european urology supplements 7 (2008) 542–547

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Intravesical Chemotherapy and BCG for the Treatment of

Bladder Cancer: Evidence and Opinion

Guillermo Urdaneta a, Eduardo Solsona b, Juan Palou a,*

a
Department of Urology, Fundació Puigvert, Barcelona, Spain
b
Department of Urology, Instituto Valenciano de Oncologı́a, Valencia, Spain

Article info Abstract

Keywords: Objectives: Review the chemotherapeutic and immunotherapeutic

BCG options for post-resection intravesical treatment of low-risk, intermedi-
Chemotherapy ate-risk, and high-risk non-muscle-invasive bladder cancer (bCA).
Disease progression Design, Setting, and Participants: The authors conducted a review of the
Immunotherapy literature on chemotherapy and immunotherapy regimens used to
Intravesical instillation reduce the risk of cancer recurrence and progression after transurethral
Non-muscle-invasive resection of the bladder (TURB).
bladder cancer Results and Limitations: The choice of post-TURB regimen for intravesical
Recurrence treatment of non-muscle-invasive bCA depends on the risk category of
the tumour: Chemotherapy is the treatment of choice for low-risk super-
ficial bladder carcinoma; intermediate-risk disease can be treated with
either chemotherapy or immunotherapy with bacillus Calmette-Guérin
(BCG); and BCG is now the treatment of choice for high-risk tumours. In
all cases, the overall aim of treatment is to prevent recurrence and delay
Please visit
disease progression. There is debate over the optimal treatment regi-
www.eu-acme.org/
mens, and the options may include sequential treatment with che-
europeanurology to read and
motherapy and BCG.
answer questions on-line.
Conclusions: Intravesical chemotherapy and BCG are both effective post-
The EU-ACME credits will
TURB treatments for non-muscle-invasive bCA, and the choice of regi-
then be attributed
men depends on the risk category of the tumour. There may also be a role
automatically.
for sequential instillations of chemotherapy and BCG.
# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Fundació Puigvert, Cartagena No. 340–350,

08025 Barcelona, Spain. Tel. +34 93 416 97 00; Fax: +34 93 416 97 30.
E-mail address: jpalou@fundacio-puigvert.es (J. Palou).

