsequent cystoscopy is advised nine months later, and then yearly for five years. Weak
3. Patients with high-risk tumours should undergo cystoscopy and urinary cytology at three months. If negative, subsequent cystoscopy and cytology should be repeated every three months for a period of two years, and every six months thereafter until five years, and then yearly. Weak
4. Patients with intermediate-risk Ta tumours should have an in-between (individualised) follow-up scheme using cystoscopy. Weak
5. Regular (yearly) upper tract imaging (computed tomography-intravenous urography [CT-IVU] or IVU) is recommended for high-risk tumours. Weak
6. During follow-up in patients with positive cytology and no visible tumour in the bladder, mapping-biopsies. Investigation of extravesical locations (CT urography, prostatic urethra biopsy) are recommended. Strong


V.6 Muscle invasive bladder cancer (MIBC)

V.6.1 Diagnosis
V.6.1.1 Symptoms
Painless hematuria is the most common presenting complaint. Other clinical signs include urgency, dysuria, increased frequency, and in more advanced tumors, pelvic pain and symptoms related to urinary tract obstruction (53). One third of patients underwent repeat TURBT might progress to muscle invasive disease and should be picked up early (54).
V.6.1.2 Physical examination
Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be found in patients with locally advanced tumors. In addition, bimanual examination under anesthesia should be carried out before and after TUR of the bladder (TURB), to assess whether there is a palpable mass or if the tumor is fixed to the pelvic wall (53).
V.6.1.3 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. Staging cross sectional imaging should be carried out prior to cystoscopy biopsy or TURB to avoid overstating of the disease (55).
V.6.1.4 Cystoscopy
Ultimately, the diagnosis of BC is made by cystoscopy and histological evaluation of resected tissue. If a bladder tumor has been visualized unequivocally by imaging studies such as computed tomography (CT), or magnetic resonance imaging (MRI), diagnostic cystoscopy may be omitted, and the patient can proceed directly to TURB for histological diagnosis and resection (55).
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 tumors, as well as a description of any mucosal abnormalities. The use of a bladder diagram is recommended (56).
Biopsy from the prostatic urethra (or bladder neck in female) is required especially when orthotopic diversion is planned (57)
V.6.1.5 Transurethral resection of invasive bladder tumors
The goal of TURB is to enable histopathological diagnosis and staging, which requires the inclusion of bladder muscle in the resection specimen (58).
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 radiation therapy is considered, CIS is to be excluded (58).
If the plan of treatment is to utilize definitive/palliative chemo-radiotherapy, safe maximum resection should be tried during the first look biopsy to avoid further need to re-anesthesia.
V.6.1.6 Imaging for staging of MIBC
The treatment and prognosis of MIBC is determined by tumor stage and grade. In clinical practice, CT with contrast and MRI are the imaging techniques used (59). The purpose of using imaging for staging MIBC is to determine:
• Extent of local tumor invasion
• Involvement of LNs
• Tumor spread to the upper tract and other distant organs (e.g., liver, lungs, bones, peritoneum, pleura, and adrenal glands)
Timing of radiological staging is preferred either before TURB or at least two weeks after resection biopsy to avoid radiological overstating (59).
V.6.1.7 Evaluation of comorbidity
Evaluation of comorbidity helps to identify the medical conditions likely to interfere with, or have an impact on, treatment and the evolution and prognosis of MIBC (60).
Age carried the highest risk for other-cause mortality but not for increased cancer-specific death, while the stage of locally advanced tumor was the strongest predictor for decreased cancer specific survival. Stratifying elderly patients according to their risk-benefit profile using a multidisciplinary approach will help selecting patients most likely to benefit from radical surgery and to optimize treatment outcomes (61).
V.6.2 Disease management
V.6.2.1 Neoadjuvant therapy (NAC)
The standard treatment for patients with urothelial MIBC and MIBC with variant histologies is radical cystectomy. However, radical cystectomy only provides 5-year survival in about 50% of patients (62).
There are theoretical advantages and disadvantages of administering chemotherapy before planned definitive surgery to patients with resectable muscle-invasive urothelial carcinoma of the bladder and cN0M0 disease (62):
• Chemotherapy is delivered at the earliest time-point, when the burden of micro metastatic disease is expected to be low.
• Potential reflection of in-vivo chemo sensitivity.
• Tolerability of chemotherapy and patient compliance are expected to be better pre-cystectomy.
• Patients might respond to NAC and reveal a favorable pathological status, determined mainly by achieving pT0, pN0 and negative surgical margins.
• Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy, although published studies on the negative effect of delayed cystectomy only include chemo-naïve patients (63).
Diabetes, hypertension, pulmonary and cardiac diseases are prevalent in this age group, preoperative medical assessment and correction are a must, and the operation should be performed in well-equipped hospital
V.6.2.2 Pre-operative radiotherapy
Pre-operative radiotherapy (RT) should not be offered for operable MIBC since it will only result in down-staging, but will not improve survival (64).
V.6.2.3 Post-operative radiotherapy
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. It is not recommended in routine daily practice (64).

