Intravesical therapy for BCG-refractory non-muscle invasive bladder
cancer: An update
Todd M. Morgan and Sam S. Chang
Vanderbilt University
for
This article also appeared in AUANews, November 2009, pp 23-24. Reprinted with permission.
Introduction
Like the differing definitions of “BCG-refractory”, there is no singular treatment
approach for patients with recurrent and/or resistant bladder cancer following BCG.
While the standard therapy, radical cystectomy, provides a significant survival benefit, it
may in fact “overtreat” many patients and is associated with potential morbidity. There
continues to be a real need for intravesical agents capable of altering the course of
recurrence, and, more importantly, progression in patients with BCG-refractory bladder
cancer. In the absence of strong evidence supporting a single regimen for these
patients, a multitude of intravesical agents and therapies have been utilized. This article
will briefly review the current options for therapy
There are several treatment-guideline principles of intravesical therapy for non-muscle
invasive bladder cancer. First, maintenance BCG therapy is superior to mitomycin C
(MMC) in the prevention of tumor recurrence and, for CIS, likely decreases the chance
of progression. Second, patients with CIS who undergo BCG treatment have a complete
response rate of up to 75%. Third, maintenance BCG treatment provides a sustained
survival benefit in these patients but can be associated with treatment toxicity. Fourth,
patients who have a recurrence after a single induction course of BCG may undergo
another induction and/or maintenance course of BCG and obtain a positive response.
However, failure to respond after the initial course—and continued disease after
additional treatments—signals particularly high-risk disease.
Optimizing current regimens
The current bladder-sparing approach to treating patients with BCG-refractory disease
can be divided into three categories: optimization of current regimens, newer
intravesical chemotherapeutic agents, and new immunogenic agents. There are several
ways in which traditional agents are being augmented to improve their efficacy. The
addition of intravesical interferon-a (IFN-a) to BCG has held the theoretical promise of
synergistically enhancing the immune response produced by BCG. In a multicenter
phase II trial of 1,007 patients previously failing BCG, 45% were disease free 24-months
after the administration of BCG plus IFN- a
IFN-a cannot be determined from this study, it does show that this regimen can be
successful for some patients failing intravesical BCG. Not surprisingly, patients failing
only one prior course did better than those who had already received two courses of
BCG; however, it was still effective for a small group of patients failing BCG twice if there
was at least a one-year lapse between disease recurrences.1 Additional predictors of
poor response included tumor size (>5cm), T1 disease, and multifocality (>5 tumors).
Significant efforts have also been made to optimize MMC for the treatment of BCGrefractory patients. In particular, studies have focused on two novel delivery methods—
microwave hyperthermia (Synergo) and electromotive drug administration (EMDA).
Both methods appear to be safe and outperform MMC alone, although the efficacy
EMDA in BCG failures has not been reported. EMDA is thought to work by increasing
MMC uptake across cell membranes and has shown efficacy similar to BCG in
treatment-naïve patients.2 Similarly, microwave hyperthermia increases cellular
permeability, however it may also rely on the increased heat-sensitivity of malignant
cells compared with benign urothelium. A recent study evaluated 51 patients with CIS,
most previously treated with either BCG (n=34) or another intravesical agent. The
authors reported a 92% complete response rate and a 45% durable response at 2 years.
Further prospective evaluation is needed to determine whether the efficacy of these
treatments is sufficient to justify use of these devices.
Newer chemotherapeutic agents
A large number of newer chemotherapeutic agents are being evaluated for the
treatment of BCG-refractory disease (Table 1). Currently, valrubicin, now available again,
remains the only FDA-approved drug specific for the treatment BCG-refractory CIS. In a
heavily pre-treated albeit small group of patients, it has demonstrated a 21% complete
response rate and a median response duration of at least 18 months. Additionally, 10
patients who were non-responders had disease regression from CIS to low-grade
papillary tumors.
Table 1: Intravesical chemotherapeutic agents utilized and/or under investigation in the
treatment of BCG-refractory superficial bladder cancer.
Drug
Mechanism
Regimen
Mitomycin C
Antibiotic, alkylating agent, inhibits DNA
synthesis
40mg/20mL qweek x 6 weeks, 2 hrs per
treatment
Gemcitabine
Deoxycytidine analog, inhibits DNA
synthesis, triggers apoptosis
2000mg/50mL qweek x 6 weeks, 1-2 hrs
per treatment
Docetaxel
Microtubule inhibitor, causes cell cycle
arrest and cell death
75mg qweek x 6 weeks, 2 hrs per
treatment
Doxorubicin
Antibiotic, intercalates DNA and inhibits
topoisomerase II
50mg/mL qweek x 6wks, 1-2 hrs per
treatment
Valrubicin
Doxorubicin analog, inhibits DNA synthesis
800mg/75mL qweek x 6 weeks, 2 hrs per
treatment
Suramin
Polysulfonated naphthylurea, inhibits DNA
synthesis, blocks EGF
6000mg/60mL qweek x 6weeks, 2 hrs per
treatment
Alkylating agent, inhibits DNA synthesis
4mg/40mL qweek x 6 weeks, 1 hr per
treatment
Apaziquone
Gemcitabine is another intravesical agent that may hold some therapeutic potential for
BCG-refractory patients. In a Phase II study of 30 patients previously treated with BCG,
50% (15/30) achieved a complete response;3 however, 12/15 (80%) recurred at a
median of 3.6 months. Intravesical gemcitabine has also been used in combination with
MMC for BCG-refractory cancer, with 6 of 10 patients recurrence-free at a median of 14
months. An ongoing phase II trial (SWOG-S0353) is evaluating the efficacy of
gemcitabine in patients with superficial bladder cancer failing two courses of BCG (Table
2).
