Non Muscle Invasive Bladder Cancer
Marc C. Smaldone, MD
Fellow in Urologic Oncology, Fox Chase Cancer Center
for
Introduction
Bladder cancer is the second most common
genitourinary malignancy, and it is has been
estimated that there will be in excess of 70,000
newly diagnosed cases of bladder cancer in the
United States in 2010, with a cancer specific
mortality of 20.8%1. There is a 4:1 male
predominance and it is twice as common in
Caucasians compared to African Americans.
Although bladder cancers are occasionally
diagnosed in young patients, the median age at
diagnosis is 70 years. Greater than 90% of bladder
cancers are urothelial carcinoma, which will be
focused on in this summary, while squamous cell
carcinomas and adenocarcinomas are decidedly more uncommon. Tobacco use appears
to be the most identifiable risk factor associated with the development of urothelial
cancer2, while other risk factors include occupational exposures such as aryl amines,
pelvic radiation, and phenacetin-containing analgesics3. In addition, chromosomal
abnormalities on chromosome 9 and resulting effects on fibroblast growth factor
receptor 3 and the tumor suppressor p53 have been recognized as key genetic pathways
in the carcinogenesis of transitional cell carcinoma4.
Of newly diagnosed cases of urothelial carcinoma, 70-80% will present with nonmuscle invasive disease, which consists of carcinoma in situ, non-invasive papillary
carcinoma, and tumors invading the subepithelial lamina propria without detrusor
muscle involvement5. Of non-muscle invasive bladder cancers (NMIBC), 50-70% will
recur despite treatment and up to 30% will progress to muscle invasive disease 3. Due to
these recurrence and progression risks, there is a lifetime need for surveillance and
need for repeat procedures, which results in a predicted lifetime health care cost in
excess of 100,000 dollars per patient6. Despite high health care expenditures, bladder
cancer screening is not currently recommended due to the low overall prevalence in the
general population, although a mortality benefit with screening has been suggested in
populations at high risk7.
Presenting Signs and Diagnostic Evaluation
The most common presenting symptom in patients with urothelial carcinoma is
microscopic or gross hematuria, while irritative lower urinary tract symptoms such as
urgency, frequency, and dysuria are also common. A complete diagnostic workup
includes direct cystoscopic visualization of the urethra and bladder and upper tract
imaging consisting either of computed tomography/magnetic resonance urography or
renal ultrasound combined with intravenous or retrograde pyelography. Cystoscopy,
which can be performed both in the office and operating room settings, is the gold
standard method for detecting bladder tumors. With the exception of CIS which can
appear as a velvety patch, most tumors have a papillary or sessile appearance, and
visualization of a lesion warrants endoscopic transurethral resections (TUR)3. Urine
cytology is an important adjunct to cystoscopy, and remains the most specific urine test
(>90) for the detection of bladder malignancy. However, while the sensitivity and
specificity is highest for high grade lesions and CIS, the utility in diagnosing low grade
tumors using urine cytology is low8. Urinary biomarkers have been assessed for utility in
initial diagnosis and to detect recurrence. Although several are approved by the FDA
including NMP22, BTA, FISH, and ImmunoCyt, currently none of the commercially
available assays obviate the need for cystoscopy and are not recommended except in
select patients9. Upper tract imaging to rule out concomittant upper tract urothelial
carcinoma is an important component of the NMIBC evaluation and conventional CT
and MR urography techniques have largely supplanted intravenous pyelography at most
centers10.
Transurethral Resection (TUR)
Cystoscopy is the gold standard for the detection of bladder cancer, and can be
performed in the office setting under local anesthesia and is well tolerated. Fulguration
of small recurrent tumors can also be performed in the office setting but only after
having been properly staged as low grade non invasive disease with TUR. TUR is vital to
determining management strategy in patients with urothelial carcinoma, and is
necessary for histologic diagnosis and determining the depth of invasion for staging
purposes3. Following initial TUR, residual disease is associated with risk of early
recurrence and progression11, and restaging TUR at 2-6 weeks in patients with high
grade disease, bulky multi-focal tumors, and T1 disease has become standard of care. In
particular, patients with T1 disease and no muscle in the specimen represent an at risk
group for under staged disease and a restaging TUR can often select patients with
previously undiagnosed muscle invasive disease or at high risk of progression who
should undergo immediate cystectomy12. Compared with conventional white light
cystoscopy, photodynamic diagnosis (PPD) with blue light and photosensitizing agents
such as hexaminolevulinate or 5-aminolevulinic acid have been shown to improve the
visualization of bladder tumors (in particular CIS), to reduce residual tumor rates
following resection, and improve recurrence free survival. Although associated with an
increased number of false positive biopsies, utilizing of PPD is increasing both in the
United States and Europe13.
