THERAPY FOR UROTHELIAL CARCINOMA OF THE URINARY BLADDER: A CRITICAL REVIEW
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DAHER C. CHADE,
SHAHROKH F. SHARIAT, GUIDO DALBAGNI
Sloan-Kettering Institute (DCC) and Urology Service (SFS,
GD), Memorial Sloan-Kettering Cancer Center, New York, NY, USA
management of non-muscle-invasive urothelial carcinoma of the bladder
(UCB) is a challenge for physicians and patients alike. This is largely
due to the heterogeneous natural history of this disease, in which tumors
range from indolent to rapidly progressive and eventually fatal. Moreover,
the high rate of recurrence and progression cause significant morbidity,
expense, and detriment to quality of life. The advent of effective and
safe intravesical therapies has improved the management of non-muscle-invasive
UCB. Nevertheless, despite over 30 years of research and clinical experience,
the mechanism, risks, benefits, and optimal regimens and treatment algorithms
remain unclear. Although immunotherapy with bacillus Calmette-Guerin (BCG)
has been the mainstay of intravesical treatment and represents a significant
advance in the interaction of immunology and oncology, its clinical effectiveness
is accompanied by a wide range of adverse events. Here, we review the
literature on intravesical immunotherapy and chemotherapy with the aim
of evaluating the clinical utility of the different treatments and providing
recommendations. Many studies over the years have compared efficacy and
toxicities of different agents and regimens, and certain conclusions are
now well supported by high-level evidence. Future perspectives and promising
advances in drug development are discussed and areas of improvement are
identified in order to promote better cancer control and decrease the
rate and severity of side-effects.
words: urinary bladder neoplasms; mycobacterium bovis; administration,
intravesical; neoplasm recurrence, local; antineoplastic agents
Int Braz J Urol. 2009; 35: 640-51
than 357,000 new cases are diagnosed worldwide, and more than 145,000
deaths are related to urothelial bladder cancer (UBC) each year (1). The
main risk factor for UBC is tobacco, which is thought to be responsible
for at least one third of the cases. Males are three to four times more
likely to develop UBC than their female counterparts. This discrepancy
has been partially attributed to the higher proportion of smokers among
males (1). At presentation, approximately 30% of patients have muscle-invasive
UBC (cT2 or higher) and 70% have non-muscle-invasive UBC, of which 70%
is pTa disease, 20% is pT1 disease, and 10% is carcinoma in situ (CIS)
(2). Both the natural history of non-muscle-invasive UBC and its treatment
strategies are highly variable. Although some patients never experience
disease recurrence, others experience disease progression and eventually
die of their disease (3). In the absence of intravesical treatment, a
patient with non-muscle-invasive UBC has a 47% probability of disease
recurrence within 5 years of diagnosis, and a 9% probability of progression
to muscle-invasive disease within that period (4).
There are few evidence and risk-based tools
to help with decision-making for patients with non-muscle-invasive UBC.
Factors predictive of outcome include clinical and pathologic features
and molecular markers such as cytology, NMP22, and FISH. While management
of cTa low-grade UBC is relatively non-controversial, the best management
of patients with high-grade cTa, CIS, or cT1 UBC has not yet been established.
The development and testing of effective intravesical therapies for non-muscle-invasive
UBC are still evolving. Indeed, major controversies still exist with regard
to the indication, type, and regimen of intravesical therapy. Other areas
of controversy are the criteria for response/failure of treatment and
for decisions regarding secondary intravesical therapy versus radical
cystectomy. In this article, we analyze the different intravesical therapeutic
strategies and critically compare their oncologic efficacy.
