Review
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CONTENTS
Intravesical chemotherapy
Intravesical immunotherapy
Alternative forms of therapy
Conclusion
Expert commentary &
five-year view
References
Affiliations
†
Author for correspondence
University of Southern California,
Department of Urology, Norris
Comprehensive Cancer Center,
Keck School of Medicine,
Los Angeles, CA, USA
Tel.: +1 323 865 3700
Fax: +1 323 865 0120
david.josephson@usc.edu
KEYWORDS:
bacillus Calmette–Guerin,
bladder, bladder neoplasm,
immunotherapy, intravesical
chemotherapy,
nonmuscle invasive
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Superficial bladder cancer: part 2.
Management.
David Josephson†, Erik Pasin and John P Stein
In the second section of a two-part article, the recent literature is reviewed and the
management of nonmuscle-invasive transitional cell carcinoma of the bladder is
discussed. Particular attention is given to the indications and timing of intravesical
chemotherapy and immunotherapy and the differences in efficacy and side-effect profiles
of the available agents. The indications and role of second-look transurethral resection are
reviewed. Additionally, the role of bacillus Calmette–Guerin in the management of this
disease in terms of definitive treatment and maintenance therapy is discussed. We also
offer a review of the literature regarding therapies for bacillus Calmette–Guerin-refractory
nonmuscle-invasive transitional cell carcinoma of the bladder and their current place
in practice.
Expert Rev. Anticancer Ther. 7(4), 567–581 (2007)
The primary goals of treating patients with second TUR, Schips and coworkers found that
superficial bladder cancer include eradicating up to 17% of patients will have histological
existing disease, preventing tumor recurrence evidence of cancer in prior resection sites [5].
and preventing tumor progression to muscle The risk of finding residual disease is increased
invasion or metastases. Transurethral resection in the context of multifocal high-grade
(TUR) is the preferred initial treatment of tumors. Also, as mentioned previously,
superficial disease, since it allows for adequate approximately half of patients with T1 cancer
histopathological assessment of the lesion. A may have pathological upstaging to T2 disease
properly performed resection should incorpo- at the time of repeat TUR or early
rate detrusor muscle in the specimen in an cystectomy [6]. These inadvertent delays in
effort to rule out T2 disease. Laser fulguration accurate staging may have a significant impact
utilizing neodymium–YAG or holmium on outcomes. Therefore, we share the belief
modalities have also been proposed for the proposed in the recent literature that all
resection of primary lesions [1,2]. There is little patients with either high-grade or T1 compo-
difference in recurrence rates between stand- nents in the original specimen undergo routine
ard electrocautery and laser fulgurations [3]. second resections within 1–4 weeks following
However, the major drawback with laser- initial TUR [7]. Importantly, all T1 or high-
fulguration procedures remains either inade- grade Ta tumors without adequate muscularis
quate or complete lack of tissue for essential propia in the surgical specimen cannot be
grading and staging. Appropriate candidates staged accurately and should therefore also
for fulgurative treatment include patients with undergo reresection with biopsy of the muscle.
low-grade papillary tumors. Adjuvant therapy following TUR is deter-
The role of a second resection soon after ini- mined by clinical and histopathological fea-
tial TUR has recently received more attention. tures. Clearly, not all patients with superficial
In a study of 214 patients with superficial dis- bladder cancer require intravesical therapy.
ease undergoing repeat TUR 4–6 weeks later, Intravesical therapy is reserved for patients at
persistent tumor was found in 27% of pTa and high risk for disease recurrence or progression.
37% of pT1 tumors [4]. In addition, despite a Traditional indications for intravesical therapy
normal cystoscopic examination just prior to a include: multiple and large tumors (>3 cm);
10.1586/14737140.7.4.567 © 2007 Future Drugs Ltd ISSN 1473-7140 567
Josephson, Pasin & Stein
early tumor recurrence; high-grade Ta tumors; any T1
tumor; presence of carcinoma in situ (CIS) or lymphovascu-
lar invasion; or positive urine cytology after resection of all
visible tumor.
Intravesical instillation is a means by which a concentrated
substance can be delivered directly in contact with tumor-bear-
ing bladder mucosa. Intravesical therapy has been applied in a
therapeutic (treatment of residual or unresected disease or CIS),
prophylactic (prevention of the development of recurrent
tumors) and adjuvant manner immediately postoperatively
(theoretically to decrease recurrences by preventing ‘seeding’ of
tumor cells caused by the resection). Intravesical therapy is
divided into chemotherapy and immunotherapy.
Intravesical chemotherapy
The most commonly used agents for intravesical chemother-
apy include thiotepa, adriamycin, mitomycin C and epiru-
bicin. A few basic principles are applicable to all intravesical
agents and should be understood regarding their administra-
tion. Distilled water is the preferred solution for drug dilution.
Diffusion and efficacy of the agent are dependent on the dose,
concentration, molecular weight and lipid solubility [8]. A
higher concentration with minimum dilutional effects will
facilitate flow of the agent across the bladder epithelium. Fur-
thermore, the bladder should be emptied immediately prior to
intravesical administration and patients should be advised to
avoid excessive fluid intake to reduce the dilutional effect in
the bladder following instillation.
The ideal dwell time for intravesical chemotherapeutic agents
is controversial. It is logical that the longer the exposure time
the more the drug will exert its cytotoxic effects. However,
urine production will decrease drug concentration during this
time as well. In patients who experience pronounced side
effects, such as fever, chills and dysuria, after initial intravesical
administration, some have suggested a dwell time of less than
30 min as an alternative to dose reduction [9].
The length of interval following TUR and the duration of
intravesical chemotherapy are other factors to consider. There
are data to suggest that earlier administration of intravesical
therapy may be more effective. In 1992, Bouffiox and associates
reported that patients in European Organization for Research
and Treatment of Cancer (EORTC) trials who received earlier
intravesical chemotherapy (less than 2 weeks following TUR)
had a longer time to recurrence compared with patients who
began intravesical chemotherapy 2 weeks or longer following
the resection of the primary tumor [10]. Similarly, numerous
other randomized studies have shown the therapeutic advan-
tage of early immediate postresection instillation with regards
to decreasing recurrence rate and prolonging the recurrence-
free interval [11,12]. In a meta-analysis of seven published rand-
omized clinical trials involving epirubicin, mitomycin C, thi-
otepa or pirarubicin, Sylvester and associates compared out-
comes of TUR versus TUR plus one instillation of intravesical
chemotherapy in the immediate postoperative setting [13]. Over
median follow-up of 3.4 years, 37% of patients who received
568
one immediate instillation (either immediately after TUR or
within 6 h of surgery) had recurrence compared with 48% of
patients who had TUR alone.
Although a role for an immediate postoperative instillation
has been visibly identified, the role for maintenance intravesical
chemotherapy is not yet clear. Some studies have shown the
efficacy of immediate single instillation to be comparable with
that of conventional delayed weekly instillations, with the
advantage of being more cost effective [14,15]. Lamm and associ-
ates analyzed 3899 patients from 22 randomized prospective
controlled trials and suggested that maintenance intravesical
chemotherapy is less effective than a single postoperative instil-
lation [16]. Also, in an analysis of 834 patients from two
EORTC Phase III trials comparing intravesical mitomycin C
or doxorubicin, maintenance therapy did not have an impact
on recurrence when treatment was administered the day of
resection [17]. In contrast, in a meta-analysis of 3707 patients
from 11 randomized trials, Huncharek and coworkers showed
that long-term maintenance therapy produced a greater reduc-
tion in recurrence rates than short-term therapy [18]. Given
these conflicting results, the definitive use of maintenance
intravesical chemotherapy cannot be recommended until fur-
ther large-scale, prospectively randomized trials are performed.
