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 BC G 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 Although the marginal benefit of adding 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 BCG-refractory 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
Apaziquone / Alkylating agent, inhibits DNA synthesis / 4mg/40mL qweek x 6 weeks, 1 hr per treatment

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 non-muscle 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 wall-DNA 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 GM-CSF; 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 Calmette-Guérin 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 wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed. J Urol, 181: 1040, 2009