Carcinoma of the Bladder

Risk factors
 Cigarette smoking is strongly associated with an increased risk of bladder cancer.
 Occupational exposure to aromatic amines (particularly 2-naphthylamine, benzidine,
and polycyclic aromatic hydrocarbons) is associated with an increased incidence of
bladder cancer (e.g., workers in dyestuff manufacturing and rubber and aluminum
industries).
 Infection with the trematode Schistosoma haematobium leads to chronic irritation of
the urothelium and to an increased risk of both squamous and urothelial carcinomas.
 Cyclophosphamide has been associated with an increased risk of urothelial carcinoma.
 Hereditary nonpolyposis colon cancer (HNPCC) syndrome, also known as Lynch
syndrome, is associated with an increased risk for the development of bladder and other
urothelial cancers, most notably upper tract tumors.

Prevention and early detection

 Smoking cessation counseling is important.
 Workers in Industrial companies that use dyes, chemicals, and rubber products should
be tested periodically with at least cytologic evaluation and urine examination and
should wear protective masks during working hours.
 Screening tests include newer urine-based tests such as UroVysion (fluorescence in situ
hybridization [FISH]), ImmunoCyt, and nuclear matrix protein mainly in early detection
of recurrence
 The current evidence is insufficient to assess the benefits and harms of screening for
bladder cancer in asymptomatic adults.

Diagnosis
C/P
 The most common presenting symptom in patients with bladder cancer is microscopic
or gross hematuria.
 Urinary frequency from irritation or a reduced bladder capacity can also develop.
 Less commonly, the presenting symptom is a urinary tract infection.
 Upper tract obstruction or pain may occur in patients with a more advanced lesion.
 Patients presenting with these symptoms should be evaluated with office cystoscopy to
determine if a lesion is present. If one is documented, the patient should be scheduled
for a transurethral resection of the bladder tumor (TURBT) to confirm the diagnosis and
determine the extent of disease within the bladder (muscle invasive or not). Urine
cytology may also be obtained around the time of cystoscopy.
Investigations
 CBC, Liver and KFTs
 Cystoscopy, TURBT (as before)
 CT scan or MRI of the abdomen and pelvis is recommended before the TURBT.
 Additional workup for all patients should include urine cytology, if not already tested,
and evaluation of the upper tracts with a CT or MR urography; a renal ultrasound or CT
without contrast with retrograde ureteropyelography; a ureteroscopy; or a combination
of techniques. CT urography is generally the preferred approach to upper tract imaging
in patients who can safely receive intravenous contrast agents.
 In the presence of a positive cytology and a normal cystoscopy, the upper tracts and the
prostate in men must be evaluated and ureteroscopy may be considered.

Pathology
 Urothelial carcinoma (TCC) may occur throughout the urinary tract (i.e., in any structure
lined by the urothelium), with more than 90% of tumors originating in the bladder.
Upper urinary tract tumors, including the renal pelvis and ureter, account for 5 to 7% of
urothelial carcinomas.
 Noninvasive urothelial neoplasia includes papilloma, CIS.
 92% of lower urinary tract tumors are urothelial carcinomas (either low grade or high
grade non muscle invasive or muscle invasive).
 Other non-urothelial carcinomas include squamous cell cancers (mostly with Sh
hematopium infection), adenocarcinomas, and small cell carcinomas.
 Lesions of mixed histology generally are variants of urothelial carcinoma.

