Abstract
BCG is the standard of care for non-muscle invasive high-risk bladder cancer. Notwithstanding the high rate of cure, cancer may recur. A non-muscle invasive high-risk recurrence may be defined as BCG refractory or naïve. BCG refractory patients have been further divided into BCG unresponsive and BCG exposed. A recurrent high-risk bladder cancer within 1 year after BCG induction plus maintenance or two courses of BCG induction defines an unresponsive disease. Any recurrence after 24 months since induction and maintenance should be considered as BCG naïve. The remaining cases are BCG exposed. The standard of care for BCG exposed and naïve patients is another cycle of BCG in the first place, while radical cystectomy should be discussed as alternative with the patient. The preferred therapy for BCG unresponsive patients is radical cystectomy according to AUA or EAU guidelines. However, systemic immunotherapy with pembrolizumab or gene therapy with intravesical nadofaragene firadenovec may be administered for patients unfit or unwilling to undergo radical cystectomy with outcomes superior to intravesical docetaxel, gemcitabine or valrubicin. Our narrative review tries to elucidate BCG refractory definition and treatment specifically regarding alternative therapies to radical cystectomy yet approved or under investigation. The last years have been exciting regarding new developments in this field after a long period of stagnation. Unfortunately, data available on some alternative therapies are mainly limited mainly to Phase I or II studies with a lack of robust evidence, but a clear trend in future treatments has just been drawn.