Chemotherapeutic agents for BCG failures are numerous, and none have demonstrated superior efficacy to the other. Importantly, the only drug specifically approved by the FDA for the treatment of BCG-refractory CIS is valrubicin which demonstrated a 21% complete response rate in the BCG-refractory population.12 Gemcitabine, which has been employed in the primary treatment setting, is often used to treat BCG failures. A Phase 2 study of 30 patients previously treated with BCG revealed a 50% (15/30) complete response rate with gemcitabine, although most of these patients suffered a subsequent recurrence.13 There are a number of ongoing trials evaluating the efficacy of gemcitabine in patients who have failed BCG therapy. Docetaxel is another chemotherapeutic agent used intravesically in this setting, and complete response rates up to 77% have been reported.

Lastly, device-assisted therapy continues to hold substantial promise. Electromotive drug administration of MMC increases the ability of MMC to penetrate the urothelium, and appears to improve its efficacy in the setting of BCG-refractory disease. In one study, 4 of 13 BCG-refractory patients (31%) remained disease-free at 15 months.14 Another MMC delivery method, microwave hyperthermia, also acts by increasing cellular membrane permeability. A study of 51 patients with CIS, most previously treated with BCG, reported a 92% complete response rate with a 45% durable response at two years. In addition to its effects on cell membranes, the thermal energy delivered via microwave hyperthermia may also improve treatment efficacy by increasing DNA cross-linking and inhibiting DNA repair.15

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Patients with BCG refractory NMIBC continue to present a management dilemma. While radical cystectomy may currently offer the best long-term cure rates, there is a need for effective intravesical agents that can improve the likelihood of bladder preservation without increasing the risk of disease-specific mortality. Identification of biomarkers that can help predict which cancers are most likely to progress despite intravesical therapy would dramatically aid in the care of these individuals. Additionally, in this era of personalized medicine, the development of biomarkers that can direct the use of specific agents based on the characteristics of each tumor remains a critical aim.