Molecular biology
 Low-grade noninvasive papillary tumors are characterized by mutations in the
HRAS gene and fibroblast growth factor receptor 3 gene (FGFR3), indicating that
receptor tyrosine kinase–Ras activation has an early and major role in bladder
cancer tumorigenesis.
 High-grade invasive tumors are characterized by defects in the p53 and retinoblastoma
protein (RB) tumor suppressor genes. P53 nuclear overexpression independently
predicts for progression and decreased survival.
 Other genetic alteration include RTK/RAS/RAF pathway (e.g., ERBB2 amplification and
FGFR3 mutation), and phosphoinositide 3-kinase (PI3K)/AKT (e.g., PIK3CA mutation and
TSC1 mutation).
 immunohistochemical expression for p53, p21, pRB, and p16 demonstrated that altered
expression of each of these cell cycle regulators was associated with poor outcome,
more metastasis, with p53 as the strongest predictor.
  Clinical application includes targeting PI3K/AKT/mTOR pathway by MTOR inhibitors,
Erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations.
 In addition to novel targets, data suggests that mutations in DNA damage repair (DDR)
genes in urothelial cancers including ERCC2, ATM, FANCC, RB1 as well as others may
predict response to platinum-based chemotherapy.
 Bladder cancer has the fourth highest mutational burden after melanoma, lung
squamous, and lung adenocarcinoma. Mutational burden have been associated with
response to novel checkpoint inhibitor immunotherapies including anti-programmed
death-1 (anti-PD-1) and anti-programmed death ligand 1 (PD-L1) antibodies in patients
with metastatic bladder cancer.

STAGING
 By cystoscopy, biopsy with radiological assessment with CT or MRI pelvis +/- bone scans
in muscle invasive or PET/CT to identify extravesical or nodal or metastatic disease.
 The NCCN Guidelines define the management according to non–muscle-invasive disease
(Ta, T1, and Tis) which is the majority of cases and muscle-invasive disease (≥T2
disease).
Treatment of Non–Muscle-Invasive Urothelial Bladder Cancer (Ta, T1, and Tis)

 Indications for cystectomy include T1 tumors with lymphovascular invasion or

variant histology e.g micropapillary features, large or diffuse T1 grade 3 tumors, pure
squamous cell or adenocarcinoma histology, prostatic duct/acinar CIS in men, T1
grade 3 disease associated with CIS, deep or extensive involvement of lamina propria,
persistent T1 grade 3 tumors on resection, recurrent or persistent high grade disease
within 6 to 12 months after initial BCG therapy, or large-volume high grade disease or
extensive involvement of bladder with inability to attain complete resection of all
visible dse despite mple attempts at TURBT
 An immediate intravesical instillation of chemotherapy may be given within 24 hours of
TURBT (ideally within 6 hours) to prevent tumor cell implantation and early recurrence
especially in low and intermediate risk .The most commonly used options for
intravesical chemotherapy are gemcitabine (preferred) and mitomycin. The role of
maintenance chemotherapy is controversial. When given, maintenance chemotherapy
is generally monthly.
 Frequency and intensity of surveillance should consider the risk of recurrence
 Bacillus Calmette-Guérin (BCG) is a live, attenuated strain of Mycobacterium bovis. Each
dose consists of a vial of reconstituted Connaught BCG (81 mg) or one 2 mL ampule of
Tice BCG (50 mg), plus 50 mL of sterile saline injected into the bladder through a
catheter and retained for two hours.
 Induction (Adjuvant) Intravesical BCG is commonly initiated 3–4 weeks after TURBT,
given once a week for 6 weeks, followed by a rest period of 4 to 6 weeks, with a full
reevaluation at week 12.
 Maintenance intravesical BCG: the strongest data support the weekly for three weeks
at 3, 6, 12, 18, 24, 30, and 36 months regimen that demonstrated reduced disease
progression and metastasis.
 A localized BCG cystitis is the most common complication. A short course of a
fluoroquinolone or isoniazid is often effective in managing symptoms. More serious
systemic infections (eg, sepsis, pneumonitis, hepatitis, arthritis) have been reported.
Multidrug antibiotic therapy for three to six months is indicated in this setting.
 Surveillance: urinary cytology and cystoscopy at 3- to 6-month intervals for the first 2
years and at increasing intervals as appropriate thereafter. Imaging of the upper tract
should be considered every 1 to 2 years for high grade tumors. Consideration may be
given to FDA-approved urinary biomarker testing by fluorescence in situ hybridization
(FISH) or nuclear matrix protein 22 in monitoring for recurrence.
 After the initial intravesical treatment and 12-week evaluation, patients with persistent
cTa, cT1, or Tis disease tumors can be given a second induction course of induction
therapy followed by TURBT.
 If residual disease is seen following TURBT, patients with persistent high-grade cT1
tumors are recommended to proceed to cystectomy.
 Non-surgical candidates can consider concurrent chemoradiation.
 N.b Pembrolizumab is indicated for treatment of patients with BCG-unresponsive ,high risk ,NMIBC with
CIS (with or without papillary) (cat 2A) and may also be considered for patients with BCG -unresponsive,
high risk,NMIBC with high -grade papillary Ta/T1 only tumors without CIS (cat 2B).
Treatment of non-metastatic Muscle-Invasive Urothelial Bladder Cancer
(stage II, III, M0 IVA)
Stage II and III Tumors >>

