Introduction

Gemcitabine (G) is a frequently used and effective systemic agent for advanced urothelial cancer (UC). However, its utility for low grade (LG) non-muscle invasive (NMI) disease when administered intravesically has not been studied extensively. This trial tested the impact of one instillation of G (2 gm/100 ml saline) versus saline (S) alone (100 ml), held for one hour immediately following transurethral resection of bladder tumor (TURBT), on time to recurrence (TTR).

Methods

Patients had suspected LG NMI UC based on cystoscopic appearance. Patients could not have a prior history of muscle invasive, upper tract or prostatic urethral UC, non-UC bladder cancer or prior HG UC or > 2 UC episodes within 18 months before index TURBT. Patients were followed quarterly with cystoscopies for 2 years, then semiannually for 2 more years. Design: Primary endpoint: TTR. Randomize 340 eligible patients, one-sided ?=0.025, 89% power to detect a hazard ratio (HR) of 0.65 (G vs S) for time to recurrence. Participants were stratified by new vs recurrent tumor and 1 vs > 1 lesion(s).

Results

From July 2007 to August 2012, 416 (406 eligible) patients were randomized to G or S. Median age was 66 yrs, 85% were male, 91% were white, 37% had recurrent disease, and 68% had one lesion at entry. 33 patients assigned to G and 28 to S did not receive instillation, primarily because of complications at TURBT or patient refusal. In the primary ITT analysis (n=406), there was a significant 34% reduction in risk of recurrence in the G arm compared to S (HR=0.66, 95% CI 0.48, 0.90, p=0.010). For the per-protocol target population, LG NMI UCs, TTR even more strongly favored G (HR 0.50 95% CI 0.33, 0.76; p=0.001). Few muscle invasive events (G 2.5%, S 4.9%) or deaths from any cause (G 8.5%, S 12.2%) occurred. Adverse events (AEs) were infrequent. There were no Grade 4 or 5 complications, and no difference in Grade 3 AEs (G 2.4%, S 3.4%).

Conclusions

Immediate post TURBT intravesical instillation of G was safe, well tolerated and significantly reduced recurrence of LG NMI UC in these participants.

Funding

Support: NIH/NCI grants CA180888, CA180819 and in part by Eli Lilly and Company_x000D_ _x000D_ Clinical Trials.gov Registry Number: NCT00445601_x000D_ _x000D_