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), > or = 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 > or = 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, alpha = 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.

• Authors: Andreas Böhle, Herbert Leyh, Christian Frei, Michael Kühn, Reinhold Tschada, Tobias Pottek, Walter Wagner, Helmut H Knispel, Wolfgang von Pokrzywnitzki, Ferruh Zorlu, Karin Helsberg, Birgit Lübben, Victoria Soldatenkova, Clemens Stoffregen, Hartwig Büttner, S274 Study Group
• Journal: European urology (Eur Urol) Vol. 56 Issue 3 Pg. 495-503 (Sep 2009) ISSN: 1873-7560 [Electronic] Switzerland
• PMID: 19560257 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Deoxycytidine
• Gemcitabine

Topics

• Administration, Intravesical
• Aged
• Antimetabolites, Antineoplastic (administration & dosage)
• Carcinoma, Transitional Cell (drug therapy, surgery)
• Combined Modality Therapy
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Double-Blind Method
• Female
• Humans
• Male
• Postoperative Care
• Urinary Bladder Neoplasms (drug therapy, surgery)
• Gemcitabine