 Neoadjuvant 3-4 cycles cisplatin-based chemotherapy (DDMVAC or Gem/Cis) is

recommended (category 1 as less recurrence and better OS) followed by radical
cystectomy and pelvic lymphadenectomy. Patients with hearing loss or neuropathy,
poor performance status, or renal insufficiency may not be eligible for cisplatin-based
chemotherapy. If neoadjuvant cisplatin-based chemotherapy cannot be given,
neoadjuvant chemotherapy is not recommended. Cystectomy alone is an appropriate
option for these patients. For patients with borderline renal function or minimal
 dysfunction, a split-dose administration of cisplatin may be considered. Carboplatin
should not be substituted for cisplatin in the perioperative setting.
 Patients who had high risk dse at cystectomy after neoadjuvant therapy (ypT2-4a or
node positive >>adjuvant nivolumab for 1 year according to checkmate 274 trial
 Partial cystectomy can be considered for stage II (cT2, N0) disease with a single tumor in
a suitable location and no presence of Tis.
 Bladder preservation with maximal TURBT followed by concurrent chemoradiotherapy
with cisplatin plus 5-FU or cisplatin plus paclitaxel or 5-FU plus mitomycin C or even
cisplatin alone may be considered patients with tumors that present without
hydronephrosis or with tumors that allow a visibly complete or a maximally debulking
TURBT. Optimal candidates for bladder preservation include T2 tumors ,solitary tumor
<5 cm,complete TURB possible ,no hydronephrosis ,no multifocal CIS,good bladder
function,compliance with follow up while it is C.I in multifocal CIS,impaired bladder
function.The overall tumor status should be reassessed 2 to 3 months after treatment. If
no residual tumor is detected (complete response), observation is appropriate. If
residual disease is present, surgical consolidation is appropriate. If residual disease is Tis,
Ta, or T1, intravesical BCG may be considered.
 In patients with extensive comorbid disease or poor performance status who are non-
cystectomy candidates, treatment options include concurrent chemoradiation or
radiotherapy alone or TURBT followed by intravesical BCG
 If no neoadjuvant chemotherapy is given, postoperative adjuvant cisplatin-based
chemotherapy for at least 3 cycles may be considered based on pathologic risk, such
as positive nodes or pT3-T4 lesions. Adjuvant RT is another option for these patients.
 Patients not eligible for adjuvant cisplatin based chemotherapy ,may be offered
adjuvant nivolumab
 Checkamte 274 :the US Food and Drug Administration (FDA) granted regulatory
approval for adjuvant nivolumab for 1 year in patients with urothelial carcinoma who
are at high risk of recurrence after undergoing radical resection of disease .High risk
of recurrence is defined as muscle-invasive (ypT2-T4a) and/or node-positive disease
for patients who received neoadjuvant cisplatin, or extravesicular extension (pT3-T4a)
and/or node-positive disease for patients who did not receive neoadjuvant cisplatin
and who were also either ineligible for or refused adjuvant cisplatin based on
improved DFS in intention to treat population(HR:0.7) ,improvement in DFS Was
more pronounced in ptn received prior neoadjuvant (HR:0.5)and PD-L 1 >1 (HR:0.5)