However, based on grade B and C evidence, the International
Consultation on Bladder Tumors review of low-grade, Ta
urothelial carcinoma of the bladder recommended that these
tumors, which are associated with prognostic factors identified
as at high risk of recurrence (multifocality, previous recurrence
rate and early recurrence), may benefit from further courses of
adjuvant intravesical chemotherapy, the duration of treatment
being less than 6 months [19].
Thiotepa
Thiotepa was the first intravesical chemotherapeutic agent used
to treat superficial bladder cancer [20]. This alkylating agent
inhibits nucleic acid synthesis and is usually delivered
30–60 mg in 30–60 ml of sterile water weekly for 6 weeks, fol-
lowed by monthly instillations for up to 1 year. The National
Bladder Cancer Study Group found that the complete response
rate for 30 mg was equal to 60 mg; therefore, the lower dose is
recommended [21].
As a prophylactic agent, thiotepa has recurrence-free rates
ranging from 35 to 45%. The National Bladder Cancer Collab-
orative Group reported that 53% of patients were tumor free at
2 years compared with 27% of control (TUR only) patients.
The benefit was seen only in patients with low-grade (G1)
tumors, while recurrence rates of high-grade (G2–3) tumors
were not significantly altered with thiotepa [21]. These data sug-
gest that thiotepa is most effective in treating low-grade, super-
ficial bladder tumors. Conversely, in a trial by the Medical
Research Council (MRC), 417 patients with newly diagnosed
superficial bladder cancer were randomized to receive one
instillation of thiotepa at the time of resection, one dose at
resection followed by 3-monthly intervals for 1 year, or no
treatment. After a median follow-up of 8 years, no differences
Expert Rev. Anticancer Ther. 7(4), (2007)

were observed among the three groups with respect to time to
first recurrence, recurrence rates or the failure-free interval
rate [22]. However, in a large review of 1007 patients treated in
multiple studies for superficial bladder cancer with thiotepa, a
12% net benefit of tumor recurrence was reported compared
with untreated patients; 44% recurrence with thiotepa com-
pared with 56% for untreated (TUR only) patients [23]. Cur-
rently, thiotepa may be a reasonable prophylactic option for
low-grade (G1) Ta bladder tumors.
The principal side effect of thiotepa is myelosuppression
(usually leukopenia or thrombocytopenia) occurring in 5% of
patients during weekly therapy, if the dose is limited to
30 mg [24]. This is a result of thiotepa’s low molecular weight
(189 Da). All patients should have complete blood cell counts
during weekly (not monthly) treatments. Other rare toxicities
include chemical cystitis and bladder contracture. Thiotepa is
the least expensive chemotherapeutic agent.
Mitomycin C
Mitomycin C is also an alkylating agent. The most common
administration dosage of mitomycin is 40 mg mixed with
20–40 ml of water. Some studies advocate a higher drug con-
centration in urine and thereby enhanced penetration of
tumor cells to improve efficacy. A recent randomized Phase III
trial comparing a standard 1 mg/ml concentration to a
pharmacokinetically enhanced concentration of 2 mg/ml
showed an improved recurrence-free interval with the higher
dosage [25]. In this study, pharmacokinetic manipulation was
carried out to increase the concentration by decreasing urine
volume and stabilizing the drug by alkalinization.
In a comparative study between mitomycin C and thiotepa
for the treatment of superficial bladder cancer, the National
Bladder Cancer Collaborative Group reported a significantly
higher complete response rate with mitomycin C (39 versus
27%; p = 0.02) [26]. In a large review of 1157 patients treated
prophylactically with mitomycin C compared with untreated
patients (TUR only) a 15% net benefit was reported; 35%
recurrence rate with mitomycin compared with 50% for
untreated patients [23]. This 15% net benefit of mitomycin C is
similar to the 12% net benefit reported with thiotepa.
The MRC reported a randomized, multicenter trial in 502
patients treated with early mitomycin C following the complete
resection of superficial Ta and T1 bladder tumors [23]. Patients
were randomized to receive either no further treatment until
the next endoscopy, a single instillation (40 mg) of
mitomycin C within 24 h of resection or an instillation within
24 h of resection and at 3-month intervals for 1 year (total of
five doses). They found that the overall recurrence rates were
lower, with a longer interval to recurrence, in patients with one
to five instillations compared with untreated patients. The esti-
mated 5-year reduction in recurrence was 15% for one treat-
ment and 23% for five treatments; however, this slight advan-
tage was not statistically significant. Likewise, in a study of 131
patients with low-risk superficial bladder cancer (no high-grade
or CIS component) who were followed for 2 years, a single
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Superficial bladder cancer: part 2. Management.
instillation of 50 mg mitomycin C within 6 h of resection was
associated with a 20% net reduction in risk of early recurrence.
This benefit was only related to early recurrences and not
maintained in long-term follow-up [27].
Systemic side effects of mitomycin C are rare because of the
large molecular weight (334 kDa). Myelosuppression is rare.
The most common side effect is a chemical cystitis seen in
10–15% of patients [28]. A desquamating palmer and genital
rash (contact dermatitis) occurs in approximately 5% of
patients receiving this drug [29]. Mitomycin C is the most
expensive intravesical chemotherapeutic agent.
Adriamycin
Adriamycin (doxorubicin) is an anthracycline antibiotic that is
an intercalating agent. Having a molecular weight of 580 Da,
systemic absorption and side effects are unlikely. However, local
chemical cystitis can occur in approximately 25% of
patients [30]. Several well-controlled studies have compared adri-
amycin with thiotepa for preventing superficial tumor recur-
rence and have found no significant differences between these
two agents [31,32]. In a large review of 1241 patients treated pro-
phylactically with adriamycin compared with untreated patients
(TUR only) a 13% net benefit was reported; 34% recurrence
rate with adriamycin compared with 47% for untreated patients
[23]. These data appear similar to thiotepa and mitomycin C.
Adriamycin has a high molecular weight and is therefore min-
imally absorbed through the urothelium. The most common
side effect is chemical cystitis, occurring in up to 25% of cases.
Epirubicin
Epirubicin is an anthracycline derivative of doxorubicin with
similar antitumor effects, yet a more favorable toxicity pro-
file. It is administered as 50–100 mg/ml instillations either as
a single postoperative instillation or for eight weekly sessions.
Although the US FDA does not currently approve its use for
the treatment of bladder cancer, studies outside the USA have
shown an approximate 30% net reduction in recurrence com-
pared with TUR alone. Furthermore, the reduction as a sin-
gle-dose immediate instillation is as effective as delayed
maintenance therapy [11].
