Preclinical analyses of intravesical chemotherapy for prevention of bladder cancer progression

Abstract

There is a critical need to identify treatment options for patients at high risk for developing muscle invasive bladder cancer that avoid surgical removal of the bladder (cystectomy). In the current study, we have performed preclinical studies to investigate the efficacy of intravesical delivery of chemotherapy for preventing progression of bladder cancer. We evaluated three chemotherapy agents, namely cisplatin, gemcitabine, and docetaxel, which are currently in use clinically for systemic treatment of muscle invasive bladder cancer and/or have been evaluated for intravesical therapy. These preclinical studies were done using a genetically-engineered mouse (GEM) model that progresses from carcinoma in situ (CIS) to invasive, metastatic bladder cancer. We performed intravesical treatment in this GEM model using cisplatin, gemcitabine, and/or docetaxel, alone or by combining two agents, and evaluated whether such treatments inhibited progression to invasive, metastatic bladder cancer. Of the three single agents tested, gemcitabine was most effective for preventing progression to invasive disease, as assessed by several relevant endpoints. However, the combinations of two agents, and particularly those including gemcitabine, were more effective for reducing both tumor and metastatic burden. Our findings suggest combination intravesical chemotherapy may provide a viable bladder-sparing treatment alternative for patients at high risk for developing invasive bladder cancer, which can be evaluated in appropriate clinical trials.