Muscle Invasive Bladder Cancer
Marc C. Smaldone
Fellow in Urologic Oncology, Fox Chase Cancer Center
for
Introduction
It is estimated that bladder cancer will account for 14,680 disease specific deaths
in 2010 in the United States, and represents the ninth leading cause of cancer-related
death in men1. Epidemiologic studies do not suggest a hereditary cause of most bladder
cancers2, although risk factors such as age, cigarette smoking, aromatic amines, aniline
dyes, arsenic, and pelvic radiation have been described3. Although microscopic or gross
painless hematuria is the presenting complaint in the vast majority of patients, irritative
voiding symptoms such dysuria, urgency, and frequency are more common in patients
with high grade papillary tumors, CIS, and invasive disease. The discovery of incidental
bladder cancer at autopsies is very low, indicating that a vast majority of patients
experience symptoms prompting workup or treatment during their lifetime4.
Approximately 20-30% of patients present with muscle invasive disease, and of patients
with non-muscle invasive tumors, 10-30% will progress to muscle invasion5.
Clinical Staging
The AUA Best Practice Policy on Asymptomatic Microscopic Hematuria defines
microscopic hematuria as ≥3 red blood cells per high-power microscopic field from 2 of
3 properly collected urinalysis specimens6. All patients undergoing a hematuria
evaluation should be evaluated with urine cytology, upper tract imaging, and
cystoscopy5. In a patient with a bladder mass diagnosed on imaging or cystoscopy, an
adequate transurethral resection is mandatory for histologic diagnosis and assessment
for invasion. During the initial evaluation, the bladder, urethra, and upper tracts should
be evaluated for presence of urothelial carcinoma. Tumors should be completely
resected, and muscularis propria should be included to ensure accurate staging. Biopsy
of the prostatic urethra should be performed in cases of bladder neck or prostatic
urethral tumors, and random bladder mapping to rule out CIS can be performed when
bladder sparing protocols are being considered or in the setting of a positive cytology
with no obvious bladder or upper tract lesions4. In patients with bulky multifocal
tumors, high grade Ta or T1 disease, or lack of detrusor muscle in the specimen, re-TUR
resection is recommended as many as 20% of patients will be upstaged to muscle
invasive disease following re-resection7.
At the time of TUR, a bimanual exam under anesthesia should be performed to
assess for local invasion. If a fixed or three dimensional mass is palpated, a clinical stage
of ≥T3b is assigned8. Cross sectional imaging is an important component of the clinical
staging workup when muscle invasive disease is present, and consists of imaging of the
chest with chest radiography or computed tomography (CT) to evaluate for pulmonary
metastases as well as abdominal imaging with CT or magnetic resonance imaging (MRI)
to evaluate for local invasion, regional metastases, and systemic dissemination of
disease. Although CT and MRI are limited in their ability to detect early metastatic
disease, newer imaging modalities such as positron emission tomography (PET) have
had poor results in patients with urothelial carcinoma due to urinary excretion and
inconsistent tracer uptake9. Regardless of imaging modality, a thickened bladder wall or
hydronephrosis raises suspicion for extravesical disease. Metastatic spread to the bone
or brain is uncommon and additional imaging is not routinely indicated unless the
patient has specific finding to indicate involvement. Despite significant improvement in
imaging techniques, 30-50% of patients are upstaged at the time of cystectomy10.
Pathologic Staging and Cancer Specific Outcomes
Per the updated TNM staging system, organ confined disease invading the
superficial or deep muscularis propria represents pT2a and pT2b disease respectively,
while tumors that extend into the perivesical fat represent pT3 disease in a microscopic
(pT3a) or macroscopic (pT3b) fashion. Tumors invading adjacent organs such as the
prostatic stroma, seminal vesicles, uterus, or vagina, is classified as pT4a disease, and
tumors invading the pelvic sidewall or abdominal wall meeting criteria for pT4b disease.
Regional lymph node staging is determined by either single (N1) or multiple regional
involved lymph nodes (N2), while metastases to the common iliac artery lymph node
chain represents N3 disease3. Any nodal or distant metastatic disease is considered
stage IV disease which imparts a very poor prognosis. The TNM system provides a useful
system for stratifying prognosis, recurrence risk, and survival outcomes. With surgery
alone, stratified by pathologic stage, 5 year survival rates are 66% for pT2 disease, 35%
for pT3 disease, and 27% for pT4 disease respectively11.
