Download Noninvasive Bladder Cancer: Diagnosis and

Case-based review
Noninvasive Bladder Cancer: Diagnosis and
Management
Emily Blum, MD, and Frank N. Burks, MD
Abstract
• Objective: To review the diagnosis and management
of noninvasive bladder cancer.
• Methods: Literature review.
• Results: Nonmuscle invasive bladder cancer is a
common malignancy that affects more men than
women. It is estimated that smoking accounts for
half of all cases. Direct visualization of the bladder
mucosa remains the standard in diagnosing bladder
malignancy. The natural history of superficial bladder
cancer is characterized by disease recurrence and
disease progression. First-line treatment of patients
with noninvasive bladder cancer is transurethral resection of bladder tumor. Adjuvant treatment with
intravesical chemotherapy and immunotherapy has
become an important component of therapy.
• Conclusion: The results of ongoing studies are eagerly anticipated and will improve our understanding
of the disease.
N
onmuscle invasive bladder cancer is a common
malignancy and the second most common
urologic malignancy after prostate cancer. It
accounts for approximately 73,500 new cancer diagnoses
yearly in the United States [1]. An estimated 14,880
persons die each year as a result of the disease. Despite
improvements in diagnosis and management of noninvasive bladder tumors, the risk of both recurrence and
progression remains significant. In this article, we review
the etiology, diagnosis, and management of noninvasive
bladder cancer.
EPIDEMIOLOGY AND risk factors
Bladder cancer affects men more commonly than women,
with an approximate 3 to 4:1 ratio [1,2]. The incidence
in men over the past 8 years has been stable, and the incidence in women has decreased by 0.3% over the same
time period. Bladder cancer affects Caucasians twice as
often as African Americans, and affects Hispanics and
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Asians even less frequently than African Americans [2].
More than 90% of patients diagnosed with bladder cancer
will be older than 55 years of age.
Histologically, urothelial (transitional cell) carcinoma
accounts for over 90% of all diagnosed bladder cancers [3].
Other subtypes in order of prevalence include squamous
cell carcinoma, adenocarcinoma, and small cell carcinomas. Of those diagnosed with urothelial carcinoma,
nonmuscle invasive (superficial) bladder cancer (NMIBC)
accounts for almost 75% of cases [2]. Muscle invasion is
seen in 20% of newly diagnosed cases, and metastatic disease is seen approximately 5% of the time.
It is estimated that smoking accounts for half of all
cases of bladder cancer, with smokers having a 2- to
6-fold greater risk of bladder cancer as compared with
nonsmokers [4–6]. At 25 years after smoking cessation,
the risk of bladder cancer continues to decrease but is still
higher than that of nonsmokers [7]. Continued smoking
despite the diagnosis of urothelial carcinoma increases the
risk of recurrence 2.2-fold [8].
Environmental exposures also have been linked to the
development of urothelial carcinoma, particularly exposure to aromatic amines [9]. Occupations associated with
an increased risk of bladder cancer include tire/rubber
workers, leather workers, textile workers, hairdressers,
painters, dry cleaners, and chemical workers.
Exposure to certain medications has been associated
with an increased risk of bladder cancer, including the
analgesic phenacetin, which has since been taken off
the market [10]. Additionally, patients treated with the
chemotherapeutic agent cyclophosphamide have a higher
risk of bladder cancer, with a dose-response relationship
between cyclophosphamide and the risk for bladder cancer [11,12]. The increased risk of bladder cancer and risk
of hemorrhagic cystitis associated with cyclophosphamide
therapy is secondary to exposure to the urinary metabolite
From the William Beaumont Hospital, Royal Oak, MI.
Vol. 21, No. 9 September 2014 JCOM 409
NonInvasive Bladder cancer
Table 1. Risk Factors for Malignancy According to
American Urological Association Guidelines
Male gender
Age > 35 years
Current or former smoker
At risk chemical or dye exposure
Analgesic abuse
Hematuria is the most common presenting feature of
bladder cancer. It is present as the initial symptom in up
to 90% of patients with urothelial carcinoma [18]. Other
symptoms include irritative voiding symptoms such as
urgency, frequency, and dysuria. Irritative voiding symptoms tend to occur more commonly with carcinoma in
situ [19].