Table V:11 Recommendations for Neoadjuvant Chemotherapy for MIBC

Recommendation

strength rating
1. Offer neoadjuvant chemotherapy (NAC) for T2-T4a, cN0M0 bladder cancer. In this case, always use cisplatin-based combination therapy. Strong
2. Do not offer NAC to patients who are ineligible for cisplatin-based combination chemotherapy. Strong
3. Do not offer pre-operative radiotherapy (RT) for operable MIBC since it will only result in down-staging, but will not improve survival. Strong
4. Do not offer pre-operative RT when subsequent radical cystectomy with urinary diversion is planned. Strong
V.6.3 Intravesical instillation treatment in MIBC
Any kind of intravesical instillation of chemo-or immunotherapy has no place at all in this sitting (64).
V.6.3.1 Radical surgery and urinary diversion
Radical cystectomy is the standard treatment for localized MIBC. Recent interest in patients’ quality of life has promoted the trend toward bladder-preserving treatment modalities, such as radio- and/or chemotherapy (64). Performance status and life expectancy 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 performance status (65).
A delay in radical cystectomy of more than twelve weeks since diagnosis has a negative impact on outcome and should be avoided (65).
V.6.3.2 Radical cystectomy: indications
Traditionally, radical cystectomy was recommended for patients with MIBC T2-T4a, N0-Nx and M0 (66). Other indications include high risk and recurrent non-muscle-invasive tumors, BCG-refractory, BCG-relapsing and BCG-unresponsive, T1G3 tumors, as well as extensive papillary disease that cannot be controlled with TURB and intravesical therapy alone (67).
Salvage cystectomy is indicated in non-responders to conservative therapy, recurrence after bladdersparing treatment, and non-UC (these tumors respond poorly to chemotherapy and RT) (63). It is also used as a purely palliative intervention, including for fistula formation, pain and recurrent visible hematuria. 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 preferable option in N2 or N3 tumors (63).
V.6.3.3 Urinary diversion after radical cystectomy
From an anatomical standpoint, three alternatives are currently used after cystectomy (68):
• Abdominal diversion, such as an uretero-cutaneostomy, 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.
• 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.
Ideal urinary diversion method should be selected for each patient considering the patient, urinary tract, oncological and anesthetic factors to minimize the perioperative morbidity and maintain long term oncological and functional outcomes (68).
V.6.3.4 Lymphadenectomy: role and extent
Regional LNs have been shown to consist of all pelvic LNs below the bifurcation of the aorta. The optimal extent of LND has not been established to date (69).
Standard lymphadenectomy in BC patients involves removal of nodal tissue cranially up to the distal inch of the common iliac artery, with the ureter being the medial border, and including the internal iliac, obturator fossa and external iliac nodes down to the lymph node of Cloquet.
The number of lymph nodes removed during radical cystectomy is ranged from 15-20 nodes from both sides. Lymphadenectomy should be bilateral. Less than 10 LN is considered inadequate procedure.
The number of lymph nodes removed during radical cystectomy is ranged from 15-20 nodes from both sides. Lymphadenectomy should be bilateral. Less than 10 LN is considered inadequate procedure.
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.
A super-extended lymphadenectomy extends cranially to the level of the inferior mesenteric artery.
No difference in outcome was reported between extended and super-extended LND. Removal of at least ten LNs has been postulated as sufficient for evaluation of LN status (69).

