In the NMIBC state, there are ongoing phase 2 trials assessing the role of immune checkpoint inhibitors in the BCG unresponsive status. These include the KEYNOTE-057 trial (Pembrolizumab), the S1605 trial (Atezolizumab), and the ADAPT-BLADDER trial (Durvalumab).
In the MIBC state, TMT strategy includes maximal/radical TURBT (shown to be the strongest predictor of both oncologic control and TMT success) and chemoradiation. Complete TURBT results in a 20% increase in complete response and long term bladder preservation. The ideal TMT patient has unifocal cT2N0M0 disease (no palpable tumor on exam), with no hydronephrosis, no CIS, good baseline urinary function, no variant histology, ability to undergo maximal TURBT, and no involvement of prostatic stroma. Unfortunately, these ideal patients represent only 10-15% of MIBC patients. The radiation component of the TMT includes 52-59 Gy to the whole bladder with tumor site boost. Chemotherapy regimens vary and include cisplatin, cisplatin with gemcitabine or paclitaxel, 5 FU and mitomycin C, and vinblastine. TMT can be given in continuous manner (a radiation induction and consolidation dose is given before and after a restaging TURBT, respectively), or in a split manner (full radiation dose is given after maximal TURBT, and 1-3 months later a restaging TURBT is performed). Long term outcomes after TMT include an overall 5 and 10 year survival of 57% and 36%, respectively.
Comparison of radical cystectomy (RC) to TMT shows similar results with a non-organ confined 5 year overall survival (OS) of 47-49% for both modalities. But RC is still the favoured therapeutic approach. This is due to several reasons: the fact that RC with neoadjuvant chemotherapy (NAC) offers best survival results, lack of response predictors in TMT, no need to “cherry pick” patients in RC as in TMT, RC eliminates all local recurrence and need for bladder surveillance, high complication rate of salvage RC after TMT precluding continent diversion, and the added benefit of lymphadenectomy and better staging of the primary tumor. Additionally, TMT non responders have a 20-40% lower 5 year cancer specific survival (CSS) following salvage RC compared to patients undergoing immediate RC.
Unfortunately there is no consensus as to the frequency of post TMT surveillance cystoscopy, and usually standard high risk NMIBC protocols are employed. The need for cystoscopy surveillance protocol significantly adds to the management costs of TMT and also affects the quality of life of patients. Even after complete response, local recurrence rate is 24-46% within the bladder and the 10 year distant metastases rate is 35%. Median time to recurrence is 18 months with up to 92% of recurrences being high risk tumors. Up to 19% of recurrences are MIBC with 30% requiring salvage RC, with its associated higher risk of complications, and need for an ileal conduit (with its accompanying quality of life issues).
Dr. Bivalacqua printed out some unresolved issues with TMT. There is a discordance between clinical staging and pathologic staging with 41.9% of patients upstaged after RC. Currently, less than 10% of MIBC patients are treated with TMT, suggesting that it is only offered in centers of excellence and therefore published outcomes may not be reproducible. There is variability in TMT administration with some centers exercising Split protocols and other continuous. There are also inconsistencies regarding therapy for pelvic nodes.
In summary, new local intravesical and systemic agents are being developed and novel clinical trials are underway in NMIBC BCG unresponsive patients. TMT is an effective treatment modality in selective MIBC patients who meet pre-defined criteria. Urinary/tissue biomarkers must be developed to assess responsiveness to TMT therapy in MIBC patients.
Presented By: Trinity Bivalacqua, MD, PhD, James Buchanan Brady Urologic Institute, Johns Hopkins Medical Institutions
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
at the 2017 Bladder Cancer Academy - June 9 - 10 - Schaumburg, Illinois, USA