Gross hematuria
History of urologic disease
Irritative voiding symptoms
Pelvic irradiations
• What are the next steps in the workup of this
patient?
History of chronic urinary tract infections
History of exposure to known carcinogens
History of chronic indwelling foreign body
Adapted from Davis R, Jones J, Barocas DA, et al. Diagnosis,
evaluation and follow-up of asymptomatic microhematuria (AMH)
in adults: AUA guideline. J Urol 2012;188(6 Suppl):2473–81.
acrolein. Concomitant administration of sodium 2-mercaptoethanesulfonate (MESNA) provides regional detoxification of acrolein in the urinary tract [13].
Urothelial carcinoma does not have a strong inherited
disease association. It is felt, however, that there are 2
separate molecular pathways that may lead to the development of bladder cancer [14]. Mutation of the p53 gene
has been shown to be associated with carcinoma in situ
and invasive disease, whereas mutation of FGFR3 is seen
more frequently with Ta disease [15]. Accumulation of
p53 in cell nuclei is an independent predictor of tumor
recurrence and overall poor prognosis [16]. The identification of molecular markers of tumor progression is an
active field of research in bladder cancer [17].
Risk factors are summarized in Table 1
Case Patient 1
Initial Presentation and Evaluation
A 63-year-old man with a 60 pack-year history of
smoking presents to a urologist with a urinalysis
from his primary care physician showing 20 to 50 red
blood cells per high-power field (RBCs/HPF). He denies
any urgency, frequency, or recent urinary tract infections.
A urine culture from his primary care doctor is negative.
• What are the common presenting features of
bladder cancer?
410 JCOM September 2014 Vol. 21, No. 9
Initial Evaluation
American Urological Association (AUA) guidelines for
the evaluation and management of asymptomatic microhematuria were updated in 2011 [20]. They recommend
that every patient who presents with microscopic hematuria (> 3 RBCs/HPF) undergo a thorough history and
physical exam, including rectal exam and bimanual evaluation in females to assess for any masses or pelvic fixation. Once benign sources of hematuria (eg, infection,
menstruation, vigorous exercise, medical renal disease,
viral illness, trauma, or recent urological procedures)
have been ruled out, further testing will include a renal
function panel, upper tract imaging, as well as cystoscopy
in high-risk patients and those older than age 35 years.
Urine cytology may be utilized in high-risk patients,
but it is no longer generally recommended for routine
workup.
Imaging
The imaging modality of choice during the hematuria
workup is the computed tomography urogram (CTU), a
multiphasic CT scan that images the urinary tract before
and after contrast administration and includes excretory
stage imaging [21]. Sadow et al found that CTU had a
negative predictive value (NPV) of 95% for the detection of bladder cancer, while cystoscopy had an NPV of
99% [22]. In addition to radiographic evaluation of the
urinary system, CT offers useful staging information regarding metastatic disease. In patients with renal failure
or other contraindications to CTU, magnetic resonance
urography (MRU) has become an acceptable alternative
for hematuria evaluation. MRU allows for improved
characterization of tissue and does not utilize ionizing
radiation. During MRU, the high T2 signal intensity
of urine is utilized to provide contrast in the images in
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Case-based review
static phase MRU and after gadolinium administration
for excretory-phase MRU [21]. The bladder is typically
best evaluated in T1-weighted images a few minutes after
gadolinium administration, before the contrast reaches
the bladder; it may also be evaluated during the late excretory phase when signal enhancement from gadolinium
is greatest. The effectiveness of MRU in collecting system
evaluation is still evolving, and therefore, in appropriately
selected patients who would benefit from further collecting system evaluation, MRU should be utilized in
conjunction with retrograde pyelograms [20]. Though
previously considered the gold standard in imaging,
intravenous pyelography is no longer a recommended
imaging modality for hematuria evaluation.
Urine Cytology and Urine Markers
Urine markers and urine cytology are a debated topic in
the workup and follow-up of bladder cancer. Urine cytology evaluates sloughed cells for malignant features [23].