Table V:12 Recommendations for radical cystectomy and urinary diversion

Recommendation

strength rating
1. Do not delay radical cystectomy (RC) for > 3 months as it increases the risk of progression and cancer-specific mortality Strong
2. Before RC, fully inform the patient about the benefits and potential risks of all possible alternatives. The final decision should be based on a balanced discussion between the patient and the surgeon. Strong
3. Do not offer an orthotopic bladder substitute diversion to patients who have a tumour in the urethra or at the level of urethral dissection. Strong
4. Offer sexual-preserving techniques to men motivated to preserve their sexual function since the majority will benefit Select men for sexual-preserving techniques based on: • organ-confined disease; • absence of any kind of tumour at the level of the prostate, prostatic urethra or bladder neck Strong
5. Pre-operative bowel preparation is not mandatory. “Fast track” measurements may reduce the time to bowel recovery. Strong
6. Offer pharmacological prophylaxis, such as low molecular weight heparin to RC patients, starting the first day postsurgery, for a period of 4 weeks. Strong
7. Offer RC in T2-T4a, N0M0, and high-risk non-muscle-invasive bladder cancer Strong
8. Perform a lymph node dissection as an integral part of RC. Strong
9. Do not preserve the urethra if margins are positive for malignancy Strong

V.6.4 Unrespectable tumors

V.6.4.1 Palliative cystectomy for muscle-invasive bladder carcinoma
Locally advanced tumors (T4b, invading the pelvic or abdominal wall) may be accompanied by several debilitating symptoms, including bleeding, pain, dysuria and urinary obstruction (70). These patients are candidates for palliative treatments, such as palliative RT.
Palliative cystectomy carries the greatest morbidity and should be considered for symptom relief only if there are no other options (70). Urinary diversion in this occasion should be as simple as required to alleviate the symptoms and minimize the morbidities.
V.6.4.1.1 Obstruction of the upper urinary tract
Unilateral (better kidney) or bilateral nephrostomy tubes provide the easiest solution for UUT obstruction (71), but patients find the tubes inconvenient and prefer ureteral stenting. However, stenting may be difficult to achieve in many occasions.
Another possible solution is a urinary diversion with, or without, a palliative cystectomy; supravesical diversion using uretero-cutanous anastomosis or palliative ileal conduit diversion (71).
V.6.4.1.2 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 tumor or with a bleeding tumor (72). Intravesical rinsing of the bladder with 1% silver nitrate or 1-2% alum can be effective. It can usually be done without any anesthesia. Radiation therapy is another common strategy to control bleeding and is also used to control pain and control of hematuria (72).

V.6.5 Bladder-sparing treatments for localized disease

V.6.5.1 Transurethral resection of bladder tumor
TURB alone in patients with muscle-invasive bladder tumors is only possible as a therapeutic option if tumor growth is limited to the superficial muscle layer and if re-staging biopsies are negative for residual (invasive) tumor (73).
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 (73).
Table V:12 Recommendations for radical cystectomy and urinary diversion

Recommendation

strength rating
1. Do not offer transurethral resection of bladder tumour alone as a curative treatment option as most patients will not benefit. Strong
2. Do not offer radiotherapy alone as primary therapy for localised bladder cancer. Strong
3. Do not offer chemotherapy alone as primary therapy for localised bladder cancer. Strong
4. Offer surgical intervention or multimodality treatments (MMT) as primary & curative therapeutic approaches since they are more effective than radiotherapy alone. Strong
5. Offer MMT as an alternative to selected, well-informed and compliant patients, especially for whom radical cystectomy is not an option. Strong