1. Introduction or immunotherapy. The goals of intravesical ther-

apy are to (1) avoid post-TURB implantation of
Transurethral resection of the bladder (TURB) is well tumour cells, (2) eradicate residual disease, (3)
established as the standard initial intervention for prevent tumour recurrence, and (4) delay or reduce
non-muscle-invasive bladder cancer (bCA) and the tumour progression. This article considers the
first step toward a correct diagnosis and subsequent mechanisms of action of the various agents used
intravesical adjuvant treatment with chemotherapy post-TURB for the intravesical treatment of non-
1569-9056/$ – see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2008.04.006
 european urology supplements 7 (2008) 542–547
Table 1 – Classification of risk groups according to the
2006 European guidelines [1]
Low risk Intermediate High
risk risk
G1–2Ta Multifocal G2Ta, Multifocal G2T1,
G1T1, solitary G2T1 G3Ta–T1, CIS
muscle-invasive bCA and the evidence for the
efficacy and safety of these treatments according
to the three main risk groups (Table 1) [1].
2. Methods
2.1. Bacillus Calmette-Guérin
Bacillus Calmette-Guérin (BCG) acts by means of an
immunological reaction strongly associated with cell apop-
tosis. Furthermore, the findings of several studies suggest
that the immune response cascade in local areas of the
bladder is involved in the anti-tumour mechanism of BCG.
However, the detailed mechanism remains to be clarified
[2,3].
According to de Boer and colleagues, there is a correlation
between the level of interleukin 8 (IL-8) produced at the initial
BCG instillation and the patient’s immune responsiveness [4].
Shintani et al also report that the clinical efficacy of BCG can be
predicted from the IL-8 level within 6 h of intravesical BCG
instillation [5]. They measured urinary cytokine levels 4 h after
the sixth instillation of intravesical BCG therapy and found
infiltration of granulocytes into the bladder wall and dom-
inancy of CD4+ cells.
2.2. Chemotherapy
The effect of early chemotherapy instillations may be
explained by their destruction of circulating tumour cells
that could otherwise implant themselves at the site of the
resection or by their ability to eradicate any small tumour that
remains following incomplete resection. To obtain the best
results from early instillation, chemotherapy must be admi-
nistered soon after TURB [6,7]. The duration of the effect (ie,
time to first recurrence) varies in different studies. Solsona
et al suggest that a single, early instillation of chemotherapy
remains effective for 2 yr post-TURB [8].
The main anti-tumour mechanism of mitomycin C (MMC),
an alkylating agent isolated from Streptomyces caespitosus, is
not known, but its union with DNA is believed to inhibit DNA
synthesis and cause double string rupture. Another theory is
that use of MMC leads to production of superoxide free
radicals that affect the integrity of DNA and cause cell necrosis
[9].
Alkalinisation of urine and low patient water intake may
improve the results of MMC treatment [10]. The clinical
efficacy of multiple intravesical instillations of MMC is difficult
to determine from the literature, because the reported series
varies in patient populations, doses, instillation volumes, and
indwelling times.
543
Doxorubicin, an anthracycline antibiotic, has limited
efficacy in bCA treatment [11]. Epirubicin, a derivative of
doxorubicin, can be effective in patients at intermediate risk
[12]. Thiotepa acts as an alkylating agent. Its efficacy for
tumour prophylaxis has been demonstrated in several trials,
but it has haematological side effects resulting from systemic
absorption [13]. Gemcitabine, a deoxycytidine analogue used
in chemotherapy against several tumours, including systemic
therapy for advanced bCA, inhibits growth activity, mediates
apoptosis, and has been shown to be effective and well
tolerated. It appears to be one of the most active systemic
therapies against transitional cell carcinoma (TCC), with
significantly better activity than intravesical thiotepa, doxor-
ubicin, epirubicin, or MMC, but further studies are needed
to establish its usefulness as an intravesical treatment
[14,15].
2.3. Treatment options
TURB followed by early intravesical chemotherapy instillation
(for example, with MMC) is the treatment of choice for low-risk
superficial bladder carcinoma (Table 2). This strategy has been
shown to reduce the risk of recurrence and possibly prevent
the implantation process [6].
The treatment of choice for intermediate-risk non-muscle-
invasive bCA is either chemotherapy or immunotherapy,
according to the 2006 guidelines from the European Associa-
tion of Urology (EAU) [1]. A meta-analysis of 11 randomised
controlled trials comparing various intravesical chemothera-
pies with TURB alone has shown that intravesical chemother-
apy is associated with a 44% reduction in tumour recurrence at