Comparison of different intravesical chemotherapy agents
Overall, when comparing the various forms of intravesical
chemotherapy employed prophylactically, there appears to be
little difference among the aforementioned drugs [33,34]. In a
prospective, multicenter study of patients treated with short-
and long-term mitomycin or doxorubicin, Huland and
coworkers found no statistical difference in recurrence rates
based on duration of maintenance or between the two intravesi-
cal agents [35]. In addition, although these are not prospective
randomized data, Herr and Lamm reviewed results on 3852
patients entered from 29 randomized trials to evaluate the effect
of intravesical therapy on the risk of recurrence for superficial
bladder cancer and found little difference from a net-benefit
standpoint among the aforementioned agents [23].
569
Josephson, Pasin & Stein
Although some may consider tumor recurrence a surrogate
end point for disease progression, this may not be entirely
appropriate. In other words, preventing tumor recurrence does
not necessarily avoid the potential for tumor progression and
metastases [36,37]. Data from ten studies employing intravesical
chemotherapy, which included progression data, demonstrated
that in 1612 patients no apparent difference was noted with the
use of intravesical chemotherapy: an 8.3% progression rate in
1039 treated patients compared with 8.6% progression rate in
573 untreated (TUR only) patients [23]. Similarly, a combined
analysis of 2535 patients from four EORTC and two MRC tri-
als found a statistically significant impact of intravesical treat-
ment with regards to prolonging the recurrence-free interval but
did not have an impact on progression or overall survival [36].
Intravesical immunotherapy
Bacillus Calmette–Guerin
In 1976, Morales first reported the results of a 6-week course of
bacillus Calmette–Guerin (BCG) and the successful treatment
in seven out of nine patients with high-risk bladder cancer
(Ta/T1) [38]. Since then, many studies have been performed to
evaluate the efficacy of BCG. Although intravesical chemother-
apy results in a reasonable short-term cancer response, the dura-
ble net benefit for tumor recurrence is marginal and there
appears to be no response with regards to tumor progression
with intravesical chemotherapy. There are sufficient data to
suggest that, today, BCG may be considered the best form of
intravesical therapy for high-risk bladder cancer.
The exact mechanism of action of BCG is still being eluci-
dated. Ratliff demonstrated that the direct contact of the bacillus
organism with the transitional epithelium allows cell-surface
binding through fibronectin binding sites and activation of the
immune response [39]. An intact T-cell system is required for an
appropriate CD3, CD4 and CD8 immunological
response [40,41]. It has also been reported that the degree of T-cell
infiltration into the bladder wall is proportional to the clinical
response of patients, with responders demonstrating more blad-
der wall infiltrate than nonresponders [42]. It now seems that the
efficacy of BCG is based on a complex and long-lasting local
immune activation of multiple cell lines, including neutrophils,
macrophages, T cells and natural killer cells, with the most
important being the direct antitumor activity of interferons
(IFN) and cytotoxic activity of natural killer cells [43].
BCG is generally well tolerated but side effects can occur
both locally and systemically. Irritative symptoms in the form
of self-limited cystitis are common, with approximately a
fourth experiencing either microscopic or gross hematuria [44].
Persistent hematuria is a relative contraindication for BCG
instillation, as it increases the risk of systemic toxicity. Systemic
manifestations, including low-grade fevers, chills, malaise and
arthralgias, may also occur in a third of patients. Generally,
these symptoms are also self limited, with most responding to
antipyretics, nonsteroidal anti-inflammatory drugs and anti-
cholinergics. Persistent symptoms or fever to 39.5 °C may rep-
resent a more serious problem requiring cessation of BCG
570
therapy in addition to oral isoniazid 300-mg daily for
3 months [45]. BCG sepsis is a relatively rare yet potentially fatal
side effect that warrants aggressive support measures, three-
agent antituberculsosis medications (isoniazid 300 mg orally
daily, rifmapin 600 mg orally, daily, ethambutol 1200 mg
orally, daily) for a total of 6 months of therapy and an antibi-
otic to cover Gram-negative rods. Fluoroquinolones are pre-
ferred due to their broad Gram-negative coverage in addition to
presumed anti-Myobacterium properties [46].
Prophylaxis
Multiple trials directly comparing TUR alone with TUR plus
BCG for tumor prophylaxis have shown a significant benefit
for BCG plus TUR for reduction in recurrence rates [47–49].
Herr and Lamm evaluated the efficacy of six studies comparing
BCG with TUR only and reported a 42% net benefit; 31%
recurrence rate with use of BCG compared with 73% with
TUR only [23]. This 42% net benefit, although not representing
randomized data, is significantly better than the 12–15% bene-
fit seen with the common intravesical chemotherapy agents. It
is important to note that there are no trials evaluating the effi-
cacy of immediate postoperative instillation of BCG. Adminis-
tration of intravesical BCG before the resection site has begun
to re-epithelialize can lead to potentially fatal consequences of
systemic absorption and must be avoided.
In randomized studies comparing prophylactic BCG with
chemotherapy, most studies confirm that BCG immunotherapy
significantly reduced the number of recurrences when compared
with thiotepa, adriamycin or epirubicin for Ta and T1 tumors
of all grades and CIS [50–53]. Numerous other studies have com-
pared BCG with mitomycin C; however, these have shown
mixed results. The recurrence rates in these trials are vastly dif-
ferent; this may be related to many factors, including dosing,
schedule, strain of agent and type of tumors treated. These dif-
ferences must be kept in mind when analyzing data and why
any attempt to compare results across different series that are
not prospective and randomized is not ideal.
In 1996, a randomized multicenter German trial comparing
TUR versus TUR plus adjuvant mitomycin C versus TUR plus
BCG was reported in 337 patients by Krege and associates.
With a median follow-up of 20 months, a decrease in relative
risk of recurrence was noted for both mitomycin C (0.51) and
BCG (0.62) compared with TUR only. There was no signifi-
cant difference between the mitomycin C and BCG instillation
groups and the progression rate was comparable in all three
study groups [49]. By contrast, in a prospective randomized
study of 91 patients from Finland, BCG was shown to be supe-
rior to mitomycin C. At 2-year follow-up, complete response
was seen in 79% of patients in the mitomycin C groups as
compared with 97% in the BCG group [54]. However, this
study should be evaluated with caution as approximately two-
thirds of the Ta/T1 tumors in this study were grade 1 tumors
and were used in the overall analysis, thus resulting in abnor-
mally high complete response rates. Furthermore, in a large
Southwest Oncology Group (SWOG) randomized trial that
Expert Rev. Anticancer Ther. 7(4), (2007)

compared BCG with mitomycin C in 469 high-risk patients
with Ta or T1 disease, there was also a significant reduction in
tumor recurrence with the use of BCG (p = 0.017) [55]. With
a median follow-up of 2.5 years, 60% of patients in the BCG-
treated group were without evidence of recurrence, compared
with 46% of patients in the mitomycin group. In addition,
there was a significant reduction in toxicity with mitomycin
(p = 0.003). To resolve this issue, a recent formal meta-analy-
sis of 11 clinical trials involving over 2700 patients treated by
either BCG or mitomycin C was carried out. With a follow-
up period of 26 months, 38.6% of the patients in the BCG
group and 46.4% of those in the mitomycin C group had
tumor recurrence. In seven of 11 trials, BCG was significantly
superior to mitomycin C, in three studies no significant dif-
ference was found, while in one study mitomycin C was sig-
nificantly superior to BCG. Overall, a statistically significant
superiority of BCG versus mitomycin C efficacy in reducing
tumor recurrence was detected. This superiority was especially
prominent in the subgroup analysis of six studies utilizing
BCG maintenance therapy [56].
