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Durability of Response: The Achilles Heel of Salvage Combination Immunotherapy with Intravesical Bacillus Calmette Guerin and Interferon-Alpha 2B
Sandip M. Prasad, MD, M. Phil., Stephen J. Eyre, MD, William V. Shappley, III, MD, Kevin R. Loughlin, MD, MBA.
Harvard-Longwood Program in Urology, Boston, MA, USA.

ABSTRACT
Background: The advent of intravesical immunotherapy therapy has significantly improved outcome in high-risk bladder tumors, but the natural history of these tumors following immunotherapy failure has not been examined. We report our institution’s experience with bacillus Calmette-Guerin (BCG) alone and combined with interferon-α2B (INF) in regards to bladder cancer recurrence, disease progression, eventual cystectomy and survival for a cohort of patients receiving these treatment strategy following initial BCG failure.

Methods: We identified a consecutive series of 139 patients undergoing intravesical instillations of BCG alone or with interferon-α2B performed at Brigham and Women’s Hospital, Boston between 2002 and 2007. All patients previously received an initial 6 week course of BCG therapy and subsequently had BCG failure on follow-up cystoscopy. Time to cancer recurrence, progression of disease, eventual cystectomy and mortality were analyzed.

Results: At a median follow-up of 64.7 months from initial BCG administration, 92% treated with BCG + INF had disease recurrence. The average time to recurrence was less than one year, and 63% of these patients had recurrence on the first post-treatment biopsy. Among patients with a positive first biopsy, 52% had disease progression on initial surveillance. Overall, disease progression was seen in 54% of patient receiving BCG + INF therapy, and 25% of all patients eventually underwent radical cystectomy. All outcomes occurred more frequently in patients undergoing combination intravesical therapy compared with BCG alone. Only one patient died during this period.

Disease recurrence and progression stratified by treatment
BCGBCG + interferonp-value
Mean follow-up (months)
From initial BCG34.764.7<0.001
From initial BCG-interferon43.6
Patients with disease recurrence
Disease recurrence5292<0.001
Mean time to recurrence (days)2192480.36
Age (years)69.965.40.07
Male gender74590.17
Multifocal disease56640.53
Aggressive disease (CIS, T1, G3)58680.39
>2 recurrences2982<0.001
Patients with disease progression
Disease progression23540.002
Age (years)68.568.30.48
Male gender74540.26
Multifocal disease37620.19
Aggressive disease (CIS, T1, G3)63621
>2 recurrences30850.002
Failure on first biopsy37630.02
Progression on first biopsy11330.006
Progression on positive first biopsy30520.09
Mean time to recurrence (days)2192480.36
Patients undergoing cystectomy7250.01
All values in percentages unless otherwise noted


Conclusions: Combination BCG + INF immunotherapy may have a short-term therapeutic benefit on cancer recurrence, but we did not find evidence that it significantly decreases disease progression. Patients undergoing salvage intravesical interferon at our institution have greater than a 50% chance of recurrence and progression, and one-quarter eventually proceed to radical cystectomy. Randomized trials are needed to clarify the issues present in these findings and to determine the appropriate role for concomitant interferon therapy in BCG failure.
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