A phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury
A phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury
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DOI：
10.1126/scitranslmed.abm6543
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发表时间：
2023-02-22
影响因子：
17.1
通讯作者：
Tang, Yamei
中科院分区：
文献类型：
--
作者：
Cheng, Jinping;Jiang, Jingru;Tang, Yamei
放射性脑损伤（RIBI）是治疗头颈部癌症的放射治疗后的一种使人衰弱的后遗症，20 - 30%的RIBI患者对贝伐单抗和皮质类固醇的一线治疗无效或有禁忌症。在这里，我们报告了一项Simon的最小最大两阶段，单臂，2期临床试验（NCT 03208413），以评估沙利度胺在对贝伐单抗和皮质类固醇治疗无反应或有禁忌症的RIBI患者中的疗效。该试验达到了主要终点，58名患者中有27名患者在治疗后液体衰减反转再精细化磁共振成像（FLAIR-MRI）显示脑水肿体积减少≥ 25%（总反应率，46.6%; 95%CI，33.3%至60.1%）。根据晚期效应正常组织-主观、客观、管理、分析（LENT/索马）量表，25例（43.1%）患者表现出临床改善，根据蒙特利尔认知评估（莫卡）评分，36例（62.1%）患者出现认知改善。在RIBI的小鼠模型中，沙利度胺恢复血脑屏障和脑灌注，这归因于沙利度胺升高血小板衍生生长因子受体β（PDGFR β）表达继发于周细胞的功能性拯救。因此，我们的数据表明沙利度胺治疗放射性脑血管损伤的治疗潜力。
Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon's minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing >= 25% reduction in the volume of cerebral edema on fluid-attenuated inversion re-covery-magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues-Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalido-mide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor beta (PDGFR beta) expression by thalido-mide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation -induced cerebral vasculature impairment.