Intravesical BCG Immunotherapy
first BCG strain was isolated in 1921 by Albert Calmette and Camille Guerin
at the Pasteur Institute in France by attenuating the Mycobacterium bovis
bacillus, resulting in a live vaccine against tuberculosis (5). Subsequently,
laboratory and clinical studies demonstrated an anti-tumor effect of BCG
against several malignant cell lines (6-9). In 1976, Morales et al. reported
the first successful clinical study, where they evaluated nine patients
with recurrent UBC treated with intravesical BCG once a week for 6 weeks,
achieving a complete response in seven patients (78%) (10). In the following
years, both the Southwest Oncology Group (SWOG) and Memorial Sloan-Kettering
verified the efficacy of the Morales regimen against UBC in larger, well-designed
trials (11-14). These studies have led to the broad acceptance and application
of BCG intravesical therapy for muscle-invasive UBC. Currently, multiple
substrains of BCG are in use for intravesical immunotherapy throughout
the world; these include Pasteur, Armand-Frappier, TICE, RIVM, Glaxo,
Tokyo, as well as others (15). Several trials have compared strains, with
different dosages and regimens, showing comparable clinical results (16).
Several well-designed clinical trials have
directly compared transurethral resection (TUR) alone with TUR followed
by induction BCG. They have unanimously demonstrated a statistically significant
reduction of approximately 32% in UBC recurrence rates, with the rates
for BCG-treated patients ranging between 20% and 57% at median follow-ups
of 2 to 7 years (11,17-20). The median time from TUR to first recurrence
was prolonged from 1-2 years with TUR alone to 2 to 4 years with TUR plus
intravesical therapy. It has been shown that the use of BCG was associated
with a relative risk for UBC recurrence of 0.39 (21,22). These encouraging
results were sustained even in patients with recurrent or aggressive disease,
including patients whose prior intravesical chemotherapy had failed (11,23).
While reducing and/or delaying disease recurrence
is an important endpoint for the management of patients with non-muscle-invasive
UBC, an even more important endpoint is preventing progression to higher
stage disease. Addition of intravesical BCG to TUR lowers the progression
rate by a statistically and clinically significant margin. A large meta-analysis
involving 4,863 patients from 24 clinical trials revealed a 27% reduction
(9.8% vs. 13.8%) in the odds of disease progression at a mean follow-up
of 2.5 years for patients treated with TUR plus BCG (induction and maintenance)
compared to those treated with TUR alone (24). The corresponding reduction
in the risk of death due to bladder cancer was 19%; this effect was, however,
not statistically significant. More recently, a meta-analysis of 25 trials
including 4,767 patients confirmed these results with an odds ratio of
0.61 for tumor recurrence with TUR plus BCG vs. TUR alone (25). Finally,
combinations of BCG with other intravesical therapies have shown some
early promise. The combination of BCG and interferon, for example, has
shown some potential benefit, with recurrence-free rates of 59% and 45%
in BCG-naïve and BCG-failure patients, respectively, within a 2-year
median follow-up (26).
As with any treatment, optimal response
depends on patient selection. Obviously, residual tumor after an incomplete
TUR will result in treatment failure. Predictors of decreased response
are stage cT1, multifocality, large tumor size, prior BCG failure, short
time to previous BCG failure, and, most importantly, accurate staging
using re-resection; however, none of these characteristics is an exclusion
criterion. A repeat TUR within around 6 weeks of initial TUR will improve
selection by re-classifying approximately 30% of understaged patients
and eliminating the residual tumor in another 50% (27).
With few exceptions, most investigators
believe that the efficacy of BCG therapy can be maximized with maintenance
therapy (28). Indeed, in an EORTC meta-analysis, Sylvester et al. reported
that only trials involving maintenance therapy showed a significant decrease
in disease progression for BCG plus TUR compared to TUR alone (odds ratio
0.63) (24). Even in patients with CIS alone, maintenance therapy with
BCG results in the highest reduction of disease recurrence and progression
rates (29). Therefore, based on these and other studies, the European
Association of Urology and American Urological Association uniformly recommend
at least a year of maintenance therapy for all high-risk patients getting
BCG. The optimal maintenance schedule remains undecided. The SWOG program
is the most widely applied schedule, with 3-week mini-series given at
scheduled intervals of 3,6,12,18,24,30, and 36 months (30).