Due to the lack of cohesion of carcinoma in situ cells and
high-grade lesions, these cells are more likely to slough
than are low-grade lesions [24]. The range of sensitivity
of urine cytology reported in the literature varies widely.
Studies report that the sensitivity of urine cytology in
high-grade tumors approaches 95%, and in carcinoma
in situ is up to 100% when 3 consecutive specimens are
obtained [25]. However, Yafi et al recently reported that
the sensitivity of urine cytology in high-grade tumors is
51% and in low-grade tumors is only 10% [26]. It is recommended that urine cytology be evaluated as part of a
hematuria work-up in high-risk patients.
Aside from cytology, more than a dozen urine marker
tests for bladder cancer detection and surveillance have
been developed [27]. Current urine markers tests include
protein-based assays such as the nuclear matrix protein 22
(NMP22) assay (NMP22 Test Kit; Alere, Waltham, MA)
and bladder tumor antigen assays (BTA stat and BTATRAK; Polymedco, Cortlandt, NY) as well as cellular
marker tests such as UroVysion FISH (Abbott Molecular,
Abbott Park, IL) and ImmunoCyt (Scimedx, Denville,
NJ) [27–31]. NMP22 is a nuclear matrix protein that is
elevated in bladder cancer patients, and BTA stat/TRAK
(qualitative/quantitative) detects complement factor H.
Much controversy surrounds the utilization of these markers for screening and monitoring of bladder cancer, and
currently they are not routinely recommended for these
purposes nor are they recommended for follow-up in patients with bowel interposition [32].
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Cystoscopy
Ultimately, direct visualization of the bladder mucosa remains a gold standard in diagnosing bladder
malignancy. Office-based cystoscopy allows for rapid
assessment and also allows biopsy to be performed for
suspicious lesions. It can be performed easily with local
anesthetic.
The use of fluorescence and narrow-band cystoscopy has been evaluated in recent years. The premise of
fluorescence cystoscopy is that there is preferential accumulation of porphyrin in neoplastic cells. Therefore,
intravesically instilled photoactive heme precursors such
as 5-aminolevulinic acid (5-ALA) or hexaminolevulinate
(HAL) have increased uptake within these neoplastic
cells and subsequent enhancement. Preliminary studies
have shown that approximately one quarter to one third
more cases of small papillary tumors and carcinoma in
situ are identified using fluorescence cystoscopy as compared with standard white light cystoscopy [33–36]. In
one prospective study, the use of fluorescence cystoscopy
resulted in a 16% decrease in the recurrence rate [37].
Denzinger et al found that 8-year recurrence-free survival in those who underwent fluorescence transurethral
resection (TUR) was 71% as compared with 45% in
conventional TUR patients [36]. Caution is required,
however, because false-positives may occur in patients
with inflammatory lesions.
Narrow-band cystoscopy works by filtering white
light into bandwidths of 415 and 540 nm, wavelengths
absorbed by hemoglobin. This allows for added contrast
between vascular structures and normal urothelium
[38]. Narrow-band imaging has an advantage over fluorescence cystoscopy in that no preoperative intravesical
instillations are required. Detection rates of NMIBC
were as high as 94.7% with narrow-band imaging, as
compared to 79.2% with white light cystoscopy [39]. In
the case of recurrent low-grade papillary lesions, resection with narrow-band imaging reduces recurrence rates
by approximately 30% when patients are followed for 3
years [40]. While both fluorescence cystoscopy and narrow-band imaging appear to be promising technology,
higher false-positive rates are seen with both as compared
to white light cystoscopy [3,41]. Neither modality is a
recommended treatment option [42].
Case 1 Continued
On office-based cystoscopy, a 2.5-cm papillary
lesion is noted on the left lateral wall of the blad-
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NonInvasive Bladder cancer
der. There are no other suspicious lesions within the bladder. A CTU is obtained, which reveals no hydronephrosis
or lymphadenopathy and correlates with the cystoscopic
examination of a bladder lesion on the left lateral wall.
• What are the next steps in management?