Table 2: Ongoing clinical trials of intravesical agents in patients with BCG-refractory nonmuscle invasive bladder cancer
Agent
Mechanism
Institution/Sponsor
Phase
Status
Tremelimumab
Anti-CTLA-4 monoclonal antibody;
ihhibits negative costimulatory
receptor on T cells
University of
Wisconsin
I
Not yet
open
CG0070
Oncolytic virus expressing GM-CSF
Cell Genesys, Inc.
I
Ongoing, not
recruiting
Mycobacterium w
Atypical mycobacterium;
immunomodulator
Cadila
Pharmaceuticals
I
Enrolling
Gemcitabine
Deoxycytidine analog, inhibits DNA
synthesis, triggers apoptosis
SWOG (S0353)
II
Enrolling
Vicinium
Anti-EpCAM antibody conjugated to
pseudomonas endotoxin A
Viventia Biotech
II
Ongoing, not
recruiting
DTA-H19/PEI
DNA plasmid carrying diptheria toxin
A gene driven by transcription factor
upregulated in tumor cells
Biocancell
Therapeutics Ltd
II
Enrolling
Abraxane
Paclitaxel (microtuble stabilizer)
bound to albumin nano-particles
Columbia University
I/II
Enrolling
Mycobacterial cell wallDNA complex
Mycobacterial cell walls complexed to
mycobacterial DN; immunomodulaor
Bioniche Life
Sciences, Inc.
II/III
Ongoing, not
recruiting
Different formulations of docetaxel are also in clinical trials. A recent evaluation of 13
BCG-refractory patients treated docetaxel reported a complete response in 10/13 (77%)
and a durable response in 6/13 (46%) at a median follow-up of 13 months.4 Other
intravesical agents under investigation include apaziquone, an MMC derivative with
increased potency, and Vicinium, an anti-EpCAM antibody.
New immunogenic agents
The third approach to intravesical therapy for patients failing BCG involves the use of
new immunogenic agents. Mycobacterial cell wall-DNA complex, composed of
mycobacterial cell walls complexed to mycobacterial DNA on the wall surface, has
demonstrated significant in vitro activity and appears to have efficacy in the post-BCG
setting. A report of 55 patients, most of whom had failed prior treatment with BCG,
gave a complete response rate of 27% and 46% in patients receiving 4mg and 8mg
doses, respectively.5 Treatments were well-tolerated overall, and toxicity was likely less
than would be anticipated with BCG. A Phase II/III trial in BCG-refractory patients is
currently ongoing. Other immunologic agents under investigation include
tremelimumab, an inhibitor of the CTLA-4 negative costimulatory receptor on T cells
(thus activating the immune system); CG0070, a cancer-selective virus expressing GMCSF; and Bexidem, an autologous activated macrophage preparation.
Patients with non-muscle invasive bladder cancer who fail BCG treatment are at
significant risk of disease progression and death from bladder cancer. While some may
benefit from one or more second-line intravesical therapy, the potential advantages
must be balanced with the risk of disease progression. Prompt, timely cystectomy in
treatment-refractory patients, when feasible, currently provides the best chance of
long-term disease-free survival. Yet, continued advances in intravesical therapies are
necessary to provide viable, successful options for these high-risk patients.
References
1.
Gallagher, B. L., Joudi, F. N., Maymi, J. L. et al.: Impact of previous bacille
Calmette-Guérin failure pattern on subsequent response to bacille CalmetteGuérin plus interferon intravesical therapy. Urology, 71: 297, 2008
2.
Di Stasi, S. M., Riedl, C.: Updates in intravesical electromotive drug
administration of mitomycin-C for non-muscle invasive bladder cancer. World J
Urol, 27: 325, 2009
3.
Dalbagni, G., Russo, P., Bochner, B. et al.: Phase II trial of intravesical
gemcitabine in bacille Calmette-Guerin-refractory transitional cell carcinoma of
the bladder. J Clin Oncol, 24: 2729, 2006
4.
Barlow, L., Mckiernan, J., Sawczuk, I. et al.: A single-institution experience
with induction and maintenance intravesical docetaxel in the management of
non-muscle-invasive bladder cancer refractory to bacille Calmette-Guerin
therapy. BJU Int, 104: 1098, 2009
5.
Morales, A., Phadke, K., Steinhoff, G.: Intravesical mycobacterial cell wallDNA complex in the treatment of carcinoma in situ of the bladder after standard
intravesical therapy has failed. J Urol, 181: 1040, 2009