The toxicities of BCG therapy vary from
local urinary symptoms to severe inflammatory response. Most patients
develop self-limited cystitis that may increase in intensity with later
treatments (31,32). Systemic manifestations present as fevers, chills,
flu-like malaise, and rarely muscle and/or joint pain. Fever after BCG
therapy is not always a sign of systemic BCG infection since most fevers
are limited to 24 hours’ duration (33). However, patients with fever
lasting beyond 24 hours, especially if the fever persists more than 48
hours or has an intermittent evening pattern, are more likely to have
systemic BCG infection. These patients usually require hospitalization
and the administration of anti-tuberculosis agents, which in some cases
should be accompanied by a short period of fluoroquinolone and systemic
steroids (34). A progressively increasing symptomatology with each BCG
cycle should prompt a delay, a lower dose, or interruption of BCG instillations,
which may preclude long-term complications related to the immunotherapy.
Reiter’s syndrome (urethritis, arthritis, conjunctivitis) may occur
during BCG treatment; if it does, interruption of the schedule is mandatory
The tolerability of BCG can be improved by dose reduction, with one-third
the standard dosage associated with a 30% to 50% reduction in toxicity
with near equivalent efficacy (36).
antineoplastic agents have been tested for the treatment of non-muscle-invasive
UBC. Mitomycin C (MMC) is the most commonly used intravesical chemotherapy
to date. Alternative agents are gemcitabine, doxorubicin, and epirubicin
(not approved for clinical use in North America).
MMC is an anti-tumor antibiotic, which acts
by inhibiting DNA synthesis. A review of nine randomized trials (n = 1,774)
revealed that only five were able to show a statistically significant
benefit in using intravesical MMC after TUR compared to TUR alone. The
average recurrence rate was 54% in the TUR alone group versus 38% in the
TUR plus MMC group (37). Dysuria and frequency were the most common side-effects,
occurring in 41% of the patients (38). Response rates have varied widely
across studies, due in part to differences in MMC preparation and protocol.
Recently, Gao et al. demonstrated that tumor uptake and consequently oncologic
efficacy of intravesical MMC were proportional to the drug concentration
(39). In an attempt to optimize MMC delivery, a multi-institutional phase
III trial was carried-out randomizing patients to the standard regimen
versus the optimized regimen (40 mg MMC in 20 mL of sterile water, manipulations
to reduce urine production, and alkalinization of urine). The recurrence
rate at 5 years was decreased from 75% for the standard regiment to 49%
for the optimized regimen. Moreover, the median time to recurrence was
delayed from 12 to 29 months (40).
The optimization of intravesical chemotherapy
with MMC consists of increasing the urinary pH, reducing the volume of
urine production and buffering the intravesical content. This is achieved
by restricting fluids for 8 hours before and during the treatment, oral
sodium bicarbonate starting 12 hours prior to, until immediately before
the instillation, and emptying the bladder with an urethral catheter before
While MMC has been shown to decrease the
risk for disease recurrence (by ~14%), the more important question for
the management of patients with non-muscle-invasive UBC is whether MMC
reduces tumor progression and mortality. A meta-analysis of 22 prospective
randomized trials including 3,899 patients did not show any decrease in
the risk of tumor progression with addition of MMC to TUR compared to
TUR alone (41). Similarly, addition of MMC to TUR did not improve survival
in an analysis of four EORTC and two Medical Research Council randomized
trials including 2,535 patients with Ta and T1 UBC (4). Huncharek et al.
performed a meta-analysis of 11 randomized trials comparing patients treated
with intravesical chemotherapy after TUR versus TUR alone; the study focused
on primary TUR, excluding patients with recurrent disease (42). The authors
reported that addition of chemotherapy to TUR decreased the risk of tumor
recurrence at one year by 44%. Patients receiving chemotherapy for two
years showed the greatest decrease in recurrence rates. In a follow-up
meta-analysis of eight chemotherapy studies focusing on patients with
recurrent tumors, Huncharek et al. found a 38% reduction in the risk of
disease recurrence at one year; this rate improved with prolonged treatment
beyond 2 years (43). In these studies, doxorubicin appeared to be less
effective than MMC.
Although earlier reports suggested that
the beneficial effects of adjuvant intravesical chemotherapy are temporary,
several studies have since demonstrated durable effects. A trial comparing
one and five instillations of MMC after TUR versus TUR alone demonstrated
a decrease in the recurrence rate after a median follow-up of seven years
(20,42). Similarly, a phase III trial comparing a standard versus an optimized
dose of MMC showed a decreased recurrence rate at five years for the optimized
dose (12). The role of maintenance chemotherapy and sequential chemo-immunotherapy,
however, remains unclear.
