Single Postoperative Instillation of Gemcitabine in Patients with Non-muscle-invasive Transitional Cell Carcinoma of the Bladder: A Randomised, Double-blind, Placebo-controlled Phase III Multicentre Study

Abstract Background Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. Objective To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1–3). Design, setting, and participants This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1–3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), ≥pT2 disease, or intraoperative complications, patients were discontinued. Intervention We used a single, postoperative 30–40-min instillation of GEM (2000mg/100ml of saline) or PBO (100ml of saline) followed by continuous bladder irrigation for ≥20h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guerin (BCG) instillations were allowed. Measurements Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, α=0.050). Results and limitations Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1–3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1–G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8–84.3]; PBO: 75.3% [66.3–82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64–1.39], log-rank test, p =0.777). Conclusions In this study of NMIBC, the immediate single instillation of GEM 2000mg/100ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.