Stage IVA M0 Tumors

 In general, stage IVA disease is considered unresectable.
 Primary treatment recommendations for patients with M0 disease include systemic
therapy or concurrent chemoradiotherapy followed by evaluation with cystoscopy, EUA,
TURBT, and imaging of the abdomen and pelvis. If no evidence of tumor is present after
primary treatment, consolidation systemic therapy or completion of definitive radiation
therapy may be considered.
Management is complex for patients with high risk Ms invasive urothelial carcinoma of the bladder at
cystectomy.The role of adjuvant chemotherapy in these patients hasnot been established in adequately
powered trials .Neoadjuvant chemotherapy followed by cystectomy remains the preferred approach for these
patients.However ,some clinicians and patients opt for initial treatment with definitive surgery ,reserving the
option of adjuvant treatment for those at high risk for recurrence based on pathologic staging

High risk dse at cystectomy is defined as either no prior neoadjuvant cisplatin-based chemotherapy with
pathologic (p) T3-T4a and/or node-positive disease ,or prior neoadjuvant cisplatin based chemotherapy with
pathologic (yp) T2-4a and/or node-positive disease

Some clinicians prefer gemcitabine plus cisplatin over MVAC regimens due to a better toxicity profile.However
others prefer MVAC regimens for fit patients ,extrapolating from data suggesting a survival benefit for MVAC
in the neoadjuvant setting.Since the use of adjuvant chemotherapy is controversial,patients may alternatively
choose observation or clinical trial enrollment.For patients who choose adjuvant systemic therapy ,we initiate
treatment as soon as surgical recovery permits,typically around six to eight weeks postoperatively and no later
than three months after radical cystectomy.
Treatment of metastatic Urothelial Bladder Cancer
Role of surgery
 Surgery may be considered only in patients with favorable response to systemic
therapy, solitary metastatic lesions, and lung or lymph node sites of disease.

Systemic therapy
Treatment of metastatic urothelial cancer
Chemotherapy

 Both GC and ddMVAC with growth factor support are category 1 recommendations for
metastatic disease followed by avelumab maintenance for 2 years (cat1) if stable or
regressive disease
 DD MVAC was associated with better response and OS
 Alternative first-line regimens also include carboplatin/Gemcitabine followed by
avelumab maintenance for 2 years (cat1) if stable or regressive disease or taxane-based
regimens (category 2B) or single-agent chemotherapy e.g gemzar (category 2B).
 Other 2nd line regimens include Gem/MTX/Pemetrexed/Ifosphamide.