The common indications of adjuvant intravesical
chemotherapy instillations are directly related to the risk of tumor recurrence
and progression. Despite no clear evidence of reducing progression rates
with chemotherapy, classifying the patients according to their risk is
essential to improve the outcomes. Both intermediate- and high-risk groups,
defined by multiple tumors, tumor size > 3 cm, prior recurrence rate,
T1, CIS, and grade (EORTC risk tables), are eligible for intravesical
chemotherapy. However, patients at high-risk of progression should certainly
consider intravesical immunotherapy, due to the lack of evidence supporting
the efficacy of chemotherapy in this setting (42,43).
Finally, although single instillations are
not the focus of this review, ample evidence shows that the immediate
single post-operative instillation of chemotherapy reduces the recurrence
rate when compared to TUR alone. Authors have shown a recurrence risk
reduction by half at 2 years of follow-up and over 15% reduction at 5
years, rendering a routine recommendation for single post-operative instillation
of MMC in Ta low-risk patients (44). The timing of the instillation has
previously been evaluated by a large meta-analysis of randomized clinical
trials, which showed to be sufficient if performed within the first 24
hours after the TUR (45). Complications have been rarely reported, except
when bladder perforation occurs (44). The results are best in patients
with a single small tumor that was entirely resected (45). However, this
has shown a relatively low acceptance by the urological community to the
routine use in clinical practice.
Recently, Dalbagni et al. tested the efficacy
of intravesical gemcitabine in patients with BCG-refractory, high-risk
non-muscle-invasive bladder cancer in a phase II prospective trial. Results
showed that 50% of patients had a complete response and 21% were free
of disease at one year (46).
Comparison of Intravesical
Chemotherapy and Immunotherapy
will focus on the comparison between BCG and MMC since several studies
have shown the superiority of BCG to other chemotherapeutic agents (47).
A multitude of studies has compared BCG to MMC. While some have found
no significant differences between BCG and MMC, others have shown a greater
reduction in recurrence and progression rates with BCG. This discrepancy
may be attributable, in part, to differences in study design, patient
selection, tumor biology, regimen, and dosages. We note that none of these
studies used the optimal MMC regimen discussed above. Nevertheless, in
patients with CIS, the verdict is largely in favor of BCG over MMC, regardless
of whether the regimen included maintenance therapy.
BCG was superior to MMC in time to recurrence
in two reported large meta-analyses. In a meta-analysis involving 2749
patients with intermediate- to high-risk tumors, Böhle et al. found
a significant superiority of BCG over MMC, with 61% of the patients in
the BCG group and 53% in the MMC group being recurrence-free after a median
follow-up of 29 months (48). The odds ratio was 0.56 in favor of BCG (48).
Interestingly, the recurrence-free advantage of BCG was only seen in those
studies that used BCG maintenance (odds ratio 0.43 for BCG with maintenance
vs. MMC). The trade-off, though, was a 1.8-fold increased risk of cystitis
in patients treated with BCG (53.8% vs. 39.2%). Shelley et al. found no
significant difference in the efficacy between BCG and MMC therapy in
their overall meta-analysis of 1,901 patients (49); however, they reported
a highly significant reduction in recurrence in favor of BCG in a subgroup
analysis involving patients with highly recurrent disease. Böhle
et al. concluded that at least 12 BCG instillations or one-year duration
of therapy were needed to achieve the significant superiority of BCG over
With regard to disease progression, the results for BCG versus MMC are
less clear. Sylvester et al. were able to demonstrate a statistically
significant advantage of BCG versus MMC for disease progression (OR =
0.73) (24). Also, Böhle et al., using a large database, found a statistically
significant reduction in the odds ratio of disease progression for patients
treated with BCG compared to those treated with maintenance MMC (OR =
Given the non-conclusive evidence, MMC should
be considered a viable alternative for patients with papillary tumors
at low or intermediate risk of disease progression. Nevertheless, we lack
level I evidence for this assumption as there are no prospective clinical
trials of optimized MMC.