Intravesical Therapy
Since the 1970s, perioperative instillation of chemotherapy immediately
following TUR has been advocated to destroy residual microscopic tumor cells and to
prevent re-implantation. Intravesical therapy with immunomodulating and
chemotherapeutic agents has also been employed in an induction and/or maintenance
fashion to provide long-term immuno-stimulation of chemotoxicity in an effort to
prevent disease recurrence14. Chemotherapeutic agents are preferred to BCG in the
immediate perioperative period due to reduced risks of systemic absorption following
TUR. In a meta-analysis of 7 randomized trials comparing TUR alone to TUR plus one
immediate instillation of chemotherapy (most commonly Mitomycin C), Sylvester et al.
reported a 39% reduction in risk of recurrence (OR 0.61, p<0.0001), particularly in
patients with solitary lesions15. Based on these data, the current AUA superficial bladder
cancer guidelines recommend that a single dose of intravesical chemotherapy be
administered immediately postoperatively (<6hrs) in patients with small volume solitary
tumors when there is no evidence of bladder perforation5.
In large meta-analyses, intravesical administration of BCG as induction therapy
for NMIBC has been shown to delay the time to first recurrence16 and may reduce the
risk of disease progression17. Of importance, these benefits were only seen in patients
receiving maintenance therapy and there was no effect in overall or disease specific
survival. Induction treatment regimens of BCG typically begin 2 to 4 weeks following
resection and are most commonly administered weekly for a six week interval.
However, although response has been demonstrated with maintenance therapy, there
is debate as to optimal dosing schedule and controversy remains regarding its long-term
effects on disease recurrence and progression18. The use of BCG can be limited by its
side effect profile and subsequent intolerance that occurs in approximately 20% of
patients during induction or maintenance therapy, and a substantial proportion of
patients recur or progress despite BCG therapy5. In patients refractory or intolerant to
BCG, Mitomycin C, BCG plus interferon α2b, gemcitabine and anthracyclines
(doxorubicin, epirubicin, valrubicin) have demonstrated durable clinical responses in
select patients. Phase I trials investigating alternative cytotoxic agents such as
apaziquone, taxanes (docetaxel, paclitaxel), and suramin are reporting promising data.
Novel immunomodulating agents have demonstrated promise as efficacious alternatives
in patient’s refractory to BCG who will not tolerate a cystectomy14.
Surveillance
Surveillance cystoscopy is essential after TUR to detect tumor recurrence. Per
the NCCN bladder cancer guidelines, patients with NMIBC should undergo cystoscopy
every 3 months for 1-2 years, then every 6 months for 2 years, and annually thereafter.
Urine cytology should be evaluated with each cystoscopy. If recurrent disease is
detected, surveillance should be re-initiated starting at 3 month intervals19. Although
the timing is subject of debate, imaging to detect upper tract recurrence is mandatory in
patients with high grade disease. In these cases imaging should be performed at 1-2
year intervals, and can consist of intravenous pyelography, renal ultrasound, or CT/MR
Urography in patients with adequate renal function 3.
Role of Early Radical Cystectomy
There is increasing evidence that intravesical therapy, while effectively reducing
recurrence rates, may not show a definitive disease progression or survival benefit in
patients with NMIBC. In addition, recent data has shown a disturbing trend towards
decreasing disease free survival rates in patients with T1 disease undergoing radical
cystectomy following intravesical therapy20. Of significant concern in these patients is
the high prevalence of clinical understaging5, which supports the consensus that the
timing of radical cystectomy for high grade NMIBC is critical to prognosis and long term
survival. Early cystectomy has been shown to result in better outcomes in patients with
BCG refractory T1 disease as well as CIS21. Furthermore, the case for performing early
cystectomy in appropriate surgical candidates is strengthened by recent reports
demonstrating improved perioperative morbidity and mortality rates22 as well as
improved patient satisfaction following orthotopic urinary diversions23. While
intravesical therapy is an important component of the oncologist’s armamentarium in
the treatment of superficial bladder cancer, a radical cystectomy should be considered
in all patients who have failed conservative management or who have T1 high grade
disease and tumor characteristics with high prognostic risk for progression such as
histologic variants (squamous, sarcomatoid or micropapillary elements) or extensive
lymphovascular invasion.
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Marc C. Smaldone, MD
Fellow in Urologic Oncology, Fox Chase Cancer Center