Antitumor Efficacy of Intravesical BCG, Gemcitabine, Interferon-α and Interleukin-2 as Mono- or Combination-Therapy for Bladder Cancer in an Orthotopic Tumor Model

OBJECTIVE: To reduce adverse effects and improve efficacy of intravesical BCG for bladder cancer, alternative treatment options were investigated in an orthotopic rat tumor model. METHODS: Superficial bladder cancer was established in syngeneic female rat bladders by instillation of AY-27 cells. Animals were randomly assigned to treatment groups including dose escalation of intravesical BCG with or without interferon-α (IFN-α) or interleukin-2 (IL-2); or graded doses of gemcitabine alone; or BCG plus gemcitabine. Treatments were given twice weekly for 3 weeks. Rats in control groups received saline instillations. Treatment response was monitored by animals’ well-being, survival days, tumor growth inhibition, and histological examination at necropsy. RESULTS: Rats receiving monotherapy with intravesical BCG, gemcitabine, or IFN-α, attained significantly better survival and tumor reduction compared with control (P = 0.002; 0.001; 0.002, respectively, Log-rank Test). A dose-dependent treatment response was observed in animals with established bladder tumor receiving escalated BCG instillations. Only high-dose BCG significantly improved animal survival. Although high-dose BCG plus gemcitabine or IFN-α did not increase benefit over monotherapies, low-dose BCG plus IL-2 did show improved efficacy (P = 0.01). CONCLUSION: Intravesical monotherapies with gemcitabine and IFN-α were as effective as BCG for treatment of early non-muscle-invasive urothelial bladder cancer in this immune competent rat model. Combining these agents with high-dose BCG did not further increase efficacy. However, combining low-dose BCG with IL-2 enhanced BCG effectiveness.