Furthermore, Herr and associates reported that with long-
term follow-up (10 years) there appears to be no reduction in
the incidence of tumor recurrence in patients treated with
intravesical chemotherapy, while nearly 31% of patients treated
with BCG remain tumor free [57]. These data suggest that BCG
immunotherapy may demonstrate a more active and durable
response than intravesical chemotherapy for superficial bladder
cancer recurrence.
Progression
Unlike intravesical chemotherapy, there is evidence to suggest
that BCG may be effective in reducing tumor
progression [47,58,59]. Herr and associates performed a rand-
omized trial from 1978 to 1981, and after 5 years demon-
strated that intravesical BCG therapy delayed disease progres-
sion, prolonged the period of time for bladder preservation and
improved survival [58]. With increased follow-up of 10 years,
this trial demonstrated that BCG therapy maintained a pro-
gression-free advantage of 62% compared with only 37% in the
control group (p = 0.006) [59]. In a multivariate analysis of
1529 patients in a Spanish registry, BCG instillation was also
independently associated with a 0.3 relative risk reduction in
disease progression [60]. By contrast, there have been studies to
suggest that BCG does not significantly delay disease progres-
sion [47,61]. Lamm reported that the rates of progression to mus-
cle invasion were lower in the BCG-treated group compared
with the control group (8 vs 3%) but this did not reach statisti-
cal significance [47]. A randomized study by Melekos and associ-
ates also failed to demonstrate any significant difference in stage
progression among the BCG-treated group compared with
those treated with TUR alone [61]. To better evaluate this ques-
tion, the EORTC recently performed a formal meta-analysis of
24 trials involving a total of 4863 patients. This meta-analysis
considered randomized trials comparing TUR plus intravesical
BCG with TUR alone or TUR plus treatment other than
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Superficial bladder cancer: part 2. Management.
BCG. Based on a median follow-up of 2.5 years, with a maxi-
mum of 15 years, the authors report a statistically significant
27% reduction in the odds of progression for those patients
receiving BCG (9.8%) compared with the control group
(13.8%). However, it should be emphasized that only patients
receiving maintenance BCG therapy benefited with regards to
progression [62].
When comparing BCG with different types of intravesical
chemotherapy in terms of tumor progression, the results from
the aforementioned EORTC meta-analysis were not as conclu-
sive. In a separate analysis of six trials, which incorporated pro-
gression data specifically comparing BCG and mitomycin C,
an overall 14% reduction in progression risk was observed;
however, this was not statistically significant (p = 0.2). It
should be noted that the analysis of trials comparing BCG plus
BCG maintenance versus mitomycin C was not performed,
presumably because there was only a small number of such tri-
als. On the other hand, a more recent meta-analysis by Bohle
and Bock considered nine studies with data on tumor progres-
sion and compared intravesical BCG with intravesical
mitomycin C, involving a total of 2410 patients. Again, in all
nine individual studies, no statistically significant difference in
the odds ratio for progression was found between the BCG-
and mitomycin C-treated groups. However, a subgroup analy-
sis of five studies incorporating BCG-maintenance data
showed a statistically significant superiority of BCG plus main-
tenance over mitomycin C (odds ratio 0.66; p = 0.02) [63]. In a
recent randomized control trial from Italy, it was found that
the sequential use of electromotive mitomycin C and BCG was
superior to BCG alone for high risk, T1 transitional cell carci-
noma (TCC) of the bladder in terms of lower rate of recur-
rence and progression and improved overall and disease-spe-
cific survival [64]. Specifically, with a median follow-up of
88 months, 21.9% of patients progressed in the BCG group
compared with 9.3% in the sequential group. The authors sug-
gested that the sequential use of electromotive mitomycin C
after BCG allows mitomycin C to reach target tissues more
effectively as a result to the increased permeability created by
BCG-induced mucosal inflammation.
Definitive treatment
When comparing BCG therapy with intravesical chemotherapy
for therapeutic purposes, it also appears that BCG demon-
strates superiority. Herr and Lamm compiled a large amount of
data from multiple studies that had a minimum follow-up of
1 year [23]. They evaluated the response rates of both papillary
tumors and CIS, with a complete response defined as no evi-
dence of tumor on cystoscopy, biopsy and urine cytology for at
least 1 year. The complete response rate to BCG therapy was
significantly better (72%) compared with thiotepa (34%),
mitomycin C (47%) and adriamycin (42%).
In addition, BCG may be particularly effective for CIS.
Overall, a 70% complete response rate has been reported with
BCG for CIS [65]. A recent evidence-based guideline commit-
tee from the EORTC reported their analysis of 12 different
571
Josephson, Pasin & Stein
randomized trials that included patients with CIS and com-
pared BCG with different intravesical chemotherapy
regimens [66]. Overall, the panel noted a 68% complete
response rate with BCG versus a 48% complete response rate
with chemotherapy. Furthermore, based on a median follow-
up of 3.75 years, the overall disease-free rates were 51% for
BCG and 27% for chemotherapy. Moreover, a meta-analysis of
the results of randomized clinical trials evaluating BCG versus
chemotherapy for the intravesical treatment of patients with
CIS of the bladder revealed that BCG significantly reduces the
risk of short- and long-term treatment failure compared with
chemotherapy [67]. Therefore, these results have established
BCG as the recommended therapy of choice for both primary
and concomitant CIS.
Despite these encouraging results there are some data to
indicate that, with long-term follow-up of nonmuscle-invasive
TCC of the bladder treated with BCG, patients remain at sig-
nificant long-term risk of stage progression, upper tract and
prostatic recurrence, and even death from bladder
cancer [68–70]. Cookson reported on 86 patients with high-
grade Ta and T1 bladder cancer alone or mixed with CIS
treated initially with BCG and followed for a median of
15 years: 34% died of bladder cancer, 27% died of other causes
and 37% were alive (27% with an intact bladder) [68]. These
data suggest that patients with high-risk nonmuscle-invasive
bladder cancer can be effectively treated with BCG but require
close and vigilant long-term follow-up.
Maintenance, reinduction & dosing
The optimal course of BCG should prevent tumor recurrence
and progression. It has been 30 years since the clinical applica-
tion of BCG was first introduced; however, the ideal dosing
and schedule regimen still remains unknown. It is clear that a
single 6-week course of BCG therapy is inadequate in a number
of patients who ultimately respond to an additional 6-week
course of BCG. Several groups have reported a 7–32% com-
plete response rate when a second and even third course of
BCG was delivered following failure of an initial 6-week
course [71–74]. However, it is important to note that a significant
percentage of patients who respond to BCG may require cyst-
ectomy, develop distant metastasis and ultimately die of bladder
cancer. One study of 77 complete responders to BCG not
receiving maintenance therapy found that after a median fol-
low-up of 7.6 years, 39% recurred in the bladder, 17% had
locoregional extravesical recurrence, 9% developed distant
metastasis and 21% died of bladder cancer. Thus, in complete
responders, the response to BCG is not completely durable and
lifelong surveillance is required [75].
