Carcinoma of The Bladder: Risk Factors
Carcinoma of The Bladder: Risk Factors
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.
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)
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.