Karsy Michael, Hoang Nguyen, Barth Talmadge, Burt Lindsay, Dunson William, Gillespie David L, Jensen Randy L
Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA.
School of Medicine, University of Utah, Salt Lake City, Utah, USA.
World Neurosurg. 2016 Feb;86:210-9. doi: 10.1016/j.wneu.2015.09.060. Epub 2015 Sep 30.
Previous in vitro and in vivo results suggested that hydroxyurea (HU) and verapamil could suppress meningioma growth individually and synergistically. We evaluated the clinical efficacy and safety of this approach for the treatment of refractory recurrent/progressive meningiomas and expanded our studies in a xenograft orthotopic mouse model.
Six women and 1 man, aged 26-76 years (median, 56 years), with magnetic resonance imaging-proven progression of ≥ 25% in cross-sectional area of recurrent meningioma (2 World Health Organization grade I, 5 grade II) within the preceding 6 months received HU 1000 or 1500 mg/day (20 mg/kg/day, twice daily) as well as verapamil sustained-release tablets with dose escalation every 2 weeks (120-240 mg/day). They underwent magnetic resonance imaging every 3 months during therapy. To augment the clinical trial results, we performed mouse orthotopic xenograft experiments using similar dosing to test tumor growth, vascularity, and drug bioavailability.
After a mean of 8.1 cycles of treatment, the patients demonstrated no significant radiographic responses during mean follow-up of 14.5 ± 4.8 months. Median progression-free survival (PFS) was 8.0 months, and 6-month PFS was 85%. Side effects occurred in 6 (86%) patients. Xenograft studies showed no effect of individual or combined treatments on meningioma growth. Neither HU nor verapamil was detectable in mouse brain tumor tissue despite adequate serum levels within therapeutic ranges.
Our results showed no effect of HU or verapamil on tumor recurrence, PFS, and in vivo tumor burden reduction. Drug delivery to the tumor may be a major limitation.
既往的体外和体内研究结果表明，羟基脲（HU）和维拉帕米可单独或协同抑制脑膜瘤生长。我们评估了该方法治疗难治性复发性/进展性脑膜瘤的临床疗效和安全性，并在异种移植原位小鼠模型中扩展了研究。
6名女性和1名男性，年龄26 - 76岁（中位年龄56岁），经磁共振成像证实，在过去6个月内复发性脑膜瘤（2例世界卫生组织I级，5例II级）横截面积进展≥25%，接受HU 1000或1500 mg/天（20 mg/kg/天，每日两次）以及维拉帕米缓释片，每2周递增剂量（120 - 240 mg/天）。治疗期间每3个月进行一次磁共振成像检查。为了增强临床试验结果，我们使用相似的给药方案进行小鼠原位异种移植实验，以测试肿瘤生长、血管生成和药物生物利用度。
平均治疗8.1个周期后，患者在平均14.5 ± 4.8个月的随访期间未显示出明显的影像学反应。中位无进展生存期（PFS）为8.0个月，6个月PFS率为85%。6例（86%）患者出现了副作用。异种移植研究表明，单独或联合治疗对脑膜瘤生长均无影响。尽管血清水平在治疗范围内充足，但在小鼠脑肿瘤组织中均未检测到HU或维拉帕米。
我们的结果表明，HU或维拉帕米对肿瘤复发、PFS和体内肿瘤负荷降低均无影响。药物向肿瘤的递送可能是一个主要限制因素。