V.6.5.2 External beam radiotherapy
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 EBRT in BC is 64-66 Gy, with a subsequent boost using external RT or interstitial RT (74).
EBRT can be an alternative treatment in patients unfit for radical surgery, as it can be used to control bleeding (75).
V.6.5.3 Systemic chemotherapy
Chemotherapy alone rarely produces durable complete remissions. In general, a clinical complete response rate of up to 56% is reported in some series, which must be weighed against a staging error of > 60% (76).
Response to chemotherapy is a prognostic factor for treatment outcome and eventual survival although it may be confounded by patient selection (77).
Several groups have reported the effect of chemotherapy on resectable tumors (neoadjuvant approach), as well as unresectable primary tumors.
V.6.5.4 Multimodality bladder-preserving treatment
Multimodality treatment (MMT) or trimodality treatment combines TURB, chemotherapy and RT (78). The rationale to combine TURB with RT is to achieve local tumor control in the bladder and adjacent nodes. The addition of systemic chemotherapy or other radiosensitisers is aimed at the potentiation of RT (79). Micrometastases are targeted by platinum-based combination chemotherapy. 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.
V.6.6 Adjuvant therapy
V.6.6.1 Role of adjuvant platinum-based 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 (80). V.6.6.1.1 The general benefits of adjuvant chemotherapy include (80): Chemotherapy is administered after accurate pathological staging, therefore treatment in patients at low risk for micrometastases is avoided
No delay in definitive surgical treatment V.6.6.1.2 The drawbacks of adjuvant chemotherapy are (81): Assessment of in vivo chemosensitivity of the tumor is not possible and overtreatment is an unavoidable problem;
Delay or intolerability of chemotherapy, due to post-operative morbidity
V.6.6.2 Role of adjuvant immunotherapy
To evaluate the benefit of PD-1/PD-L1 checkpoint inhibitors, a number of randomised phase III trials comparing checkpoint inhibitor monotherapy with atezolizumab, nivolumab or pembrolizumab have been performed but no data have been presented so far (82). This line of treatment is still in its infancy and should be tried in high volume centers within controlled trials.
V.6.6.3 Critical consideration in management of MIBC
Patient informed consent is always needed in all the treatment modalities and enough time should be allowed to the patient and his family explaining the disease, the outcome, morbidity and quality of life (QoL) for each treatment option.
Laparoscopic and robotic radical cystectomy may be utilized but never replace the standard open approach, The use of such techniques is still in its infancy in Egypt and should be restricted to a well experienced surgeon who would be able to treat any unexpected complications.
The patient should be well informed about the technique without any bias from the surgeon and the operation should be performed in a well-equipped place.
Radical cystectomy and urinary diversion should be strictly performed by a high volume surgeon, (at least 30-50 cystectomy per year) in a well-equipped hospital, high caliber anesthetic team, ICU, Blood transfusion, well trained nursing staff, stoma therapist, nutritionist, and preferably social or psychiatric support team.

V.7 Metastatic bladder cancer

Approximately 50% of patients with muscle-invasive UC relapse after RC, depending on the pathological stage of the primary tumor and the nodal status (83). Local recurrence accounts for 30% of relapses, whereas distant metastases are more common. Ten to fifteen percent of patients are already metastatic at diagnosis (83).
The patient and his family should be informed about such natural history of metastatic outcome, QoL and survival rate.
V.7.1 First line systemic therapy for metastatic disease
V.7.1.1 Standard first-line chemotherapy for fit patients
Methotrexate, vinblastine, Adriamycin plus cisplatin (MVAC) and GC prolonged survival compared to monotherapy and older chemotherapy combinations (84).
High-dose intensity MVAC (HD-MVAC) combined with granulocyte colony-stimulating factor (GCSF) is less toxic and more efficacious than standard MVAC in terms of dose density, complete response (CR), and survival rate (84).
Carboplatin-containing chemotherapy is not equivalent to cisplatin combinations, and should not be considered interchangeable or standard (85).
V.7.1.2 Non-platinum combination chemotherapy
Different combinations of gemcitabine and paclitaxel have been studied as first- and second-line treatments (86). 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 (86).
V.7.1.3 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 (87). Responses with single agents are usually short-lived, complete responses are rare, and no long-term DFS has been reported.
V.7.1.4 Immunotherapy in first-line treatment
Several randomised phase III trials are currently investigating the use of checkpoint inhibitors in the first-line setting for cisplatin-eligible and ineligible patients using combinations with chemotherapy or CTLA-4 inhibitors as well as monotherapy (88).

V.7.2 Second-line systemic therapy for metastatic disease

V.7.2.1 Second-line chemotherapy
Second-line chemotherapy data are highly variable and mainly derive from small single-arm phase II trials apart from a single randomised phase III study which for the first time established prognostic factors (89).
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 single agent treatment with paclitaxel (weekly), docetaxel, nab-paclitaxel oxaliplatin, ifosfamide, topotecan, pemetrexed, lapatinib, gefitinib and bortezomib have ranged between 0% and 28% (90). Gemcitabine has also shown good response rates in second-line use but most patients receive this drug as part of their first-line treatment.

