Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study

Abstract

Intravesical gemcitabine (Gem) has shown promising activity against transitional cell carcinomas (TCC) of the bladder, with moderate urinary toxicity and low systemic absorption. The present phase II study evaluated the activity of biweekly intravesical treatment with Gem using a scheme directly derived from in vitro preclinical studies. Patients with Bacille Calmette-Guérin (BCG) -refractory Ta G3, T1 G1-3 TCC underwent transurethral bladder resection and then intravesical instillation with 2000 mg Gem diluted in 50 ml saline solution on days 1 and 3 for 6 consecutive weeks. Thirty-eight (95%) of the 40 patients showed persistent negative post-treatment cystoscopy and cytology 6 months after Gem treatment, while the remaining 2 patients relapsed at 5 and 6 months. At a median follow-up of 28 months, recurrences had occurred in 14 patients. Among these, four had downstaged (T) disease, three had a lower grade (G) lesion and three had a reduction in both T and G. Urinary and systemic toxicity was very low, with no alterations in biochemical profiles. In conclusion, biweekly instillation of Gem proved active in BCG-refractory Ta G3, T1 G1-3 TCC. Our results highlight the importance of preclinical studies using in vitro systems that adequately reproduce the conditions of intravesical clinical treatment to define the best therapeutic schedule.

Bladder cancer

“…Additional phase I/II studies [48][49][50] of intravesical gemcitabine published this year confirm these results. One showed that 13 out of 28 (46%) patients with recurrent bladder tumors had a complete response to four weekly instillations [50].…”

1064 a Novel Simulation Model of Non-Muscle Invasive Bladder Cancer a Platform for a Virtual Randomized Trial of Conservative Therapy vs Cystectomy in BCG Refractory Patients

“…This is lower than in the recent Phase II clinical trial comparing salvage intravesical gemcitabine (33% progression) vs. additional induction BCG (37.5% progression) in patients with recurrent NMIBC despite BCG at 2 years follow-up [11]. The rate of cystectomy was 62% at 5 years which is higher than previously published clinical trials which range from 33% to 56% at a follow-up of 1.5 to 3 years [11][12][13][14][15]. The differences are largely attributable to the fact that in our series we assumed perfect compliance and follow-up as well as strict adherence to NCCN guidelines, which are more aggressive than real-world settings.…”

“…The study population of 1300 virtual patients is significantly higher than most published series on BCG refractory patients which range from 20-100 patients [11][12][13][14][15]. Our virtual series contained 58% of patients with clinical stage T1 urothelial carcinoma prior to randomization which falls within the range of previous BCG failure trials where 47%-78% had cT1 tumors [11,15].…”

Gemcitabine versus bacille Calmette‐Guérin after initial bacille Calmette‐Guérin failure in non‐muscle‐invasive bladder cancer

“…Finally, Gunelli et al 25 presented a phase 2 study evaluating the activity of biweekly intravesical treatment with gemcitabine. Patients with BCG-refractory Ta-1G3 non-muscle-invasive BC underwent TUR of the bladder and then intravesical instillation with 2000 mg diluted in 50 mL saline solution on Days 1 and 3 for 6 consecutive weeks.…”