Given the recognizable benefits of reinduction therapy,
attempts have also been made to prolong the relapse-free inter-
val by administering abbreviated schedules of BCG in the
absence of visible recurrence. Early clinical trials were not able
to demonstrate an advantage when either monthly or quarterly
single-treatment maintenance schedules were used following
the administration of an initial 6-week course of therapy [76,77].
572
However, an excellent prospective randomized trial was
recently performed by the SWOG in which patients were
assigned to receive no further treatment after a 6-week induc-
tion course, versus three weekly BCG instillations at 3 and
6 months, and every 6 months for 3 years [78]. For patients
with CIS or papillary tumors, maintenance therapy resulted in
an improved, estimated, median recurrence-free survival from
36 to 77 months, and an improved overall 5-year survival from
78 to 83%. In randomized patients with papillary tumors, free-
dom from worsening disease increased from 70 to 76% with
maintenance therapy. Also, patients with CIS were noted to
have a complete response rate of 84% with maintenance versus
68% without maintenance. A role for maintenance therapy has
also received indirect support from the aforementioned large
meta-analyses on disease progression and recurrence with the
use of BCG. In the meta-analyses by Bohle and coworkers,
BCG demonstrated recurrence-free and progression-free supe-
riority over mitomycin C, mainly in those trials where mainte-
nance therapy was utilized [56,63]. Similarly, in the EORTC
meta-analysis, the observed benefit of decreased odds of pro-
gression with BCG was only apparent in those trials utilizing
maintenance therapy [62].
Treatment toxicity and tumor progression must be kept in
mind when treating patients with either repeat induction or
maintenance therapy. It should be noted that only 16% of
patients in the SWOG maintenance study completed all sched-
uled maintenance cycles, as roughly half of the patients did not
complete more than three cycles due to intolerance [78]. There
clearly is a toxicity price to pay with maintenance therapy and
one must ask if this benefit outweighs the risk of toxicity on an
individual patient basis. Also, patients with persistent CIS or
high-grade T1 tumors following two 6-week courses of BCG or
on follow-up during maintenance therapy should be considered
for alternative forms of therapy. Importantly, these patients
should be counseled on possibly undergoing radical cystectomy.
Concerning the dosing regimens, efforts to decrease toxicity
without compromising efficacy have lead to several studies sug-
gesting lower doses of BCG. In the most recent randomized
prospective trial from Spain, a standard 81-mg dose of BCG
was compared with a 27-mg dose in 155 patients with high-risk
superficial disease (Tis and high-grade T1) [79]. With a median
follow-up of 61 months, recurrence and progression rates did
not differ between the two groups, yet local and systemic toxic-
ity was significantly less pronounced with the decreased dose. In
the standard-dose arm, 70% had local side effects versus 48% in
the reduced arm. Similarly, 16% of patients in the standard-
dose arm experienced systemic side effects compared with 6%
in the lowered-dose arm. However, the number of patients
withdrawn from the trial due to intolerability did not differ
between the two arms. In general, this trial and other nonrand-
omized studies have shown decreased toxicity with a reduced
BCG dose without compromising overall efficacy [80–82]. Never-
theless, caution must be employed when interpreting these
studies owing to their heterogeneity. Different tumor grades and
stage are included, as are different BCG strains, used as both
Expert Rev. Anticancer Ther. 7(4), (2007)

prophylaxis and maintenance. Larger scale randomized trials
with homogenous groups of patients are needed before BCG
dose reduction can be universally recommended.
Alternative forms of therapy
Although BCG is effective for superficial disease, approxi-
mately 30% of patients manifest BCG-refractory superficial
disease. Several alternative agents and methods have been
employed to treat or salvage these so-called ‘BCG-refractory’
patients; including IFN, valrubicin, gemcitabine, bropirimine,
photodynamic therapy and megadose vitamin therapy.
Interferon
IFNs are naturally occurring glycoproteins with antiviral and
antiproliferative properties. The most active IFN for bladder
cancer is IFN-α, which primarily stimulates natural killer cell
maturation. Initial studies with IFN-α-2b as a single intra-
vesical agent demonstrated activity in bladder cancer at doses
of 50–100 MU with minimal toxicity [83,84]. IFN administra-
tion is similar to that of BCG: the 50–100 MU of IFN-α-2b
is mixed in 50 ml of sterile water, instilled into the bladder
and retained for approximately 2 h. This is repeated for
6–8 weeks. Side effects are related primarily to malaise and/or
flu-like symptoms.
As primary therapy for superficial bladder cancer, IFN is
thought to be inferior to both BCG and intravesical chemo-
therapy [11,85]. In a randomized, prospective, double-blind trial
of 90 patients with pT1 cancer, weekly instillations of IFN for
12 weeks followed by monthly instillations until 1 year did not
show prophylaxis benefit over a placebo group [86]. Also, a ran-
domized study of 78 patients treated by 12 instillations of
either recombinant IFN-α or BCG showed significantly lower
rates of recurrence in the BCG group at the follow-up period
of 25 months (60 vs 16%, respectively) [87].
Interestingly, responses with IFN-α-2b have been docu-
mented in patients who have failed BCG or intravesical
chemotherapy. Response rates of 66% were initially reported,
which made it a potential attractive option for second-line
therapy [84]. However, large clinical trials establishing a dura-
ble long-term response have yet to be performed. Novel appli-
cations of IFN include the combination of IFN with BCG or
chemotherapy in the hope of providing a synergistic effect
with improved efficacy and with a reduction in toxicity [88,89].
Recent nonrandomized clinical trials suggest combined
IFN-α plus BCG may be superior to each agent alone and
allow dose reduction without compromising efficacy. Using
combination low-dose BCG plus IFN, a 55% complete
response rate at 2.5 years was reported by O’Donnell and
associates in patients who previously failed BCG therapy [90].
More recently, a national multicenter Phase II trial of combi-
nation BCG–IFN was evaluated in 490 patients with super-
ficial bladder cancer [91]. While the criteria for enrollment
were liberal, resulting in significant tumor heterogeneity, after
a 6-week induction course of standard dose BCG plus 50 MU
of IFN-α-2b followed by three 3-week maintenance cycles of
www.future-drugs.com
Superficial bladder cancer: part 2. Management.
combined low-dose BCG plus IFN at 3, 9 and 15 months, the
study demonstrated 40 and 52% recurrence rates in BCG-
naive and BCG-failure patients, respectively. Also, with a
median follow-up of 2 years, less than 5% of patients in each
group had evidence for progression. Most patients tolerated
therapy with only mild-to-moderate complaints, with the
objective incidence of serious adverse effects being less than
6% in both groups of patients. Despite these encouraging
results, whether combination therapy offers a true advantage
over BCG monotherapy cannot be determined from this trial.
Further investigation is required to better define the current
role of IFN in superficial bladder cancer.
Valrubicin
Valrubicin is no longer available and is described herein for his-
torical purposes only. Valrubicin is a potent analog of doxoru-
bicin that rapidly traverses cell membranes and accumulates in
the cytoplasm. The first study to evaluate the safety of intravesi-
cal valrubicin noted minimal systemic side effects, while most
patients experienced transient mild-to-severe irritative symp-
toms [92]. In fact, many patients receiving valrubicin experi-
enced severe cystitis that often necessitated cessation of therapy.