Treatment Options
The gold standard treatment for clinically localized muscle invasive urothelial
carcinoma is radical cystoprostatectomy or anterior pelvic exenteration with extended
regional lymphadenectomy and creation of an incontinent or continent urinary
diversion. Currently performed via an open or minimally invasive approach, large
institutional series from centers of excellence report overall 5 year survival rates ranging
from 45-66% with perioperative mortality rates less than or equal to 3%12, 13, and
perioperative complication rates ranging from 25-57%13, 14 Recent evidence has
suggested a 5-8% overall survival benefit with the administration of systemic
chemotherapy15, 16, and current consensus recommends that neoadjuvant cisplatin
based chemotherapy be considered in all patients with muscle-invasive urothelial
carcinoma8. Poor candidates for upfront chemotherapy include patients with a poor
performance status (ECOG ≥2) or poor renal function (eGFR <45-60)17. Although
adjuvant therapy offers the advantage of being administered in only patients with
known prognostic factors of recurrence its role has been poorly defined to date due to
limited trials with methodological flaws. However, a recent meta-analysis of 6
randomized trials investigating the use of cisplatin based adjuvant therapy suggested a
25% relative reduction in the risk of death for patients receiving adjuvant therapy versus
local therapy alone18.
Less conventional treatments for muscle invasive bladder cancer include partial
cystectomy, localized radiotherapy, and radical TUR in combination with radiotherapy
and chemotherapy, which offer the potential for decreased morbidity, nerve
preservation for potency, improved patient body image, and maintenance of bladder
function. Using strict selection criteria including solitary primary tumors and absence of
CIS, small series utilizing partial cystectomy have reported equivalent early oncologic
results to radical cystectomy, although these findings are limited by selection bias 19.
Historically, radiation therapy was reserved for patients unfit medically for radical
cystectomy, or as palliative therapy in patients with locally advanced or metastatic
disease20. Contemporary bladder-preserving protocols utilizing chemoradiation
following complete TUR in patients with clinically staged muscle-invasive bladder cancer
have reported complete response rates of 60-85%, 5-year survival rates of 50-60%, and
survival rates with an intact bladder of 40-45%21. Important considerations for bladderpreserving therapy include careful patient selection; combined therapy with maximum
TUR, radiation and concurrent chemotherapy; cystoscopic assessment of the response
to therapy with prompt salvage cystectomy for non-responders or invasive recurrence.
Although there are no randomized comparison studies with radical cystectomy, longterm contemporary data suggests that overall and disease-specific survival rates in
contemporary bladder sparing protocols may be comparable to large radical cystectomy
series in select patients22. However, until level I evidence exists, radical cystectomy will
remain the treatment of choice in patients with localized muscle invasive urothelial
carcinoma.
In patients with locally advanced or systemic disease, the role of surgery shifts to
palliation for the relief of symptoms including pain, bleeding, lower urinary tract
symptoms, and fistula formation17. In patients with unresectable locally advanced
primary tumors, palliative cystectomy or simply urinary diversion leaving the bladder in
situ is a potential alternative in intractably symptomatic patients. In patients presenting
with metastatic disease, cisplatin based chemotherapeutic regimens including
methotrexate. vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine/cisplatin
(GC) have demonstrated comparable survival rates and response rates ranging as high
as 46-49%23. Although these combinations show similar efficacy, GC is more tolerable
with a significantly less toxic side effect profile. Carboplatin based therapy is less
effective with less pronounced response rates and remains second line therapy24.
Surveillance
Although significant variation exists between protocols, patients with muscle
invasive urothelial carcinoma are at high risk for recurrence/metastasis following
cystectomy and require close surveillance. Per the NCCN guidelines, following
cystectomy a urine cytology, serum chemistries, chest radiography, and
abdominal/pelvic cross sectional imaging should be obtained every 3-12 months for two
years and as clinically indicated8. A urethral washing is recommended every 6-12
months but recent data suggests that while uncommon (5-15%), urethral recurrences
usually present symptomatically, and routine urethral washings do not appear to have a
survival benefit25. Upper tract recurrences are also uncommon (<10%) and often tumors
are not detected prior to the development of clinical symptoms. The most common
distal sites for recurrence include lung, liver, and bone, and as many as 50% of patients
will develop systemic disease following cystectomy26. Scoring algorithms based on
independent predictors of recurrence at the time of cystectomy have been utilized to
tailor surveillance protocols based on an individual patient’s pathologic characteristics
and we expect the role of such algorithms to grow in the near future27. For bladder
sparing protocols, patients should be evaluated with cystosopy, urine cytology, and
consideration of bladder biopsy every 3-6 months for two years and then at increasing
intervals3.
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Marc C. Smaldone, MD
Fellow in Urologic Oncology, Fox Chase Cancer Center