Transurethral Resection
Transurethral resection of bladder tumor (TURBT) is
paramount in the treatment and diagnosis of bladder
tumors. TURBT allows for complete resection of the
tumor and also allows for histologic diagnosis, staging,
and grading. The bladder wall consists of 3 principle layers: the mucosa, submucosa, and muscularis. An important factor in identifying the stage of disease is determining the depth of invasion as well as the size and mobility
of masses. Adequate resection, with inclusion of muscle
in the TURBT specimen, allows for proper staging of
urothelial carcinoma. When pathology reveals high-grade
Ta or T1 disease or does not contain muscle, re-resection
is recommended [42]. In a study involving 150 patients
with bladder tumors, when re-resection was undertaken
within 2 to 6 weeks, 29% of NMIBC lesions were upstaged, and treatment options were changed based on
re-resection results in one third of patients [43].
TURBT is a relatively safe procedure that can be
performed in an outpatient setting. The most common
complications of TURBT are urinary tract infection and
hematuria [44]. Other complications include the risk of
bladder perforation with deep resection. In the event of
bladder perforation, it is important to determine the location and depth of the perforation to decide on appropriate treatment. Many small extraperitoneal perforations
may be managed with simple Foley drainage, whereas
large perforations may require open or laparoscopic repair [45–46]. The incidence of extravesical recurrence of
NMIBC after bladder perforation varies in the literature
from 0% to 6% [47]. Numerous studies report open bladder repair following any intraperitoneal perforation, but
laparoscopic repair is becoming more common [48,49].
In any case of intraperitoneal rupture, the recommendation is for close follow-up for the rare event of recurrence.
While performing TURBT, one must be cognizant
of the obturator nerve reflex. The obturator nerve runs
in close proximity to the inferolateral wall of the bladder.
Stimulation from the electrocautery current will cause
412 JCOM September 2014 Vol. 21, No. 9
external rotation and adduction of the thigh in a sudden
jerking movement, thus increasing the risk of bladder
perforation [50]. Bipolar technology has been found to
be a safe alternative to conventional monopolar electrocautery for resection of bladder tumors, with decreased
length of catheterization and fewer bladder perforations
documented [51]. While bipolar technology may decrease stimulation of the obturator reflex, it is important
to note that it still may occur, resulting in bladder perforation [52.53].
Staging, Grading, and Risk Stratification
The American Joint Committee on Cancer’s staging system, updated in 2010, defines the stage of bladder cancer
based on tumor invasion, node status, and metastasis
present (Table 2). NMIBC is defined as Ta, Tis, and T1
lesions [54].
In 2004 the World Health Organization revised the
classification of urothelial malignancies to include tumors designated as either high- or low-grade as well as
carcinoma in situ [55]. The differentiation of low- and
high-grade is based on the degree of nuclear anaplasia
and architectural abnormalities. Those with high-grade
tumors as well as increased depth of invasion have an
increased risk of recurrence and progression of disease
compared to low-grade tumors [56].
When determining treatment and surveillance options
for NMIBC patients, not only are the stage and grade
determining factors, but future risk of recurrence and
progression dictates treatment options. Bladder cancer
patients may be stratified into low-, intermediate-, and
high-risk groups (Table 3).
Intravesical Chemotherapy/Immunotherapy
Intravesical therapy is the use of chemotherapeutic or immunotherapeutic substances instilled within the bladder.
It is indicated for the treatment of NMIBC but is not the
recommended treatment for T2 or greater lesions. The
goals of intravesical therapy are to reduce recurrence and
progression of resected disease and eradicate carcinoma in
situ as well as incompletely resected papillary tumor [42].
Intravesical chemotherapeutic agents include mitomycin C, thiotepa, doxorubicin, valrubicin, epirubicin,
and gemcitabine [42]. Mitomycin C is an alkylating
agent that acts by inhibiting DNA synthesis. Because of
mitomycin C’s relatively high molecular weight, systemic
absorption is minimal, although there is a small risk of
myelosuppression. Thiotepa is an alkylating agent that
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Case-based review
cross-links nucleic acids. Doxorubicin, epirubicin, and
valrubicin are intercalating agents that inhibit DNA synthesis. Gemcitabine is a deoxycytidine analog that also
inhibits DNA synthesis.
