Dalbagni Guido, Benfante Nicole, Sjoberg Daniel D, Bochner Bernard H, Machele Donat S, Herr Harry W, Mc Coy Asia S, Fahrner Alicia J, Retinger Caitlyn, Rosenberg Jonathan E, Bajorin Dean F
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Bladder Cancer. 2017 Apr 27;3(2):113-119. doi: 10.3233/BLC-170095.
Standard treatment for BCG-refractory urothelial cancer is radical cystectomy. Identification of active agents is clearly warranted. To determine a safe dose of oral everolimus in combination with standard intravesical gemcitabine and to evaluate the efficacy of this combination. Patients with carcinoma refractory to intravesical bacillus Calmette-Guérin and refusing cystectomy were eligible. Patients in the phase I part of the trial received one of three dose levels of oral everolimus. Patients also received a fixed dose of intravesical gemcitabine. Maintenance everolimus was given for 12 months in patients achieving a complete response confirmed by cystoscopy and cytology. Patients in phase II received continuous everolimus administered at 10 mg daily with intravesical gemcitabine followed by everolimus maintenance for 12 months of total therapy. The enrollment goal for the phase II was 33 patients. 14 patients were enrolled in phase I of the trial. 23 patients were enrolled in phase II of the trial and 19 were evaluable for primary and secondary endpoints. Four patients withdrew consent prior to treatment initiation. Of the 19 patients evaluable for response, 3 (16%, 95% confidence interval [CI] 3% - 40%) were disease free at 1 yr. The probability of RFS was 20% (95% CI 5% - 42%) at 12 months. Ten patients out of 19 had grade 3 or greater toxicity events. Seven withdrew consent or were taken off study. Many patients withdrew, and enrollment was halted. Continuous oral everolimus plus intravesical gemcitabine was not well tolerated in this patient population where the threshold for tolerability is low.
卡介苗难治性尿路上皮癌的标准治疗方法是根治性膀胱切除术。显然有必要确定有效的治疗药物。目的是确定口服依维莫司与标准膀胱内注射吉西他滨联合使用的安全剂量，并评估该联合用药的疗效。入选患者为膀胱内注射卡介苗治疗无效且拒绝膀胱切除术的癌症患者。在试验的I期，患者接受三种剂量水平之一的口服依维莫司治疗。患者还接受固定剂量的膀胱内吉西他滨注射。对于经膀胱镜检查和细胞学检查确认达到完全缓解的患者，给予维持性依维莫司治疗12个月。II期患者接受每日10毫克的持续口服依维莫司治疗，并联合膀胱内注射吉西他滨，随后进行12个月的依维莫司维持治疗。II期的入组目标是33名患者。14名患者参加了试验的I期。23名患者参加了试验的II期，其中19名可评估主要和次要终点。4名患者在治疗开始前撤回同意书。在19名可评估反应的患者中，3名（16%，95%置信区间[CI] 3% - 40%）在1年时无疾病。12个月时无复发生存率为20%（95% CI 5% - 42%）。19名患者中有10名发生3级或更高级别的毒性事件。7名患者撤回同意书或退出研究。许多患者退出，试验停止。在这个耐受性阈值较低的患者群体中，持续口服依维莫司联合膀胱内注射吉西他滨的耐受性不佳。