1 yr, with an odds ratio of 0.56 (95% CI, 0.48–0.65; p < 0.00001)
[16]. The analysis also showed that short-term, 1-yr and 2-yr
schedules of intravesical therapy are associated with—
respectively—a 32%, 31%, and 73% reduction in tumour
recurrence compared with TURB alone. This suggests that
longer schedules may be more beneficial than shorter
schedules. In two meta-analyses focusing on the intermedi-
ate-risk group, there seemed to be no difference in recurrence
between intravesical chemotherapy and immunotherapy
[17,18].
For high-risk tumours, post-TURB treatment with BCG has
become one of the most successful and low-cost immu-
notherapies available. It is highly effective for the prevention
Table 2 – Treatment options by risk group
Risk group Treatment
Low risk Early chemotherapy
Intermediate risk Early chemotherapy
Chemotherapy
Immunotherapy
High risk Immunotherapy
Chemotherapy + immunotherapy
Chemotherapy + hyperthermia
Chemotherapy + EMDA
Cystectomy
EMDA, electromotive drug administration.
544 european urology supplements 7 (2008) 542–547
of recurrence and progression of Ta and T1 bladder tumours
and carcinoma in situ (CIS) compared with TURB alone [1].
Unfortunately, all of the above adjuvant treatments have
limitations in terms of disease recurrence or progression and
morbidity. There is increasing interest in alternative first-line
drugs (eg, gemcitabine and apaziquone [EO9]) [19,20], although
the results are not yet mature, and in second-line therapies
(eg, intravesical microwave hyperthermia in combination
with intravesical chemotherapy or electromotive drug admin-
istration [EMDA; 21,22]). The combination of intravesical
mitomycin and the application of hyperthermia (428, delivered
using a microwave applicator) has been shown to reduce
recurrence [21]. Furthermore, there is evidence of a decrease in
disease recurrence and even in disease progression with the
sequential combination of BCG and electromotive mitomycin,
which increases the penetration of the drug into the bladder
wall [23].
3. Results
A meta-analysis of the results of randomised clinical
trials comparing TURB alone with TURB plus one
immediate instillation of chemotherapy (epirubicin,
MMC, thiotepa, or pirarubicin) has shown that a
single, immediate chemotherapy instillation signif-
icantly decreases the risk of bCA recurrence in
patients with stage-Ta/T1 single and multiple
bladder tumours, and the authors recommend this
strategy as the treatment of choice for patients with
one low-risk papillary tumour [6]. Further intrave-
sical treatment is needed for patients with inter-
mediate-risk and high-risk tumours, although
patients who have received an early post-TURB
instillation do not seem to require long-term
maintenance—6 mo of intravesical chemotherapy
produces good results [24].
In a Cochrane meta-analysis, Shelley et al con-
clude that post-TURB instillation of BCG provides
significantly better prophylaxis of tumour recur-
rence in Ta and T1 urothelial bCA compared with
TURB alone [25]. Two meta-analyses have also
demonstrated delayed disease progression in
patients treated with BCG [26,27].
3.1. BCG versus chemotherapy
Various studies have shown that intravesical BCG
produces better results than chemotherapy [28–31].
For example, in one multicentre study of patients
with Ta and T1 tumours and without CIS, the
estimated probability of being disease free at 5 yr
was 17% after doxorubicin, compared with 37% after
BCG immunotherapy ( p = 0.015) [11].
However, there have also been several studies
showing few differences between chemotherapy
and immunotherapy in intermediate-risk bCA, so
both types of treatment are accepted as standard in
this patient group [1]. One randomised, multicentre
phase 4 clinical trial of short-term and long-term
MMC versus short-term BCG after TURB for non-
muscle-invasive bCA suggests that patients with Ta/
G1 tumours are significantly less likely to experience
recurrence after long-term MMC (3 yr) than after
short-term BCG (6 wk) or short-term MMC (6 wk),
and without enhanced toxicity [31]. Patients treated
with short-term BCG instillations had a 25.1%
recurrence rate at 1 yr, compared with 25.7% in
the short-term MMC group and 10.4% in those
receiving long-term MMC. Recurrence-free rates in
the second and third year were, respectively, 70.5%
and 68.6% for short-term MMC, 68.5% and 65.5% for
short-term BCG, and 88.3% and 86.1% for long-term
MMC. Sekine et al have compared the efficacy of
intravesical therapy with MMC plus doxorubicin
versus BCG in 42 patients with CIS and conclude that
both strategies are equally effective as initial
therapy and that a combination of both would be
the most efficient treatment for CIS [32]. In 2007, the
Greek Bladder Cancer Study Group presented the
results of a prospective, randomised, comparative
study of high-dose (80 mg) intravesical epirubicin
and BCG as prophylaxis for cancer recurrence in
234 patients with intermediate-risk superficial TCC
