Arneson Kyle, Mondschein Joshua, Stavas Mark, Cmelak Anthony J, Attia Albert, Horn Leora, Niermann Kenneth, Puzanov Igor, Chakravarthy A Bapsi, Xia Fen
Department of Radiation Oncology, Vanderbilt University Medical Center, 22nd at Pierce Avenue, B1034, Nashville, TN, 37232-5671, USA.
Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, 37232-6307, USA.
J Neurooncol. 2017 Jun;133(2):435-442. doi: 10.1007/s11060-017-2455-3. Epub 2017 May 9.
We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1-4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1-4 brain metastases from solid malignancies. Sorafenib was begun 5-7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.
我们假设，口服多激酶抑制剂索拉非尼（BAY 43 - 9006）与立体定向放射外科（SRS）联合使用将改善整体颅内控制。这项I期研究评估了索拉非尼与SRS联合用于治疗1 - 4个脑转移瘤的安全性、耐受性和最大耐受剂量。这是一项带有扩展队列的开放标签I期剂量递增研究。符合条件的成年人有1 - 4个来自实体恶性肿瘤的脑转移瘤。索拉非尼在SRS前5 - 7天开始使用，并在其后持续使用14天。索拉非尼的剂量递增通过“3 + 3”剂量递增设计进行。在SRS后1个月确定剂量限制毒性（DLT），并定义为≥3级神经毒性。23名患者入组。在剂量水平1（每日400毫克）或剂量水平2（每日两次，每次400毫克）未出现DLT。17名患者的扩展队列在剂量水平2接受治疗。出现6例3级毒性反应：高血压（n = 2）、皮疹（n = 1）、淋巴细胞减少（n = 1）、低钾血症（n = 1）、疲劳（n = 1）和手足综合征（n = 1）。所有这些均归因于索拉非尼，而非与SRS联合使用所致。至中枢神经系统进展的中位时间为10个月，1年中枢神经系统无进展生存率为46%，中位总生存期为11.6个月，1年总生存率为46%。索拉非尼与SRS同时用于治疗1 - 4个脑转移瘤，每日两次，每次400毫克时安全且耐受性良好。我们推荐的索拉非尼与SRS联合使用的II期剂量为每日两次，每次400毫克。