Immunotherapy utilizes bacillus Calmette-Guérin
(BCG), a live, attenuated strain of Mycobacterium bovis.
Though the mechanism of action of BCG is not fully
understood, it is known that instillation of BCG stimulates a large immune response [57]. BCG is taken up by
antigen-presenting cells as well as urothelial cells and
bladder cancer cells, initiating the immune response. Cytokine release in response to BCG is thought to be mediated by macrophages and activated lymphocytes as well as
urothelial cells directly [58]. Recent studies have found
that interleukin-17 plays an important role in neutrophil
recruitment and the generation of the Th1- cell response,
which mediates the antitumor effect [59,60]. The innate
immune response is also felt to be important in the antitumor effect of BCG, with studies suggesting that BCG
is ineffective in the absence of natural killer cell activity
and that neutrophils and macrophages are important in
the immune response [58,61,62].
Administration of BCG is typically held for at least 2
weeks following TURBT to minimize the risk of sepsis and adverse events. BCG also should not be used in
patients who have had traumatic catheterization, recent
gross hematuria, or urinary tract infection, in immunocompromised hosts, or in patients with active autoimmune
disease, known allergy, or history of BCG sepsis. Adverse
events associated with BCG use include sepsis, prostatitis,
epididymitis, cystitis, and flu-like symptoms [63].
Interferon alpha-2b is a cytokine that helps modulate
the immune response. In cases of refractory bladder
cancer that have failed BCG treatment, modulation with
interferon alfa-2b therapy has been investigated. In vitro
studies show that administration of interferon alfa-2b
enhanced the ability of BCG to induce interferon-gamma
production, upregulated tumor necrosis factor-α and
interleukin-12, and down-regulated interleukin-10, thus
favoring the upregulation of the Th1 immune-mediated
response [64]. Used in conjunction with BCG in patients
who have failed BCG therapy, interferon alfa-2b has been
shown to have a 2-year recurrence-free survival rate of up
to 45% [65].
Immediately following TURBT, it is recommended
that patients with low-risk disease undergo single-dose
intravesical chemotherapy [66]. When performed within
24 hours (and ideally 6 hours) of resection, intravesiwww.jcomjournal.com
Table 2. American Joint Committee on Cancer (2010)
TNM Staging System for Bladder Cancer
T: Primary Tumor
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Ta
Noninvasive papillary carcinoma
Tis
Carcinoma in situ: “flat tumor”
T1
Tumor invades subepithelial connective tissue
T2
Tumor invades muscularis propria
pT2a
Tumor invades superficial muscularis propria (inner
half)
pT2b
Tumor invades deep muscularis propria (outer half)
T3
Tumor invades perivesical tissue
pT3a
Microscopically
pT3b
Macroscopically (extravesical mass)
T4
Tumor invades any of the following: prostatic stroma,
seminal vesicles, uterus, vagina, pelvic wall, abdominal
wall
T4a
Tumor invades prostatic stroma, uterus, vagina
T4b
Tumor invades pelvic wall, abdominal wall
N: Lymph Nodes
NX
Lymph nodes cannot be assessed
N0
No lymph node metastasis
N1
Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph
node)
N2
Multiple regional lymph node metastases in the true
pelvis (hypogastric, obturator, external iliac, or presacral
lymph node)
N3
Lymph node metastases to the common iliac lymph
nodes
M: Metastasis
M0
No distant metastasis
M1
Distant metastasis
Adapted with permission from American Joint Committee on Cancer. Urinary bladder. In: Edge SB, Byrd DR, Compton CC, et al,
editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer;
2010:497–505.
