Many different definitions for BCG failures exist in the literature. This has impaired adequate comparison of trials simply on the basis of improper risk assessment. While several authors have proposed variations in definitions of “failure,” what is practically important is to differentiate “refractory disease” from “recurrent disease.”
Patients have BCG refractory disease if they fail to achieve a disease-free state within six months (after induction with or without maintenance). BCG recurrent (or relapsing) disease implies recurrence of disease after being rendered disease-free at the six-month evaluation. Patients who develop a recurrence in the first year (or even first two years) are different from those who develop a late recurrence and are important for trial design.
Lastly, O’Donnell recommends that we consider an additional group of patients as “BCG intolerant,” i.e., recurrence in the setting of inadequate BCG dosing due to patient intolerance (World J Urol. 2006;24:481-487).
Possible management of BCG relapses and early failures include repeat courses of BCG; however, this must be undertaken with extreme caution because there are few studies examining the long-term effects on progression (Hinyokika Kiyo. 2005;51:539-543; Br J Urol. 1995;75:180-184; J Urol. 1990;143:710-712).
A second course of BCG in this population may achieve a response rate of up to 34%. Nonetheless, especially for high-grade disease, radical cystectomy should be offered as definitive therapy in BCG failures; especially in those receiving adequate doses of BCG with induction and with persistent disease at three to six months.
For patients who recur “late” (two or more years after response), re-induction with BCG can be considered, but close follow-up is required to monitor for progression.
BCG + interferon alpha 2b
Interferon alpha 2b (IFN·-2b) has been intensely studied in its application to bladder cancer, and has not been shown to decrease progression as a monotherapy (Br J Urol. 1998;82:829-834; Urol. 1997;49:187-190). IFN-2b combined with BCG has been tried for BCG failures. (IFN-2b is typically given between 50-100 million units along with dose reductions of BCG.)
A phase II multicenter trial evaluated 1,007 patients, and of BCG failures treated with IFN-2b + BCG, 45% were disease-free at a median follow-up of 24 months (Urol Oncol. 2006;24:344-348). This trial found overall no advantage to the addition of IFN-2b to BCG versus what one would expect in historical controls of BCG alone in BCG-naïve patients.
For this reason, BCG should be given alone as first-line therapy. It is noteworthy that this trial failed to show any benefit for combination therapy in patients who had failed two prior courses of BCG or those who had recurrence of disease within two years of induction therapy. Thus, the initial enthusiasm for combination therapy with IFN-2b must be tempered with the realization that radical cystectomy remains the mainstay of therapy for patients failing BCG therapy (provided they have received at least nine instillations, i.e., one induction and at least one maintenance course).
In 1996, a pooled meta-analysis of 2,535 patients by the European group EORTC and the Medical Research Council (MRC) found a significant prolongation of the disease-free interval, but no effect on progression, metastasis, or survival with intravesical chemotherapy after TUR (J Urol. 1996;156:1934-1940). There are no data in the literature that demonstrate in-travesical chemotherapy prevents progression.
However, not all patients will be able to receive BCG (i.e., patients that have received the BCG vaccine or immunosuppression secondary to transplantation) and not all BCG-failing patients are willing to undergo radical cystectomy. Thus, in select patients, intravesical chemotherapy is useful.
Mitomycin C (MMC) is an alkylating agent that inhibits DNA synthesis in G1 and S phases of the cell cycle (molecular weight [MW] 334 kDA). Studies that have compared MMC to BCG have shown that BCG with maintenance is superior to MMC (Urology. 2004;63:682-686; Urol. 1998;52:403-410; Eur J Cancer. 1993;29A:1672-1676). Gardmark et al recently published 10-year data on patients who received BCG with maintenance versus MMC for high-risk bladder cancer.
They found no significant difference in recurrence or progression (BJU Int. 2007 Jan 22 [published online ahead of print]. Intravesical use of MMC after TUR is growing. A meta-analysis of 1,476 patients who received intravesical chemo-therapy immediately after TUR showed a 39% reduced odds of recurrence (J Urol. 2004;171[6 Pt 1]:2186-2190). For high-risk bladder tumors, 40 mg of MMC in 20 mL of normal saline should be instilled in the bladder for 60 minutes. Common adverse effects are chemical cystitis and severe contact dermatitis if in contact with the skin.
BCG + electromotive MMC
In a novel approach, Di Stasi et al randomized 212 patients with pT1 bladder cancer to receive BCG alone or BCG for two weeks followed by electromotive MMC (in-travesical current 20 mA for 30 min). After a median follow-up of 88 months, they found that BCG + electromotive MMC group had a higher disease-free interval versus BCG alone (69 vs. 21 months) (Lancet Oncol. 2006;7:43-51).
Additionally, the BCG + electromotive MMC group had lower recurrence rates, decreased progression, and decreased overall and disease-specific mortality. The same authors showed in a previous study using electromotive MMC that serum levels of MMC were six times that of normal intravesical MMC (J Urol. 2003;170:777-782). These higher, possibly “chemotherapeutic,” systemic levels in theory may be the reason there are better overall outcomes in this study. Importantly, the value of this approach has not been evaluated in BCG failures.
Anthracycline antibiotics work by binding nucleic acid base pairs, inhibiting topoisomerase II (DNA gyrase) and protein synthesis, making its action cell cycle non-specific. Most commonly used anthracycline antibiotics for intravesical therapy are doxorubicin (MW 543.5 kDA), epirubicin (MW 580 kDA), and valrubicin (MW 723.6 kDA). Small studies have shown that doxorubin results in a decreased recurrence rate compared with TUR alone, but is inferior to BCG (J Urol. 1990;143:502-506).
Its side effect profile has made it less utilized clinically. Epirubicin has established activity in NMI bladder cancer. A recent EORTC trial compared BCG versus epirubicin for CIS of the bladder and found no differences in terms of complete response rates (BCG 65% and epirubicin 56%), time to progression, or survival (J Urol. 2005;173:405-409). Epirubicin had few adverse effects but BCG appeared to produce more durable responses. Valrubicin is a semi-synthetic derivative of doxorubicin, being lipid-soluble, and it rapidly traverses cell membranes.
Steinberg et al studied valrubicin as a second-line therapy in patients with BCG refractory disease with a total of 90 patients and found that 21% achieved a complete response at a median follow-up of 30 months (J Urol. 2000;163:761-767). Valrubicin was voluntarily taken off the market in 2002 secondary to drug stability issues but may be re-released later this year.