The clinical management decision in UBC
involves the assessment of individual risk for recurrence and progression
(3). In the low-risk patients, a single immediate instillation of chemotherapy
is recommended (45). However, in the Ta low-grade group, other possible
options are no adjuvant therapy or an induction course of chemotherapy,
while for high-grade or T1 disease BCG is the preferred option. Either
BCG or MMC is recommended for patients with an increased risk of recurrence
but with a low risk of progression (51).
Induction versus Maintenance
Regimens for Immunotherapy
early randomized studies compared no maintenance to maintenance with either
one dose of BCG every 3 months or one dose monthly for 2 years. Neither
trial demonstrated a statistical advantage to maintenance therapy (52,53).
Furthermore, patients in both trials had additional local toxicity attributable
to BCG maintenance. Palou et al., in a large randomized Spanish trial,
reported an 11% overall benefit of routine 6-week courses every 6 months
for 2 years in patients with no evidence of disease 6 months after TUR
and induction BCG, but this difference did not reach statistical significance
Despite the negative results of these early
trials, the SWOG 8507 trial, which was specifically designed to answer
the maintenance question, indicated the utility of BCG maintenance, although
for an alternative schedule (30). Patients were randomized to no maintenance
versus maintenance using mini-series of three weekly treatments administered
at 3 and 6 months, then every 6 months for 3 years. Over a one-year follow-up,
there was a statistically significant difference in favor of maintenance
therapy. Among the 233 patients with CIS, a complete response occurred
in 84% with maintenance BCG therapy versus 68% of patients without (P
= 0.004). Among 254 patients with papillary disease and complete resection
at the time of randomization, 87% of the patients in the maintenance arm
were disease-free at two years compared to 57% without maintenance. A
differential recurrence-free survival rate of at least 20% persisted up
to 5 years. For patients with CIS or papillary disease, median recurrence-free
survival was roughly doubled in the maintenance arm, from 36 to 77 months.
Treatment with maintenance BCG in fact lowered the progression rate by
a statistically significant margin of 6%. However, one quarter of patients
on maintenance therapy experienced grade 3 toxicity, and less than half
completed more than three cycles, with only 16% completing all seven planned
cycles. Since the maintenance group as a whole benefited even without
most patients completing a full 3 years of therapy, maximum benefit may
have been achieved earlier.
Additional, indirect support for BCG maintenance
has come from large meta-analyses of prior clinical trials. As noted above,
Sylvester et al. found that only trials employing maintenance therapy
contributed to the observed benefit of BCG over MMC (24). Similarly, Böhle
et al. found that a statistically significant improvement in tumor recurrence
favoring BCG over MMC was apparent only in trials using at least one year
of BCG maintenance (48).
Malmström et al. recently published
a meta-analysis including 9 trials and 2820 patients (55). Compared to
patients receiving MMC, patients receiving BCG with maintenance had a
32% reduction in risk of recurrence, while patients receiving BCG without
maintenance had a 28% risk increase. Progression did not differ significantly
for either BCG treatment or MMC.
Collectively, these data suggest that BCG maintenance should be considered
in patients with high-risk non-muscle-invasive UBC.
Induction versus Maintenance
Regimens for Chemotherapy
a prospective multicenter study, Huland et al. found no significant difference
in recurrence rate among patients treated with and without maintenance
MMC or doxorubicin (56). Two EORTC prospective randomized trials comparing
early versus delayed and short-term versus long-term (6 versus 12 months)
treatment with MMC and doxorubicin found no significant difference in
the disease-free interval between any of these groups. However, the recurrence
rate was worse among patients with delayed treatment and no maintenance
(57). This was further confirmed by a randomized trial of maintenance
versus no maintenance after early instillation of epirubicin, showing
no difference in disease recurrence (58). In contrast, Koga et al. reported
a higher efficacy for long-term instillation of epirubicin versus short-term
instillation (59). In a prospective randomized trial, the patients received
their first treatment within 24 hours of TUR, followed by epirubicin for
3 months or 12 months. The 3-year recurrence rate was 36% in the 3-month
group versus 15% in the 12-month group. Conrad et al. similarly found
that 3 years of monthly MMC maintenance was superior to no maintenance
(recurrence 14% vs. 31%) in Ta G2/3 and T1 G1-3 tumors at median follow-up
of 2.9 years (60). In a meta-analysis of 11 randomized trials, Huncharek
et al. suggested that chemotherapy for 2 years had the greatest effect
on decreasing the recurrence rates (42). Given these mixed results, the
role of maintenance chemotherapy is not yet clear. Further prospective
randomized trials are needed before recommendations can be made based
on high-level evidence.