V.7.3 Post-chemotherapy surgery and oligometastatic disease

With cisplatin-containing combination chemotherapy, excellent response rates may be obtained in patients with LN metastases only, good performance status and adequate renal function (91).
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 mainly anecdotal (92).
in the absence of data from RCTs, patients should be evaluated on an individual basis and discussed by an interdisciplinary tumor board.

V.7.4 Treatment of patients with bone metastases

The prevalence of metastatic bone disease in patients with advanced/metastatic UC is 30-40% (93). Skeletal complications due to bone disease have a detrimental effect on pain and QoL and are also associated with increased mortality.
Bisphosphonates such as zoledronic acid (ZA) reduce and delay skeletal-related events (SREs) due to bone metastases by inhibiting bone resorption, as shown in a small pilot study (94).

V.7.5 Follow-up in metastatic 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 (95).
V.7.5.1 Site of recurrence
V.7.5.1.1 Local recurrence
Local recurrence takes place in the soft tissues of the original surgical site or in LNs (96). Contemporary cystectomy has a 5-15% probability of pelvic recurrence which usually occurs during the first 24 months, most often within 6 to 18 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 (96). Patients generally have a poor prognosis after pelvic recurrence.
V.7.5.1.2 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. 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%) (97).
The most likely sites for distant recurrence are LNs, lungs, liver and bone. Nearly 90% of distant recurrences appear within the first three years after RC, mainly in the first two years, although late recurrence has been described after more than 10 years (97).
V.7.5.1.3 Urethral recurrence
After RC, the incidence of new urethral tumors was 4.4% (1.3-13.7%) (98). Risk factors for secondary urethral tumors are urethral malignancy in the prostatic urethra/prostate and bladder neck (in women). Orthotopic neobladder was associated with a significant lower risk of urethral tumors after RC (98).
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.
V.7.5.1.4 Metachronus upper urinary tract urothelial carcinoma
UTUC occurs in 4-10% of cases and represents the most common sites of late recurrence (99). Multifocality increases the risk of recurrence by three-fold, while positive ureteral or urethral margins increase the risk by seven-fold. Frozen section of the lower cut end of the ureter is preferable to be examined especially if the tumor is of high grade, multifocal, invading the trigone or with concomitant CIS (99).
V.7.5.2 Time schedule for surveillance
Although, based on low level evidence only, some follow-up schedules have been suggested, guided by the principle that recurrences tend to occur within the first years following initial treatment (100).
A schedule suggested by the EAU Guidelines Panel includes a CT scan (every 6 months) until the third year, followed by annual imaging thereafter. Patients with multifocal disease, NMIBC with CIS or positive ureteral margins are at higher risk of developing UTUC, which can develop late (> 3 years) (100). In those cases, monitoring of the UUT is mandatory during follow-up. Computed tomography is to be used for imaging of the UUT.
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 individualized recommendations and may increase recurrence detection (101). 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 (101).
V.7.6 Follow-up of functional outcomes and complications
Apart from oncological surveillance, patients with a urinary diversion need functional follow-up. Complications related to urinary diversion are detected in 45% of patients during the first five years of follow-up (102). This rate increases over time, and exceeds 54% after 15 years of follow-up. Therefore, long-term follow-up of functional outcomes is desirable.
The functional complications are diverse (102) 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. Especially in women approximately two-thirds need to catheterize their neobladder, while almost 45% do not void spontaneously at all. Recently a 21% increased risk of fractures was also described as compared to no RC, due to chronic metabolic acidosis and subsequent long-term bone loss. Since low vitamin B12 levels have been reported in 17% of patients with bowel diversion, in case of cystectomy and bowel diversion, vitamin B12 levels should be measured annually.
V.8 Summary:
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in the male population worldwide, while it drops to eleventh when both genders are considered. Proper stagging and grading are the cornerstone in management of Urinary bladder tumors. Management may differ from endoscopic resection to a radical cystectomy based on the nature, extent and depth of invasion of the tumor
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