San Diego, CA USA (UroToday.com) Dr. Cookson gave an overview on the management of BCG refractory NMIBC. BCG has been shown to be a standard for most intermediate and all high-risk NMIBC. It is superior to intravesical chemotherapy and has been endorsed by multiple international guidelines. The efficacy is best with maintenance therapy. SWOG 8507 trial illustrates a 2-year recurrence free survival (RFS) of 82% vs 62% with and without maintenance respectively.
Despite the benefits of BCG, long-term disease free and progression free survival is difficult to achieve. Up to 50% with high risk NMIBC will recur after BCG therapy. Risk of progression also increases with each round of failed therapy. Disease progression can be lethal and effective salvage therapy is needed. Potential causes of BCG failure are host immune incompetence, inadequate resection, resistant or non-antigenic tumor, inadequate treatment schedule inadequate dose, inadequate contact of BCG and excess BCG inducing immunosuppression.
Definitions of BCG failure are critical:
1. Intolerant: recurrent disease in setting of inadequate BCG dose due to side-effects.
2. Resistant: recurrence of or improving disease that resolves with further BCG.
3. Relapsing: recurrence after achieving 6 month of complete relapse.
4. Refractory: No complete relapse by 6 months after BCG. Not improving or worsening disease despite two courses of BCG or maintenance.
Six months is the treatment period to identify high-risk tumors as truly refractory. While anatomic definition of refractory state is the standard, the group from MD Anderson is investigating a molecular definition of failure using FISH assays.
Cystectomy has a high rate of cure in BCG refractory NMIBC but before progression to muscle invasion. However, morbidity remains high and not all patients are candidates for cystectomy.
Valrubicin is approved by FDA as an intravesical therapy in patients who are BCG refractory. While initial results were exciting (32% complete relapse at 6 months), late results were not so much (only 8% remained NED at 30 months). This highlights the need for additional bladder-conserving therapies.
Other modalities that are under investigation are intravesical Gemcitabine, Taxane, and BCG + IFN. Hyperthermia Synergy is also being investigated. It involves delivery of hyperthermic chemotherapy with temperatures of 41 to 44 degree Celcius. It is thought that this would lead to direct cytotoxic effect and enhanced penetration of chemotherapy agent. Photodynamic Therapy and checkpoint inhibitors are also under investigation.
Dr. Cookson concludes that clinical BCG failure is now better defined. Cystectomy is the standard of care. Best salvage therapy is yet to be defined. Single agent chemotherapy has modest complete response and best results are seen with maintenance. In future, we need to develop molecular tools to predict response or failure, better surgical strategies to eradicate CIS, and a personalized therapy tailored to individual patient and tumor risk profiles.
Presented By: Michael S. Cookson , MD