BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG

Abstract

Intravesical immunotherapy with live attenuated BCG remains the standard of care for patients with high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but recurrence is frequent and progression to invasive cancer is a concern. No established and effective intravesical therapies are available for patients whose tumours recur after BCG, representing a clinically important unmet need. Development and discovery of treatment options for BCG-unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care expenditures, and mortality related to bladder cancer. This Review of treatment options after BCG failure focuses on principles of optimal management emerging therapies, thus enabling a synthesis of recommendations for management for such patients.

Current clinical trials in non–muscle invasive bladder cancer

“…[7] In general, while most patients are free of recurrence at 1 year with induction and maintenance BCG, as many as 75% develop a new tumor in 5 years, with a proportion progressing to muscle-invasive bladder cancer. [7] Many clinical trials are exploring new treatment options for these patients, and here we discuss the recently completed and currently ongoing trials in BCG naïve NIMBC patients (see table 1 and figure 1). …”

“…More specifically, BCG-refractory refers to presence of persistent high-grade cancer 6 months after the start of induction therapy, or cancers that have progressed by grade or stage 3 months after the start of the induction therapy. [7] On the other hand, “BCG-relapse” refers to patients who experience cancer recurrence after achieving a disease-free state at 6 months after treatment. [7] These are relatively new definitions and may not be reflected in trials started before 2015.…”

“…[7] On the other hand, “BCG-relapse” refers to patients who experience cancer recurrence after achieving a disease-free state at 6 months after treatment. [7] These are relatively new definitions and may not be reflected in trials started before 2015. The standard-of-care for these patients remains radical cystectomy, which has been shown to have significant disease-specific survival advantage if performed “early” (within 2 years of initial BCG treatment).…”

“…The standard-of-care for these patients remains radical cystectomy, which has been shown to have significant disease-specific survival advantage if performed “early” (within 2 years of initial BCG treatment). [7,29] When cystectomy is not an option, Valrubicin is the only FDA approved intravesical agent available, albeit only for BCG-refractory CIS, with the disease-free response rate 16% at 12 months. [7] Therefore, many trials have emerged in this space (Figure 1 and table 2).…”

Alternative therapies in patients with non-muscle invasive bladder cancer

“…[7] A recent systematic review suggested that 6 weeks of induction therapy with BCG is associated with a decreased recurrence (RR 0.56 95% CI 0.43-0.1) and progression (RR 0.39, 95% CI 0.24-0.64) risk compared to TUR-BT alone. [8] Some patients may have contraindications to BCG and some patients and physicians may prefer to use intravesical chemotherapy in recurrent low grade tumors. Several agents are being used for intravesical chemotherapy; primarily exert their effects by disrupting DNA synthesis, such as mitomycin C (MMC) which is the most commonly used chemotherapeutic agent.…”