对于难治性脑放射性坏死(RN)的安全且快速有效的疗法存在未满足的需求。这项前瞻性单臂II期试验的目的是评估在患有类固醇难治性脑RN的成年患者血脑屏障破坏(BBBD)后单次低剂量靶向贝伐单抗输注的安全性和有效性。
十个类固醇难治性成人,纳入2016年11月至2018年1月影像学证实的脑RN,并在治疗后随访12个月.在BBBD后立即给予2.5mg/kg贝伐单抗作为一次性靶向动脉内输注。主要结果包括安全性和损伤体积减少>25%。图像由董事会认证的神经放射科医生分析,该医生对审前诊断和治疗状态视而不见。次要结果包括头痛的变化,使用类固醇,以及功能状态和神经认知后遗症的缺失。使用Fisher精确检验进行比较分析,Mann-WhitneyU-test,线性混合模型,Wilcoxon符号秩检验,和重复测量单因素方差分析。
10名成年人(平均±SD[范围]35±15[22-62]岁)参加了这项研究。没有患者死亡或表现出系统性贝伐单抗的严重不良反应。3个月时,80%(95%CI44%-98%)和90%(95%CI56%-100%)的患者显示RN和血管源性水肿体积减少>25%,分别。12个月时,RN量减少了74%(中位数[范围]76%[53%-96%],p=0.012),水肿体积减少50%(中位数[范围]70%[-11%至83%],p=0.086),头痛减少了84%(中位数[范围]92%[58%-100%],在8例无RN复发的患者中,p=0.022)。在试验结束时,只有1例(10%)患者是类固醇依赖性的。16个神经认知指数中的12个(75%)得分增加,从而支持大脑白质恢复的模式。2例(20%)患者在10个月和11个月时表现出需要进一步治疗的RN复发,分别,贝伐单抗输注后。
第一次,根据作者的知识,作者证明,单次低剂量靶向贝伐单抗输注可使80%的患者在治疗后12个月时获得持久的临床和影像学改善,且未发生贝伐单抗单独所致的不良事件.这些发现强调,靶向贝伐单抗可能是一种有效的一次性治疗成人大脑RN。需要通过随机对照试验进一步确认,以比较动脉内方法与常规多周期静脉给药方案。临床试验登记号.:NCT02819479(ClinicalTrials.gov)。
There is an unmet need for safe and rapidly effective therapies for refractory brain radiation necrosis (RN). The aim of this prospective single-arm phase II trial was to evaluate the safety and efficacy of a single low-dose targeted bevacizumab infusion after blood-brain barrier disruption (BBBD) in adult patients with steroid-refractory brain RN.
Ten adults with steroid-refractory, imaging-confirmed brain RN were enrolled between November 2016 and January 2018 and followed for 12 months after treatment. Bevacizumab 2.5 mg/kg was administered as a one-time targeted intra-arterial infusion immediately after BBBD. Primary outcomes included safety and > 25% decrease in lesion volume. Images were analyzed by a board-certified neuroradiologist blinded to pretrial diagnosis and treatment status. Secondary outcomes included changes in headache, steroid use, and functional status and absence of neurocognitive sequelae. Comparisons were analyzed using the Fisher exact test, Mann-Whitney U-test, linear mixed models, Wilcoxon signed-rank test, and repeated-measures 1-way ANOVA.
Ten adults (mean ± SD [range] age 35 ± 15 [22-62] years) participated in this study. No patients died or exhibited serious adverse effects of systemic bevacizumab. At 3 months, 80% (95% CI 44%-98%) and 90% (95% CI 56%-100%) of patients demonstrated > 25% decrease in RN and vasogenic edema volume, respectively. At 12 months, RN volume decreased by 74% (median [range] 76% [53%-96%], p = 0.012), edema volume decreased by 50% (median [range] 70% [-11% to 83%], p = 0.086), and headache decreased by 84% (median [range] 92% [58%-100%], p = 0.022) among the 8 patients without RN recurrence. Only 1 (10%) patient was steroid dependent at the end of the trial. Scores on 12 of 16 (75%) neurocognitive indices increased, thereby supporting a pattern of cerebral white matter recovery. Two (20%) patients exhibited RN recurrence that required further treatment at 10 and 11 months, respectively, after bevacizumab infusion.
For the first time, to the authors\' knowledge, the authors demonstrated that a single low-dose targeted bevacizumab infusion resulted in durable clinical and imaging improvements in 80% of patients at 12 months after treatment without adverse events attributed to bevacizumab alone. These findings highlight that targeted bevacizumab may be an efficient one-time treatment for adults with brain RN. Further confirmation with a randomized controlled trial is needed to compare the intra-arterial approach with the conventional multicycle intravenous regimen. Clinical trial registration no.: NCT02819479 (ClinicalTrials.gov).