Galsky Matthew D, Hahn Noah M, Wong Bryan, Lee Karen M, Argiriadi Pamela, Albany Costantine, Gimpel-Tetra Kiev, Lowe Nancy, Shahin Mohamed, Patel Vaibhav, Tsao Che-Kai, Oh William K
Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Cancer Chemother Pharmacol. 2015 Dec;76(6):1259-65. doi: 10.1007/s00280-015-2884-7. Epub 2015 Oct 13.
The purpose of this investigator-initiated multicenter phase II study was to determine the activity of the third-generation synthetic anthracycline, amrubicin, administered as second-line therapy in patients with advanced urothelial carcinoma.
Patients with progressive metastatic urothelial cancer despite first-line chemotherapy were eligible for enrollment. Amrubicin was initially administered at a dose of 40 mg/m(2)/day daily × 3 every 21 days, and the dose was subsequently reduced to 35 mg/m(2)/day daily × 3 every 21 days. Prophylactic granulocyte colony-stimulating factor was administered to all patients, and prophylactic antibiotics were administered to patients at high risk of febrile neutropenia. Treatment was administered for up to six cycles in the absence of intolerable toxicity or disease progression. The primary endpoint was the objective response rate.
A total of 22 patients were enrolled. Among the first three patients enrolled, all developed grade 4 neutropenia and one patient died of neutropenic sepsis. The starting dose of amrubicin was subsequently reduced, there were no further episodes of febrile neutropenia, and only one patient required a subsequent dose reduction. The most common adverse events were hematologic; grade ≥3 neutropenia occurred in 27 %, and other grade ≥3 adverse events were uncommon. Partial responses were achieved in three patients [13.6, 95 % confidence interval (CI) 0-28 %), while stable disease was the best response in 12 patients (54.5, 95 % CI 33.7-75.3 %). The trial was closed prematurely due to a development decision by the funder.
Amrubicin as second-line therapy in advanced urothelial carcinoma is associated with modest single-agent activity. While there remains a role for the introduction of novel cytotoxic agents in the management of metastatic urothelial cancer, optimal development of such therapies will likely require patient selection biomarkers.
本项研究者发起的多中心II期研究旨在确定第三代合成蒽环类药物氨柔比星作为晚期尿路上皮癌患者二线治疗的活性。
尽管接受了一线化疗但病情仍进展的转移性尿路上皮癌患者符合入组条件。氨柔比星初始剂量为40mg/m²/天，每日一次，共3天，每21天重复，随后剂量减至35mg/m²/天，每日一次，共3天，每21天重复。所有患者均接受预防性粒细胞集落刺激因子治疗，发热性中性粒细胞减少风险高的患者接受预防性抗生素治疗。在无不可耐受毒性或疾病进展的情况下，治疗最多进行6个周期。主要终点为客观缓解率。
共入组22例患者。在前3例入组患者中，均发生了4级中性粒细胞减少，1例患者死于中性粒细胞减少性败血症。随后氨柔比星起始剂量降低，未再发生发热性中性粒细胞减少事件，仅1例患者需要后续剂量降低。最常见的不良事件为血液学不良事件；3级及以上中性粒细胞减少发生率为27%，其他3级及以上不良事件不常见。3例患者获得部分缓解[13.6，95%置信区间（CI）0-28%]，12例患者疾病稳定为最佳缓解（54.5，95%CI 33.7-75.3%）。由于资助者的一项开发决定，该试验提前终止。
氨柔比星作为晚期尿路上皮癌的二线治疗具有适度的单药活性。虽然在转移性尿路上皮癌的治疗中引入新型细胞毒药物仍有作用，但此类疗法的最佳开发可能需要患者选择生物标志物。
