Choi Clara Y H, Wakelee Heather A, Neal Joel W, Pinder-Schenck Mary C, Yu Hsiang-Hsuan Michael, Chang Steven D, Adler John R, Modlin Leslie A, Harsh Griffith R, Soltys Scott G
Department of Radiation Oncology, Stanford University, Stanford, California; Department of Radiation Oncology, Santa Clara Valley Medical Center, San Jose, California.
Division of Oncology, Department of Medicine, Stanford University, Stanford, California.
Int J Radiat Oncol Biol Phys. 2017 Sep 1;99(1):16-21. doi: 10.1016/j.ijrobp.2017.04.041. Epub 2017 May 6.
To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.
In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days.
From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS.
The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.
确定伏立诺他（一种组蛋白去乙酰化酶抑制剂）与立体定向放射外科治疗（SRS）联合应用治疗非小细胞肺癌（NSCLC）脑转移瘤的最大耐受剂量（MTD）。次要目标是确定毒性、局部失败、远处颅内失败和总生存率。
在这项多中心研究中，患有1至4个NSCLC脑转移瘤且每个转移瘤≤2 cm的患者参加了一项1期、3 + 3剂量递增试验。伏立诺他剂量水平为每日口服一次200、300和400 mg，共14天。在第3天进行单次分割SRS。剂量限制毒性（DLT）定义为在30天内发生的任何与伏立诺他或SRS相关的3.0版《不良事件通用术语标准》3至5级急性非血液学不良事件。
从2009年到2014年，17名患者入组，12名患者完成了研究治疗。由于未观察到DLT，MTD确定为400 mg。10名患者（59%）报告了急性不良事件。5名患者提前停用伏立诺他并退出研究。最常见的退出原因是呼吸困难（n = 2）、恶心（n = 1）和疲劳（n = 2）。中位随访12个月（范围1 - 64个月），Kaplan - Meier总生存率为13个月。无局部失败情况。1名400 mg剂量水平、有一个2.0 cm转移瘤的患者在SRS后2个月发生组织学证实的4级放射性坏死。
伏立诺他与SRS联合应用的MTD确定为400 mg。虽然未观察到DLT，但5名患者在完成治疗疗程前退出，这一结果强调了在伏立诺他给药期间提供支持性护理的必要性。无局部失败情况。一项更大规模的随机试验可能会评估伏立诺他与SRS联合治疗脑转移瘤的耐受性和潜在的局部控制益处。