Targeted Therapies

 Maintenance avelumab (Javelin bladder 100) >> For patients with advanced bladder
cancer (regardless of PD-L1 tumor status) who do not progress (ie, achieve an objective
response or stable disease) following platinum-based chemotherapy and are eligible to
receive checkpoint inhibitor immunotherapy, we suggest maintenance avelumab,
rather than best supportive care alone, as this approach improved overall survival (OS)
and progression-free survival (PFS) in a phase III Trial. Although this study only
evaluated maintenance avelumab in patients who received gemcitabine plus platinum-
based chemotherapy, we also offer this approach to those who have not progressed on
other platinum-based chemotherapy regimens, extrapolating from the results of this
trial
 atezolizumab (IMvigor 210 study), and pembrolizumab (KEYNOTE-052 trial) are
approved as a first-line treatment option for patients with locally advanced or
metastatic urothelial cell carcinoma who are not eligible for cisplatin-containing
chemotherapy and whose tumors express PD-L1 or in patients who are not eligible for
any platinum-containing chemotherapy regardless of PD-L1 expression. According to
trials, platinum based chemotherapy is more effective than immunotherapy as 1st line.
 Pembrolizumab (phase III KEYNOTE-045 trial), , nivolumab, and avelumab are approved
as subsequent lines for the treatment of locally advanced or metastatic urothelial cell
carcinoma that has progressed during or after platinum-based chemotherapy or that
has progressed within 12 months of neoadjuvant or adjuvant platinum-containing
chemotherapy, regardless of PD-L1 expression levels. Atezolizumab, durvalumab
approval withdrawn as 2nd line after results of phase III trial
 Erdafitinib (EGFR inhibitor)may be considered as subsequent line post platinum only for
patients with susceptible FGFR3 or FGFR2 genetic alterations.Our typical approach for
patients whose tumors harbor susceptible FGFR3 or FGFR2 genetic alteration is to offer
erdafitinib after progression has occurred on both platinum based chemo & on
immunotherapy,typically 3rd line
 Enfortumab vedotin(ADC targeting adhesion nectin-4 linked to a microtubule
inhibitor) improved OS and PFS over chemo after platinum and immunotherapy
  Sacituzumab govitecan is a reasonable alternative option with a different toxicity profile
from other targeted agents.

Treatment of Non-Urothelial Carcinomas of the Bladder

 Non-urothelial bladder cancers are further classified as epithelial or non-epithelial.
Epithelial include squamous cell carcinomas, adenocarcinomas, and small cell
(neuroendocrine) tumors. Non-epithelial cancers are rare and include sarcomas,
carcinosarcoma, paraganglioma, melanomas, and lymphomas.
 For patients with non-metastatic, non-urothelial bladder carcinoma, surgery is
recommended. Adjuvant RTH may be used. No data support the use of adjuvant
chemotherapy except in small cell carcinoma, adjuvant plat/etoposide may be used.
  For patients with advanced cancer who are not
candidates for surgery, either palliative care or trial of
chemotherapy in fit patients. Type of chemotherapy
according to the histology (5-FU or taxanes for Sqcc,
plat/etoposide for SCC or as SCC of the lung.

Malignancies of the renal pelvis and ureter

 Patients with localized resectable disease >>
nephroureterectomy with excision of a cuff of normal
bladder and bladder mucosa + lymphadenectomy if high
grade. Adjuvant chemotherapy as in urothelial bladder
cancer for high-risk patients ie, T3-T4
primary and/or positive lymph nodes.
 Patients with locally advanced disease >>
neoadjuvant chemotherapy followed by surgery.
 Patients with advanced disease requiring systemic treatment.
 The chemotherapy regimens are based upon regimens
used for urothelial tumors in bladder cancer patients
(MVAC and GC). For patients with progressive disease
following platinum-based chemotherapy, checkpoint
inhibitor immunotherapy is an important option.

Urothelial Carcinomas of the Prostate

 Tumors that are limited to the mucosal prostatic urethra
with no acinar or stromal invasion can be managed with
TURP and intravesical BCG, with follow-up similar to that
for superficial disease of the bladder.
 Patients with tumors that invade the ducts,
acini, or stroma should undergo
cystoprostatectomy with or without
urethrectomy.
 Adjuvant chemotherapy may be advised for stromal invasion.
 Metastatic disease is treated like urothelial bladder cancer

Primary Carcinoma of the Urethra

 Tis, Ta, T1 >> TUR Followed by intraurethral chemotherapy or BCG
 T2 >> urethrectomy with or without
cystoprostatectomy. Adjuvant chemotherapy or
chemoradiation may be considered if pT3, pT4, or nodal
disease is found.
 Patients with T3 or T4 disease but no clinical nodes
should receive neoadjuvant chemotherapy followed
by consolidative surgery or radiation or
chemoradiotherapy without surgery if clinically +ve
LNs.
 Patients with distant metastases should receive similar
treatment as metastatic bladder cancer according to the
histology.