In this analysis of 32 patients, a significant portion of whom
had previously been pretreated with either intravesical chemo-
therapy or immunotherapy, 41% had a complete response with
a mean disease-free interval of 23 months. Steinberg and associ-
ates evaluated 90 patients with recurrent CIS after failed multi-
ple prior courses of intravesical therapy, including at least one
course of BCG [93]. A total of 19 patients (21%) had a complete
response and seven of these had a durable response with a
median follow-up of 30 months. Of the 79 patients with recur-
rence, 44 underwent radical cystectomy, where six (15%) had
stage pT3 or greater disease. The main side effects were reversi-
ble local symptoms. In a subsequent prospective Phase II study,
40 patients with refractory, superficial TCC, with or without
CIS, underwent TUR of bladder tumor at which a tumor less
than 1 cm in diameter was deliberately left in the bladder. After
six weekly instillations of valrubicin, 46% were found to be
clear of disease at the 3-month follow-up examination [94].
Although none of the patients showed evidence of progression
to invasive disease, only five patients remained clear of recur-
rence in the 2-year follow-up period. Given these poor results,
the use of valrubicin has been principally approved for the
treatment of BCG-refractory CIS in patients who either refuse
or cannot undergo radical cystectomy.
Gemcitabine
Gemcitabine is a pyrimidine antimetabolite with a broad spec-
trum of antitumor activity. It has been established as a well-tol-
erated and effective chemotherapeutic regimen in patients with
advanced or metastatic bladder cancer [95]. As opposed to most
other intravesical chemotherapeutic agents, gemcitabine has a
lower molecular weight of 299 Da, which potentially gives it a
better ability to penetrate and treat early invasive T1 cancer. At
the same time, the molecular weight is high enough to prevent
573
Josephson, Pasin & Stein
its systemic absorption from an intact bladder. Clinical studies
to date have made it a promising new candidate as a standard
intravesical chemotherapy agent in superficial bladder cancer.
An early Phase I trial evaluated different dose levels of gem-
citabine administered as two courses of intravesical treatments
(six treatments in each course) in 18 patients with BCG-refrac-
tory disease [96]. Complete response, defined as negative cytol-
ogy and post-treatment biopsy, was observed in seven patients.
This trial also demonstrated an excellent tolerability of intra-
vesical gemcitabine, with treatment doses up to 20 mg/ml
mostly causing minimal urinary symptoms. Grade 4 toxicities
were not encountered in this trial. Other Phase I studies of
patients with recurrent superficial TCC despite prior conven-
tional nongemcitabine intravesical treatments have also dem-
onstrated minimal adverse events with no grade 4 toxicity or
clinically relevant myelosuppression reported [97,98]. In the trial
by Laufer and colleagues, nine of 13 evaluable patients were
recurrence free at 12 weeks [97]. More recently, an Italian group
reported their findings from a Phase II randomized prospective
trial on one cycle 2000 mg gemcitabine (once weekly for
6 weeks) in intermediate- and high-risk superficial bladder can-
cer [99]. In terms of tolerability, 94 (81%) patients did not
report any side effects, with 14 of the remaining 22 reporting
urgency as their only complaint. In terms of efficacy, 85 (75%)
were disease free after 1 year of treatment. The overall compar-
ative analysis of the survival curves of the intermediate- and
high-risk patients did not show any significant difference
between the two groups. However, in the subset of patients
with BCG-refractory disease, 75% of intermediate-risk
patients were free of recurrence compared with 44% of those
with high-risk disease. At this point in time, the use of intra-
vesical gemcitabine for the treatment of BCG-refractory high-
risk superficial bladder cancer should be considered experimen-
tal until further large-scale, multicentric, randomized clinical
trials with adequate long-term follow-up are performed.
Bropirimine
Bropirimine is no longer available and is described herein for
historical purposes only. Bropirimine is an orally active immune
modulator that induces a wide range of antitumor, antiviral, and
immunomodulatory effects. Sarosdy demonstrated in a Phase I
trial that bropirimine is effective for CIS [100]. In a Phase II trial,
Sarosdy treated patients having CIS with positive cytology fol-
lowing biopsy for 12 weeks (3 consecutive days per week). Over
half (20/33) of the evaluable patients demonstrated a complete
response, including six of 12 (50%) patients who had failed pre-
vious BCG therapy and 14 of 21 (67%) patients who had not
received any prior BCG therapy [101].
Overall, bropirimine has been demonstrated to be effective in
treating approximately 50% of patients with CIS of the bladder
and 30% of those who failed BCG therapy. Sarosdy evaluated
patients with upper tract CIS who were treated with bropirim-
ine to determine whether this oral drug might be effective in
this setting [102]. A total of 24 patients with negative radio-
graphic findings and positive cytologic evidence for upper tract
574
CIS in one or both ureters received bropirimine (3.0 g/day
orally) for 3 consecutive days each week for up to 1 year. A total
of ten (48%) out of 21 evaluable patients had a negative ureteral
cytologic analysis after 12 weeks (five patients) or 24 weeks (five
patients). Of these ten patients, eight continued to have nega-
tive cytology for a period of 3–30 months (median: 9 months).
In two patients, negative cytology reverted to positive during
therapy. The authors concluded that orally administered bropir-
imine might be effective therapy for CIS of the ureter or renal
pelvis, with acceptable toxicity in most patients.
Based on encouraging results using single-agent bropirimine
and early laboratory studies showing potential synergistic activ-
ity with BCG, a study of oral bropirimine combined with intra-
vesical BCG for CIS was conducted between 1992 and 1997
and reported by SWOG [103]. In this multicentric trial, 50 mg
intravesical BCG was administered weekly for 6 weeks and oral
bropirimine 3.0 g/day was given 3 consecutive days each week
for 12 weeks. Out of 42 patients who were evaluable at the end
of the study, 28 (67%) had a complete response. A total of 14
relapses were noted, with three patients ultimately dying of their
disease. Adverse effects reported include grade 4 toxicity in two
patients and grade 3 toxicity necessitating interruption in ther-
apy. Based on these results, the authors concluded that bromo-
prine does not offer significant enhancement of BCG activity in
CIS and further trials studying this combination should not be
conducted. It should be noted that bromoprine failed FDA
approval for use in BCG-refractory CIS as of 1996 and remains
unavailable for further research purposes.
Photodynamic therapy
Photodynamic therapy was first introduced in 1976 as a poten-
tial alternative treatment for bladder preservation [104]. It
requires the intravenous administration of a photosensitizing
agent with subsequent in situ intravesical activation by whole-
bladder laser therapy with visible light. The tumor-localizing
photosensitizer is stimulated to generate an active form of
molecular oxygen causing vascular damage and tumor cell
death. This method has been used effectively to treat superficial
TCC as well as BCG-refractory CIS [105–107]. Manyak and Ogan
recently reported their findings on 32 patients with superficial
disease refractory to conventional treatments who underwent
photodynamic therapy. At 3 months, complete response was
noted in 44%; however, five out of the 14 responders ultimately
underwent cystectomy either for progressive disease or severe
bladder contractures [108].