cal chemotherapy has been shown to decrease the odds
of bladder cancer recurrence by up to 40% in low-risk
disease [67]. The mechanism of action of single-dose
intravesical chemotherapy instilled immediately after resection is not definitively known, but it is hypothesized
that it destroys any remaining microscopic disease and
prevents reimplantation of any freely circulating cells
[67]. Single-dose mitomycin C, however, does not decrease the rate of progression in incompletely resected
Vol. 21, No. 9 September 2014 JCOM 413
NonInvasive Bladder cancer
Table 3. Risk Stratification of NMIBC Based on Expert Panel
Review of AUA, EAU, FICBT, and NCCN Guidelines
Low Risk
Intermediate Risk
High Risk
Solitary, primary
low- grade Ta
Multiple or recurrent low-grade tumors
Any T1
Any high-grade Tis
AUA = American Urological Association; EAU = European Association of Urology; FICBT = First International Consultation on
Bladder Tumors; NMIBC = nonmuscle invasive bladder cancer;
NCCN = National Comprehensive Cancer Network. (Adapted from
Brausi M, Witjes JA, Lamm D, et al. A review of current guidelines and best practice recommendations for the management of
nonmuscle invasive bladder cancer by the International Bladder
Cancer Group. J Urol 2011;186:2158–67.)
tumors [68]. Administration of intravesical chemotherapeutic agents should be avoided when there is bladder
perforation [69].
There is some debate regarding the best approach to
treating intermediate-risk bladder cancer. In guidelines
released by the International Bladder Cancer Group, a
group of experts who evaluated and set forth guidelines
based on current recommendations from the NCCN,
AUA, European Association of Urology, and the First
International Consultation on Bladder Tumors, initiation of BCG therapy with maintenance or intravesical
chemotherapy for up to 1 year of adjuvant treatment is
recommended following the diagnosis of intermediaterisk bladder cancer [66]. Induction treatments are single
intravesical instillations administered weekly for 6 weeks
and begun 2 to 4 weeks after resection. Maintenance
courses consist of once weekly instillations for 3 weeks
undertaken at 3 months, 6 months, and then every 6
months for up to a total of 3 years of treatment [70].
For the management of high-risk disease, most guidelines concur that the optimal treatment is BCG with
maintenance, although the recommended length of
maintenance varies from 1 to 3 years [66]. The EORTCGU recently reported the results of a randomized study
in which high-risk Ta and T1 lesions were treated with
BCG maintenance; they found that a full-dose, 3-year
maintenance course of BCG decreased recurrences without increasing toxicity [71].
Although both intravesical chemotherapy and immunotherapy are recommended treatments for NMIBC,
there is a preference in the published guidelines toward the use of BCG over intravesical chemotherapy.
In multiple meta-analyses, BCG, and especially BCG
with maintenance, has been shown to have improved
414 JCOM September 2014 Vol. 21, No. 9
disease-free recurrence when compared with intravesical
chemotherapy [72,73]. Malmström et al showed a 32%
reduction in the recurrence rate in BCG-treated patients
compared with those treated with mitomycin C [74].
Similarly, high-risk patients treated with gemcitabine
therapy had a higher recurrence rate and more rapid time
to recurrence as compared with those treated with BCG
therapy; in intermediate-risk patients, the rate of recurrence was not statistically significant [75].
Cystectomy
In certain high-risk patients, it is also appropriate to
offer cystectomy as initial therapy. Though much more
invasive than other treatment options, it does offer a
chance for cure in a select group of patients with high
likelihood of progression of disease. Risk factors associated with progression and consideration for immediate
or early cystectomy include large tumor size (> 3 cm),
inability to completely resect tumor, difficult resection
site, multifocal/ diffuse disease, presence of carcinoma in
situ, prostatic urethral involvement, female sex, suspected
understaging secondary to lymphovascular invasion, or
unfavorable histology [76–81]. While tumor upstaging
has been noted in up to one-quarter of high-risk immediate cystectomy patients, it is important to note that
multiple retrospective reviews have not found a cancerspecific survival (CSS) benefit to immediate cystectomy
versus conservative treatment [82–85]. Hautmann et
al examined immediate cystectomy versus deferred cystectomy until after recurrence in high-risk patients and
demonstrated a clear 10-year CSS benefit of 79% versus
65% [86]. Because the number of patients who have
undergone immediate cystectomy is still relatively small
and predictors of aggressive disease are still evolving, immediate cystectomy is still considered a viable treatment
option in the appropriately selected patient.
