University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA,
Invest New Drugs. 2014 Feb;32(1):188-94. doi: 10.1007/s10637-013-0054-5. Epub 2013 Dec 10.
Paclitaxel has significant single agent activity in urothelial cancer. The 130 nm albumin bound paclitaxel (nab-paclitaxel, ABI-007) delivers more paclitaxel to tumor than conventional paclitaxel without cremophor related toxicities. We assessed the efficacy of nab-paclitaxel in combination with carboplatin and gemcitabine as first line therapy in advanced urothelial cancer.
Eligible patients had histologically confirmed metastatic, locally recurrent or advanced pure or mixed urothelial cancer, ECOG performance status of 0-2, no prior chemotherapy for current disease stage and no taxane for ≥ 1 year. Therapy consisted of nab-paclitaxel at 220 mg/m2 intravenously with optional dose escalation to 260 mg/m2 for subsequent cycles, with carboplatin AUC 5 on day 1 and gemcitabine at 800 mg/m2 on days 1 and 8 in 21-day cycles. Dose modifications in all three drugs to -1 and -2 levels were allowed for toxicity. Primary endpoint was overall response rate by RECIST 1.0. Secondary endpoints were safety, progression free and overall survival. Using a two-stage design, 32 patients were planned to be enrolled.
Due to poor accrual only 16 patients were enrolled. Thirteen patients had metastatic disease, 3 were women, and median age was 73.9 years (range 51.3-83). ECOG PS was 0 in 4 (25.0 %) and 1 in 11 (68.8 %) patients. Creatinine clearance by Cockroft-Gault formula was less than 60 in 43 % of patients and 50 % of patients had visceral disease at baseline. The regimen was associated with severe toxicity, mainly cytopenias. Adverse events required removal of 11 patients (68.8 %) from study. Seven patients (43.7 %) missed ≥ 1 dose due to toxicity and 7 patients were reduced to -2 dose level. Nine (56.4 %) grade ≥ 3 neutropenia and thrombocytopenia each but only 1 episode of febrile neutropenia (6.3 %) was reported. Grade ≥ 3 anemia was noted in 6 patients (37.5 %). Grade 2 neuropathy was seen in 12.5 % but no grade ≥ 3 neuropathy was observed. One patient had confirmed PR (6.7 %; 95 % CI, 0-32 %) and 2 (13.3 %) had unconfirmed PR. Six other patients (40 %) had SD. Due to censoring at study exit due to adverse events before true progression, median PFS was 11.2 months (95 % CI,2.0-11.2 m). Median overall survival was 13.1 months (95 % CI, 9.8-19.6 m).
The combination of nab-paclitaxel, carboplatin and gemcitabine was poorly tolerated in this high risk patient population at these doses and schedule. Other nab-paclitaxel based combinations should be explored in first line therapy of advanced urothelial cancer.
紫杉醇在尿路上皮癌中有显著的单药活性。130nm 白蛋白结合紫杉醇（nab-紫杉醇，ABI-007）向肿瘤输送的紫杉醇比无聚氧乙烯蓖麻油相关毒性的常规紫杉醇更多。我们评估了 nab-紫杉醇联合卡铂和吉西他滨作为晚期尿路上皮癌一线治疗的疗效。
符合条件的患者为组织学证实的转移性、局部复发性或晚期纯或混合尿路上皮癌，ECOG 体能状态为 0-2，当前疾病阶段无既往化疗且≥1 年未使用紫杉烷。治疗包括 nab-紫杉醇 220mg/m2 静脉注射，随后周期可选剂量增至 260mg/m2，卡铂 AUC5 于第 1 天，吉西他滨 800mg/m2 于第 1 和第 8 天，21 天为 1 个周期。所有三种药物均允许剂量减少 1 级和 2 级以减轻毒性。主要终点是根据 RECIST 1.0 的总缓解率。次要终点是安全性、无进展生存期和总生存期。采用两阶段设计，计划纳入 32 例患者。
由于入组人数较少，仅纳入了 16 例患者。13 例患者有转移性疾病，3 例为女性，中位年龄为 73.9 岁（范围 51.3-83）。ECOG PS 为 0 的有 4 例（25.0%），1 的有 11 例（68.8%）。按 Cockroft-Gault 公式计算的肌酐清除率<60%的患者占 43%，基线时有内脏疾病的患者占 50%。该方案与严重毒性相关，主要为细胞减少症。11 例（68.8%）患者因毒性而退出研究。7 例（43.7%）因毒性而错过≥1 剂，7 例减至-2 剂量水平。9 例（56.4%）发生≥3 级中性粒细胞减少症和血小板减少症，仅 1 例（6.3%）发生发热性中性粒细胞减少症。6 例（37.5%）出现≥3 级贫血。12.5%发生 2 级神经病变，但未观察到≥3 级神经病变。1 例患者确认有部分缓解（6.7%；95%CI，0-32%），2 例（13.3%）有未确认的部分缓解。其他 6 例（40%）患者病情稳定。由于在因不良事件而退出研究前出现真实进展而进行了截尾，无进展生存期的中位数为 11.2 个月（95%CI，2.0-11.2m）。总生存期的中位数为 13.1 个月（95%CI，9.8-19.6m）。
在这些高风险患者人群中，以这些剂量和方案使用 nab-紫杉醇、卡铂和吉西他滨联合治疗耐受性较差。应在晚期尿路上皮癌的一线治疗中探索其他 nab-紫杉醇为基础的联合治疗。