More recently, a multi-institutional randomized
phase four trial compared short- and long-term prophylaxis with MMC versus
short-term immunoprophylaxis with BCG in 495 patients (61). In intermediate
and high-risk non-muscle-invasive UBC patients, long-term MMC significantly
reduced the risk of tumor recurrence without increasing adverse events,
with 3-year recurrence-free rates of 86.1% for long-term MMC and 65.5%
and 68.6% for short-term BCG and MMC.
The guidelines and consensus panels on non-muscle-invasive
UBC (American Urological Association, National Comprehensive Cancer Network,
European Association of Urology) did not agree on the optimal maintenance
schedule and duration and therefore do not make any recommendations. However,
the best available data support the use of a six-week induction course
of BCG followed by a maintenance course for at least one year, when compared
to standard MMC treatment (48,50). Nonetheless, there are no reported
studies evaluating optimized MMC regimen in a maintenance schedule in
this setting (51). Moreover, despite published data supporting the use
of maintenance BCG for non-muscle-invasive UBC, the issue remains unclear,
since other randomized trials analyzing induction alone found evidence
of comparable benefits in reducing the progression rate (62). Furthermore,
most of the cases of BCG intolerance occur during maintenance therapy,
contributing to the reluctance by urologists to use this regimen (63).
Intravesical therapy failures indicate the
need to include radical cystectomy as an option in the management decision,
since only half of the patients will respond to conservative treatment
when recurrence is detected at 3 months after a BCG course (64). In this
setting, no strong evidence supports the use of chemotherapy as a first
option, unless the patient has shown evident signs of BCG intolerance.
Ultimately, the risk of BCG toxicity should always be considered when
recommending immunotherapy, and individual assessment is crucial when
selecting therapy for patients at higher risk for recurrence and progression.
great need for improvements is still awaited for the treatment of patients
with UBC. Apart from defining the best regimen with the available drugs,
efforts to increase efficacy have included several promising attempts
to introduce new agents to intravesical therapy, to combine them with
established agents, or to modify current regimens. Future potential means
to improve BCG efficacy can be envisioned based on mechanistic considerations.
One attractive mechanism is enhancing the T helper type 1 (TH1) regulatory
cytokine cascade. Toward this goal, the activity of inhibitory mediators
such as interleukin-10 and PGE2 can be decreased by interferon-γ and nonsteroidal
anti-inflammatory drugs, respectively. Addition of stimulatory cofactors
such as interferon-γ, interleukin-2, and GMCSF have similarly been shown
to increase the TH1-inducing effects of BCG (65). Identifying BCG resistance
mechanisms remains a high priority. A novel possibility for boosting BCG
anti-tumor activity is enhancing effector processes via death domain receptors/apoptosis
signaling suspected of being operative during BCG therapy. While some
drugs such as COX-2 inhibitors have been found to promote these effects,
novel inhibitors of apoptosis inhibitors (such as survivin, XIAP) have
the potential for doing even more. Finally, there is the prospect of genetically
modifying BCG’s properties to express tumor-associated antigens,
thereby creating a more specific cancer vaccine.
Aiming to further increase the antineoplastic
immune response, investigators have developed several recombinant vaccines.
A recombinant BCG that expresses pertussis toxin, tested in an orthotopic
animal model, had significant impacts on tumor weight and survival (66,67).
Also, data published by Liu et al. suggest promising results with recombinant
BCG that secretes human interferon-α2B, which stimulates TH1-type immune
Several novel compounds have been proposed
for the management of non-muscle-invasive bladder cancer. An agent derived
from the mycobacterial cell wall-DNA complex has entered clinical testing.