[33]. The treatments were given 2 wk after TURB,
then weekly for 6 wk, followed by 3 weekly
instillations at 3, 6, 12, 18, 24, 30, and 36 mo. The
results in 212 patients appropriate for assessment
were a disease-free survival of 23.24  10.3 mo for
the epirubicin group and 23.26  10.2 mo for those
treated with BCG ( p = 0.0778). The authors conclude
that a high dose of intravesical epirubicin in an
extended treatment schedule is well tolerated and
as effective as BCG in the prevention of recurrence
after TURB in patients with intermediate-risk super-
ficial bladder tumours.
3.2. Sequential BCG and chemotherapy
Intravesical chemotherapy and BCG have different
mechanisms of action and may thus have a
potentiating anti-tumour effect. For example, intra-
vesical chemotherapy causes a chemical cystitis,
which has a positive effect on the adherence of BCG
particles to the bladder wall—a necessary step in the
BCG mechanism [34,35]. Several studies have shown
that the efficacy of immunotherapy is increased by
prior chemotherapy [35].
Di Stasi et al have investigated the effect of
sequential BCG and MMC, but starting with BCG to
provoke inflammation of the mucosa and facilitate
penetration of MMC into the bladder wall. They also
 european urology supplements 7 (2008) 542–547
used EMDA to further enhance the penetration of
MMC. They found that BCG plus MMC produced
lower cancer recurrence and progression rates than
BCG used alone [23]. However, the Nordic Urothelial
Cancer Group found that 1 yr of BCG monotherapy
was more effective than alternating MMC and BCG
at reducing disease recurrence in a study of
304 patients with CIS [36].
A combination of a chemotherapeutic drug and
BCG can also have an impact on treatment toxicity
[35]. In a prospective, randomised, multicentre study
of 188 patients, the efficacy of alternating MMC and
BCG was equal to MMC monotherapy, and there was
less toxicity in the alternating treatment group
compared with earlier BCG monotherapy results [37].
4. Discussion
There is controversy over the optimal schedule for
BCG maintenance. Many different maintenance
schedules have been used, although the instillations
are classically given according to the empirical six-
weekly induction schedule introduced by Morales in
1976 [38]. The US Southwest Oncology Group has
shown that maintenance treatment reduces disease
recurrence and progression compared with induc-
tion therapy alone [39], but only 16% of patients in
the maintenance group finished the scheduled
instillations. It has been suggested, based on
published evidence for different BCG schedules,
that at least 1 yr of maintenance treatment is
necessary [1], but this assertion is still to be
confirmed.
In a bid to reduce the toxicity of BCG, some
authors have proposed cutting the instilled dose to
one-third or one-quarter of the normal level. For
example, a Spanish group has published the find-
ings of a multicentre, randomised, prospective trial
comparing a standard 81-mg dose of intravesical
BCG with a 27-mg dose in the treatment of super-
ficial bCA, showing no overall difference in efficacy
[40]. Nevertheless, there was a suggestion that a full
dose of BCG might be more effective in multifocal
disease. Another study compared low-dose BCG
(27 mg), very low-dose BCG (13.5 mg) and MMC [41].
The authors conclude that 27 mg (one-third of the
standard dose) appears to be the minimum effective
dose for adjuvant treatment of intermediate-risk
superficial bladder tumours. The incidence of
toxicity was similar in the low-dose and the very
low-dose groups. The European Organisation for
Research and Treatment of Cancer is now running a
trial of the one-third dose; it will be interesting to see
whether the results confirm the earlier findings.
545
5. Conclusion
For intermediate-risk patients, a cycle of che-
motherapeutic instillations—usually with MMC or
epirubicin—is safe and effective in reducing the
short-term risk of recurrence, but the usefulness of
maintenance treatment is open to debate. BCG it is
also effective in intermediate-risk patients [42] and
is accepted as an alternative to chemotherapy.
BCG has become the treatment of choice for high-
risk non-muscle-invasive bCA and for patients in
whom chemotherapy fails. It is superior to intrave-
sical chemotherapy in terms of both disease recur-
rence and progression to muscle-invasive disease
[16,27,39]. Future studies will determine whether
lower doses of BCG are enough to maintain the same
oncological results with reduced morbidity.
Conflicts of interest
Juan Palou acts as a company consultant for Sanofi
Pasteur, Eli Lilly and Company, and Amgen and has
been involved in trials funded by Eli Lilly and
Company and Zambon Group.
Acknowledgement
Janis Smy of Succinct Healthcare Communications
and Consultancy (www.succinctcomms.com) pro-
vided editorial assistance with this article.
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