The main limitation of photodynamic therapy is the signif-
icant side effects. A cystitis-like syndrome is very common
and permanent bladder contracture can occur. In addition,
treated patients must avoid sunlight for up to 6 weeks owing
to skin-induced photosensitivity.
Vitamins & minerals
There is increasing evidence to suggest that vitamins may play
an important role in the prevention and management of vari-
ous cancers. Furthermore, patients with bladder cancer have
Expert Rev. Anticancer Ther. 7(4), (2007)

been shown to have lower serum concentrations of vitamins A,
C and E and selenium [109]. A recent, small clinical trial
reported that the efficacy of BCG may be enhanced by supple-
mentation of megadose vitamins and minerals (vitamin A
40,000 international units [IU], vitamin B6 100 mg,
vitamin C 2000 mg, vitamin E 400 IU, zinc 90 mg) [110].
Lamm evaluated a total of 65 patients with biopsy-confirmed
TCC of the bladder who were enrolled in a randomized study
comparing intravesical BCG alone with intravesical BCG plus
multiple vitamins in the recommended daily allowance (RDA)
versus RDA multivitamins plus 40,000 units vitamin A,
100 mg vitamin B6, 2000 mg vitamin C, 400 units vitamin E
and 90 mg zinc. Recurrences after 10 months were markedly
reduced in patients receiving megadose vitamins. The 5-year
estimates of tumor recurrence are 91% in the RDA arm and
41% in the megadose arm. Overall recurrence was seen in 24 of
30 patients (80%) in the RDA arm and 14 of 35 (40%) in the
high-dose arm. In this study, megadose vitamins A, B6, C and
E plus zinc decreased bladder tumor recurrence in patients
receiving BCG immunotherapy. Further research will be
required to confirm these findings and identify more precisely
which ingredient(s) provide this protective effect.
Gene therapy
Investigation into novel ways of treating bladder cancer is an
area of intense research. As more is understood regarding the
molecular biology of bladder cancer and the mechanisms of
apoptosis, novel research aimed at interfering with these path-
ways may prove fruitful in the treatment of this disease. The
bladder is an ideal organ for gene therapy for several reasons.
For one, the bladder is easily accessible by noninvasive means.
Additionally, intravesical administration of an adenovirus as a
vector is well tolerated in mice [111]. Moreover, animal models
have demonstrated a reduction in the protective glycos-
aminoglycan layer on malignant cells, suggesting viral transduc-
tion may be easier in these cells [112]. Several modes of gene ther-
apy-mediated cancer cell cytotoxicity have been investigated.
One of the more popular areas of interest includes using an ade-
novirus vector to deliver apoptotic genes to malignant cells spe-
cifically [113]. Another mechanism for preferentially killing
tumor cells uses conditionally replicating adenoviruses [114].
This requires modifying a key gene required for regulation of
viral replication to have a tumor-specific promoter. In this
regard, the lytic process of the viral life cycle can induce cell
death in transduced tumor cells.
While the future holds promise for gene therapy in bladder
cancer, its widespread use as an accepted form of therapy for
both muscle-invasive and nonmuscle-invasive disease requires
further study and prospective validation.
Early radical cystectomy
Although intravesical therapy has impacted the management of
superficial bladder cancer, it is clearly not effective for every
patient, nor is it risk free. As we have shown, the cancer of a sig-
nificant number of patients will progress despite appropriate
www.future-drugs.com
Superficial bladder cancer: part 2. Management.
intravesical therapy. Those individuals who are destined to fail
must be identified early, as they may benefit from more aggressive
therapy, such as radical cystectomy, if applied early.
Radical cystectomy has become a practicable and reputable
option in the treatment of high-risk superficial bladder cancer;
the procedure has achieved excellent long-term outcomes.
Stockle and associates reported the survival rates of patients
with T1 bladder tumors who underwent either immediate or
delayed cystectomy [115]. The 5-year recurrence-free survival
rate in the immediate cystectomy group was 90% compared
with 62% in the delayed group. Although not randomized,
these data suggest the potential for improved survival with
early cystectomy.
The concept of early cystectomy with the intent to improve
survival has also been supported by Hautmann and Paiss [116].
They reported that orthotopic reconstruction decreases physi-
cian reluctance to perform cystectomy earlier in the disease
process, which consequently increased patient survival.
Hautmann and Paiss reported on 135 patients with an average
number of 2.1 TURs undergoing cystectomy and neobladder
replacement and on 78 patients with an average of 4.1 TURs
undergoing cystectomy and a conduit diversion. The interval
from the primary diagnosis to cystectomy was shorter in the
neobladder group compared with the conduit group. Although
not specific for superficial bladder cancer, earlier cystectomy in
this study translated into a significant cancer-specific 5-year
survival advantage: 76% for the neobladder group compared
with 28% for the conduit group.
Several groups have reported excellent clinical outcomes with
radical cystectomy for high-risk superficial bladder
cancer [117–120]. A large study of radical cystectomy patients with
long-term follow-up (median 10 years) for high-grade, invasive
bladder cancer included 401 patients (40%) with pathologically
superficial tumors (P0, Pa, Pis, P1) [18]. The 5-year recurrence-
free survival in those patients was excellent: 92% for P0, 78% for
Pa, 91% for Pis and 83% for P1 tumors. Furthermore, the local
recurrence rate for patients with pathologically organ-confined
tumors (including muscle invasion, pT2) was only 5%. Impor-
tantly, patients with nonorgan-confined tumors (extravesical
extension or lymph node-positive disease) demonstrated signifi-
cantly worse survival. These results indicate that the ideal win-
dow of opportunity to cure patients with high-grade, invasive
bladder cancer is when the tumor is organ confined, a clear rea-
son for not delaying. It is our recommendation that earlier radi-
cal cystectomy be considered for patients with superficial blad-
der cancer that is high grade and deeply invading the lamina
propria (T1b), T1 tumors associated with lymphovascular inva-
sion, T1 tumors associated with CIS, high-grade, nonmuscle-
invasive tumors failing initial or repeat intravesical therapy as
demonstrated by stage and/or grade progression, large endoscop-
ically uncontrollable tumors, tumors associated with bladder
diverticulum and those with prostatic tumor involvement.
However, radical cystectomy is a large surgical undertaking
with a reported early complication rate of nearly 30% and a
mortality rate of 1–5% in most contemporary series [121]. Even
575
Josephson, Pasin & Stein

after appropriate counseling, many patients with muscle-inva-
sive or nonmuscle-invasive disease with high-risk features reject
the recommendation of cystectomy. Moreover, some patients
may be inappropriate candidates for such an operation. Blad-
der-preservation protocols utilizing the multimodal approach of
aggressive TUR, systemic chemotherapy and radiation therapy
in this patient population provide the theoretical advantage of
an improved quality of life associated with an intact, native
bladder. However, improvements in surgical technique and the
growing popularity of the orthotopic neobladder as the urinary
diversion of choice have undermined this assumption. Minimal
data exist comparing multimodal bladder preservation protocols
with current standard therapies of high-risk nonmuscle-invasive
bladder cancer, and most of the published literature on this
subject focuses on muscle-invasive or locally advanced disease.