Patients receiving 4 and 8 mg achieved complete response rates of 27.3%
and 46.4%, respectively (69). Although recent studies have been reported
for several other compounds, as yet no published evidence supports their
intravesical BCG immunotherapy results in a sustained and significant
long-term reduction of disease recurrence in intermediate- and high-risk
UBC patients. Three meta-analyses confirmed that BCG after TUR is superior
to TUR alone or to TUR and chemotherapy in preventing recurrences. Two
meta-analyses demonstrated that maintenance BCG prevents, or at least
delays, the risk of tumor progression, suggesting that progression-free
survival seems to be improved. Clinical guidelines recommend that patients
at intermediate or high risk of recurrence and at intermediate risk of
progression should be treated with BCG or MMC. This recommendation is
based on meta-analyses showing that chemotherapy delays the time to first
recurrence after TUR. Chemotherapy has not, however, been shown to influence
either the time to progression to muscle-invasive disease or survival.
Despite currently perceived superiority of BCG therapy might be an artifact
resulting from prior chemotherapy failures reported in several studies,
most evidence has pointed to higher efficacy for BCG compared to most
chemotherapies. A meta-analysis of seven trials concluded that tumor recurrence
was significantly reduced with BCG compared to MMC only in the subgroup
of patients at high risk of tumor recurrence. In addition, only BCG regimens
that include maintenance appear to be superior to MMC, recently confirmed
in another large meta-analysis. Nonetheless, no studies have shown statistically
significant differences between BCG and MMC in progression, cancer-specific
survival, or overall survival.
Choosing the best treatment for patients
with non-muscle-invasive UBC depends on a number of factors. Patients
with low-risk non-muscle-invasive tumors (small, single tumor of low grade)
respond to intravesical therapy, but the low progression rate (less than
5%) does not justify treatment. Intermediate-risk patients (recurrent
and/or multifocal and/or large tumor of low grade) should undergo an initial
trial of intravesical therapy with BCG or MMC. High-risk patients (CIS
or cT1) should be treated with BCG, according to the guidelines of both
the European and American Urological Associations (51,70). To improve
outcomes of patients with non-muscle-invasive UBC, better drugs, regimens,
and molecular-based patient selection are still needed.
by The Sidney Kimmel Center for Prostate and Urologic Cancers. Chade is
a post-doctoral research fellow in urologic oncology supported by CAPES.
Shariat is a fellow in urologic oncology supported by NIH T32-CA82088.
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June 20, 2009
Dr. Daher C. Chade
Sidney Kimmel Center for Prostate &
Memorial Sloan-Kettering Cancer Center
353 East 68th Street
New York, NY 10065, USA
Fax: + 1 646 422-4394
In the review by Chade et al., the authors highlight
our current state of knowledge with regards to intravesical therapy for
urothelial carcinoma of the bladder. Since the landmark paper by Morales
et al. [ref 10] in over 30 years pertaining to intravesical BCG in the
management of bladder carcinoma, there have been significant advances
in our understanding of the tumor biology and treatment indications for
intravesical therapy. However, current instillation therapeutic agents
have limitations including: 1) potentially delaying definitive therapy
at a time when the disease may be curable, 2) their potential local and
systemic toxicity, and 3) cost of repeated instillation therapy and subsequent
requirement for disease surveillance. Certain patients with high-grade
disease (clinical stage T1G3 with or without concomitant carcinoma in
situ) refractory to repeated courses of induction BCG are best served
with radical cystectomy. Similarly, certain histological variants of bladder
carcinoma (e.g. micropapillary) are refractory to current intravesical
agents and should be treated by early radical cystectomy. Although certain
technical factors may optimize the efficacy of intravesical therapy (e.g.
urine alkalinazation, dehydration, etc.), their treatment-specific outcomes
have not significantly improved over the past decade. Hence, future clinical
applications of intravesical therapy will likely need to take into account
the clinical features and genetic signature of a bladder tumor in order
to identify the patients best suited for intravesical therapy as well
as select the most effective instillation agent and treatment regimen
for that specific patient. This personalized approach to genitourinary
oncology will likely revolutionize our practice patterns in the years
Philippe E. Spiess
Division of Urologic Oncology
H. Lee Moffitt Cancer Center
Tampa, Florida, USA