Case Patient 2
A 72-year-old woman with a history of T1 bladder cancer presents for routine follow-up. She
has completed a course of BCG with maintenance for her
initial lesion. On follow-up cystoscopy, she is found to
have multiple velvety red patches throughout the bladder
and a 1-cm sessile lesion.
• What is the follow-up for bladder cancer?
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Case-based review
Bladder cancer causes what is known as a field defect.
As urine bathes the urothelium, theoretically, so do the
carcinogens within the urine, exposing cells throughout
the bladder. Bladder cancer therefore does not just recur
at the initial site of the tumor, but can occur anywhere in
the bladder. For example, Heney et al found that initial
tumors were only occasionally located at the dome (5%
of the time), whereas new tumor occurrences were found
at the dome in 29% of patients [87].
Though there is no consensus in the literature as
to the ideal timing of cystoscopic follow-up, NCCN
guidelines recommend cystoscopy every 3 months with
increasing intervals as indicated for low-risk lesions [88].
For all other lesions, they recommend cystoscopy and
cytology every 3 to 6 months with increasing intervals as
indicated, upper tract imaging every 1 to 2 years for highgrade tumors, and the optional use of urine markers for
follow-up. The AUA varies slightly in recommending cystoscopy and cytology for all patients every 3 months for
2 years, followed by every 6 months for 2 to 3 years, and
then annually. They recommend imaging of the upper
tracts but do not specify timing, and current recommendations do not support the use of urine markers [89].
• How are recurrences/treatment failures managed?
When recurrence or treatment failure is identified, it is
important to consider the initial lesion and treatment as
well as stage and grade of any follow-up lesions. Low-risk
disease may be treated with re-resection and BCG or mitomycin C with or without maintenance [42]. With treatment failure of intermediate disease, resection followed
by a change in the modality of intravesical treatment is an
option. When recurrences occur in intermediate-risk disease, one might change modalities or reinstitute a second
induction therapy course after resection [66].
High-risk NMIBC provides a challenging dilemma
in management. In a systematic literature review of 19
published trials, van den Bosch and Witjes [90] reported
a 21% progression to muscle-invasive disease in highrisk NMIBC patients. Management of recurrences in
this population in an effort to decrease progression and
increase CSS is a highly debated topic, with no clear answer currently available. In the case of high-risk disease
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that has recurred, treatment options include a second
induction course of BCG, cystectomy, or alternative intravesical chemotherapeutic options. Those patients who
underwent early cystectomy for high-risk recurrence after
BCG therapy had an overall greater survival compared to
those who delayed cystectomy over 2 years [91]. In their
study evaluating early versus delayed cystectomy, Jäger et
al [92] found that as the number of TURBTs performed
before cystectomy for high-risk disease went from 1 to
2–4 to greater than 4, the 10-year CSS decreased from
84% to 77% to 45%. Additionally, they found that when
cystectomy was performed 1 year after initial TURBT,
the 10-year CSS decreased from 79% to 61%.
In patients who have failed BCG treatment and are
not surgical candidates or do not desire surgical intervention, intravesical valrubicin is emerging as a treatment alternative. It is currently the only therapy that is approved
by the U.S. Food and Drug Administration for treatment
of BCG-refractory carcinoma in situ in nonsurgical candidates. Dinney et al examined the efficacy and safety
of valrubicin in BCG-refractory carcinoma in situ and
found an 18% complete response rate over the 6-month
follow-up period, which correlated with the previously
reported response rates in phase II/III trials [93]. Other
therapies being investigated for BCG failure include
thermochemotherapy, photodynamic therapy, as well as
combination intravesical chemotherapies [94].
Conclusion
Though much research is under way on the surveillance,
diagnosis, and treatment of NMIBC, time-tested modalities remain the mainstay of management. Ongoing
studies will improve our understanding of the disease as
new information regarding novel ways of delivering intravesical therapeutics, surveillance modalities, and optimal
treatment and follow-up strategies becomes available.
Corresponding author: Frank N. Burks, MD, 31157 Woodward Ave., Royal Oak, MI 48073, [email protected].
Financial disclosures: None.
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