While survival rates of bladder-preservation therapy are pur-
ported to be comparable with those of radical cystectomy and
may be a reasonable option for patients at a dedicated center
with a multidisciplinary team [122], the standard of care for
invasive bladder cancer remains radical cystectomy.
Conclusion
The management of superficial bladder cancer has evolved over
the past 25 years as a result of the use of intravesical chemother-
apy and immunotherapy. The many well-performed prospec-
tive randomized trials, as well as on improved understanding of

Key issues

• With few exceptions, bladder tumors require a properly performed transurethral resection (TUR) in an effort to resect all visible
disease and for accurate staging purposes. This should incorporate muscle in the TUR specimen.
• All tumors, after initial resection, should receive one immediate instillation of intravesical chemotherapy to reduce the risk of
tumor recurrences.
• Low-grade Ta tumors with high risk of recurrence (recurrence at first cystoscopy, previous recurrence rate, multiple tumors and large
tumors) may benefit from further intravesical chemotherapy not exceeding 6 months of treatment. Bacillus Calmette–Guerin (BCG)
in this group of tumors should be reserved as second-line therapy.
• Overall, when comparing the various forms of intravesical chemotherapy employed for prophylactic measures, there appears to be
little difference among thiotepa, mitomycin C, adriamycin and epirubicin.
• There are sufficient data to suggest that BCG may be considered the best form of intravesical therapy for high-risk bladder cancer.
• BCG is generally well tolerated but side effects can occur both locally and systemically. BCG sepsis is a relatively rare yet potentially
fatal side effect that warrants aggressive support measures, three-agent antituberculsosis medications (isoniazid 300 mg orally
daily, rifmapin 600 mg orally daily, ethambutol 1200 mg orally daily) for a total of 6 months of therapy and an antibiotic to cover
Gram-negative rods.
• Early postoperative BCG administration analogous to intravesical chemotherapy must not occur. The administration of intravesical
BCG before the resection site has begun to re-epithelialize can lead to potentially fatal consequences of systemic absorption.
• Randomized studies comparing prophylactic BCG with chemotherapy confirm that BCG immunotherapy significantly reduces the
number of recurrences when compared with thiotepa, adriamycin or epirubicin for Ta and T1 tumors of all grades and carcinoma
in situ (CIS).
• BCG seems superior to mitomycin C in reducing tumor recurrence for intermediate- and high-risk tumors. This superiority is more
prominent utilizing BCG maintenance therapy particularly.
• A meta-analysis of 24 randomized trials demonstrated that BCG significantly reduces the risk of disease progression, but only when
maintenance therapy was used.
• BCG maintenance therapy is not without local and systemic toxicity.
• The optimal BCG-maintenance schedule has not been determined.
• BCG is a particularly effective therapy for CIS and is the recommended therapy of choice for both primary and concomitant CIS.
However, even in complete responders, the response to BCG is not completely durable and lifelong surveillance is required.
• Recent nonrandomized clinical trials suggest combined interferon (IFN)-α plus BCG may be superior to each agent alone and allow
dose reduction without compromising efficacy.
• BCG plus IFN-α may be used as further intravesical therapy for patients with high-grade T1 disease that recurs after initial
intravesical treatment.
• Radical cystectomy may be used for patients with high-risk disease as an initial therapy or in patients who fail previous
intravesical immunotherapy.

576 Expert Rev. Anticancer Ther. 7(4), (2007)

 Superficial bladder cancer: part 2. Management.

tumor biology, have provided clinicians with a better insight appropriately. Furthermore, and perhaps most important, the
into how to best treat patients with superficial TCC of the timely decision to abandon conservative therapy and proceed
bladder. It is important that the treatment of each individual with radical cystectomy and urinary diversion should be kept
patient be tailored to his or her specific disease characteristics. in mind to prevent the potentially lethal sequelae of invasive
Patients with favorable tumor profiles at the initial diagnosis do bladder cancer.
not require intravesical therapy. Alternatively, a single intravesi-
cal administration of chemotherapy may be performed soon Expert commentary & five-year view
following TUR. Patients with favorable tumor characteristics This review, the second of a two-part series, concentrated on
that recur with similar features may be best treated with intra- the management of nonmuscle-invasive bladder cancer. While
vesical therapy. Failure of intravesical chemotherapy with the ultimate goal in the treatment of all cancer is targeted ther-
superficial disease is an indication for BCG intravesical therapy. apy aimed at cancer cells, thus sparing normal cells the cyto-
Furthermore, patients with unfavorable characteristics should toxic effects of treatment, bladder cancer, like all other cancers,
receive intravesical therapy (preferably BCG) after all visible lacks a ‘magic-bullet’ therapy. However, the strides necessary to
tumor has been resected. Patients experiencing failure of a sin- someday achieve this end are in the making. Advances in the
gle 6-week course of BCG may respond to a second 6-week molecular biology and genetics specific to bladder cancer are
course. Other therapies are under clinical investigation for consistently being made and, while this approach to therapy is
BCG-refractory disease, including IFN and gemcitabine, but unlikely to occur within the next 5 years, it is the hope of clini-
should be considered experimental at this time. cians and patients alike that this will be realized in the not-so-
Those patients with significant risk of disease progression distant future. However, advances in the management of non-
(high grade, T1 with/without CIS) should be managed with muscle-invasive bladder cancer likely to occur within the next
caution. In fact, one could argue that they may be best 5 years involve defining the optimal dosing schedule of main-
treated early aggressive radical therapy. Furthermore, it is tenance BCG necessary to produce similar recurrence- and
clear that patients treated with BCG intravesical immuno- progression-free intervals for high-risk disease seen with today’s
therapy for high-grade superficial bladder cancer are at sig- protocols while improving treatment tolerability. In addition,
nificant long-term risk for disease recurrence, progression further intravesical therapies for BCG failures may be realized.
and even death from disease. Careful and vigilant follow-up However, a properly performed radical cystectomy has with-
is necessary for life in these patients. The urologist must be stood the test of time for cancer control in muscle-invasive dis-
extremely active and diligent when treating superficial blad- ease, and in BCG-refractory disease, and will probably con-
der cancer. An understanding of tumor biology and current tinue to be the recommendation among most urologists for the
intravesical therapies is important to treat these patients next 5 years.
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superficial bladder cancer in the era of California, Department of Urology, Norris
orthotopic urinary reconstruction. Cancer Comprehensive Cancer Center, Keck School of
76, 833–839 (1995). Medicine, Los Angeles CA, USA
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Complications of radical cystectomy. epasin59@hotmail.com
In: Complications of Urologic Surgery and
• John P Stein, MD
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122 Kim HL, Steinberg GD. The current status 1441 Eastlake Avenue, Suite 7416, Los Angeles,
of bladder preservation in the management CA 90089–9178, USA
of muscle invasive bladder cancer J. Urol. Tel.: +1 323 865 3709
164, 627–632 (2000). Fax: +1 323 865 0120
stein@usc.edu
Affiliations
• David Josephson
Urologic Oncology Fellow, University of
Southern California, Department of Urology,
Norris Comprehensive Cancer Center, Keck
School of Medicine, Los Angeles, CA, USA
Tel.: +1 323 865 3700
Fax: +1 323 865 0120
david.josephson@usc.edu
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