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

• Published in: European urology Vol. 56; no. 3; pp. 495 - 503
• Main Authors: Böhle, Andreas, Leyh, Herbert, Frei, Christian, Kühn, Michael, Tschada, Reinhold, Pottek, Tobias, Wagner, Walter, Knispel, Helmut H, von Pokrzywnitzki, Wolfgang, Zorlu, Ferruh, Helsberg, Karin, Lübben, Birgit, Soldatenkova, Victoria, Stoffregen, Clemens, Büttner, Hartwig
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier 01.09.2009
• Subjects: Administration, Intravesical; Aged; Antimetabolites, Antineoplastic - administration & dosage; Biological and medical sciences; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - surgery; Combined Modality Therapy; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Double-Blind Method; Female; Humans; Male; Medical sciences; Nephrology. Urinary tract diseases; Postoperative Care; Tumors of the urinary system; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - surgery; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Urology; Gemcitabine; Transurethral resection; Non-muscle-invasive bladder cancer; Antineoplastic agent; Phase III trial; Nephrology; Transurethral route; Urology; Myocyte; Randomization; Urethra; Urinary bladder; Surgery; Muscle; Invasive cancer; Pyrimidine nucleoside; Human; Postoperative; Urinary system disease; Non-muscle-invasive bladder; Surgical resection; Urinary tract disease; Malignant tumor; Baldder transitional cell carcinoma; Treatment; Antimetabolic; Urinary system; Non invasive method; Placebo; Pyrimidine derivatives; Surgical approach; Bladder disease; Fluorine Organic compounds; Cancer
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2009.06.010

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 (2000 mg/100 ml of saline) or PBO (100 ml of saline) followed by continuous bladder irrigation for ≥20 h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guérin (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 2000 mg/100 ml 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.