McKiernan James M, Masson Puneet, Murphy Alana M, Goetzl Manlio, Olsson Carl A, Petrylak Daniel P, Desai Manisha, Benson Mitchell C
Columbia University Medical Center, 161 Fort Washington Ave, 11th Floor, Department of Urology, New York, NY 10032, USA.
J Clin Oncol. 2006 Jul 1;24(19):3075-80. doi: 10.1200/JCO.2005.03.1161.
Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent.
This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging.
Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression.
Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.
接受膀胱内灌注药物治疗浅表性膀胱癌的患者中，高达50%会出现复发。二线膀胱内治疗的缓解率在20%至40%之间。对于这些高危患者，需要新型药物来预防复发。多西他赛是一种微管解聚抑制剂，具有独特的理化性质，使其成为作为膀胱内药物进行研究的极佳候选药物。
这项I期试验纳入了复发性Ta、T1和Tis移行细胞癌患者，这些患者至少接受过一次膀胱内治疗但治疗失败。多西他赛以5mg的起始剂量每周灌注一次，共6次，采用剂量递增模型，直至达到最大耐受剂量（MTD）。主要终点是剂量限制性毒性（DLT）和MTD。通过膀胱镜检查及活检、细胞学检查和计算机断层扫描成像评估疗效。
18名患者（100%）完成了试验，分期分布为6例Tis患者、7例Ta患者和5例T1患者。108次输注中未出现3级或4级DLT，且没有患者出现多西他赛的全身吸收。18名患者中有8名（44%）出现1级或2级毒性，其中尿痛最为常见。18名患者中有10名（56%）在治疗后的膀胱镜检查及活检中未发现疾病迹象。所有复发的患者均无疾病进展。
在首次人体膀胱内临床试验中，膀胱内灌注多西他赛显示出最小的毒性且无全身吸收。这表明多西他赛是一种安全的药物，可在II期试验中进一步评估其疗效。
