中国癌症杂志 ›› 2018, Vol. 28 ›› Issue (9): 649-656.doi: 10.19401/j.cnki.1007-3639.2018.09.002

• 专家述评与论著 • 上一篇    下一篇

贝伐单抗联合亚硝基脲类药物治疗复发高级别胶质瘤的单臂Ⅱ期临床研究

陈迪康1,丁骁杰1,张振宇2,文剑波3,耿道颖3,姚 瑜1   

  1. 1. 复旦大学附属华山医院神经外科,上海 200040 ;
    2. 郑州大学第一附属医院神经外科,河南 郑州 450000 ;
    3. 复旦大学附属华山医院放射科,上海 200040
  • 出版日期:2018-09-30 发布日期:2018-10-26
  • 通信作者: 姚 瑜 E-mail: yu_yao@fudan.edu.cn

single-arm phase Ⅱ clinical study of bevacizumab plus nitrosoureas treatment in patients with recurrent high-grade gliomas

CHEN Dikang1, DING Xiaojie1, ZHANG Zhenyu2, WEN Jianbo3, GENG Daoying3, YAO Yu1   

  1. 1. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; 2. Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China; 3. Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
  • Published:2018-09-30 Online:2018-10-26
  • Contact: YAO Yu E-mail: yu_yao@fudan.edu.cn

摘要: 背景与目的:复发高级别胶质瘤目前尚无标准治疗。该研究旨在评估贝伐单抗联合亚硝基脲类药物治疗复发高级别胶质瘤的疗效和安全性,并探索预测疗效的分子标志物。方法:本研究为一项单臂Ⅱ期临床试验(编号NCT02698280),入组复发高级别胶质瘤[世界卫生组织(WorldHealthOrganizationWHO)Ⅲ~Ⅳ级]患者。每6周为1个疗程,患者每3周接受1次贝伐单抗5 mg/kg静脉滴注,每6周静脉滴注亚硝基脲1次,每次90mg/m2。每6周根据神经肿瘤临床疗效评价(responseassessmentinneuro-oncologyRANO)标准评价疗效。主要疗效指标为无进展生存期(progression-freesurvivalPFS)、6个月无进展生存率(progression-free survival at 6 monthsPFS-6)及影像学评价,次要疗效指标为总生存期(overall survival,OS),并观察不良反应。统计O6-甲基鸟嘌呤DNA甲基转移酶(O6-methylguanine-DNAmethyltransferaseMGMT)启动子甲基化、异柠檬酸脱氢酶(isocitratedehydrogenaseIDH)及端粒酶逆转录酶(telomerase reversetranscriptaseTERT)启动子等分子病理状态对疗效的指示作用。结果:共入组23例患者,最终可分析的患者有20例。中位随访时间为8.2个月(3.2~23.1个月),PFS-625%,中位PFS3.7个月(95%CI1.85~5.55)。根据RANO标准,6例患者部分缓解,9例患者疾病稳定,5例患者对治疗无反应,直接评价为疾病进展,客观缓解率(objectiveresponserateORR)为30%。中位OS9.2个月(95%CI7.27~11.13)。不良反应大部分为常见不良反应事件评价标准(The Common Terminology Criteria for Adverse EventsCTCAE1~2级,血小板下降、高血压及乏力多见。可分析组织的分子病理结果显示,TERTp野生型患者(n=11)的PFSTERTp突变型(n=7)更长(6.0个月 vs1.9个月,P=0.02),MGMT启动子甲基化(n=10)较非甲基化患者的ORR(n=8)具有更好的趋势(30.0% vs 12.5%,P=0.18),TERTp野生型(n=11)较TERTp突变型(n=7)患者的ORR具有更好的趋势(36.3% vs 14.2%,P=0.32)。结论:贝伐单抗联合亚硝基脲类药物治疗复发高级别胶质瘤有效且安全;TERT启动子野生型提示更长的PFS。MGMT启动子甲基化和TERT启动子野生型的ORR趋于更好。

关键词: 胶质瘤, 贝伐单抗, 亚硝基脲, 分子标志物

Abstract: Background and purpose: There is no standard treatment for recurrent high-grade gliomas. This study aimed to evaluate the curative efficacy and safety of bevacizumab plus nitrosoureas regimen in patients with recurrent high-grade gliomas, and to explore the molecular biomarkers for efficacy prediction. Methods: This was a single-arm phase Ⅱ clinical trial (Number NCT02698280) enrolling patients with recurrent high-grade gliomas. Every 6 weeks was defined as one therapeutic cycle. Bevacizumab was administered intravenously at 5 mg/kg every 3 weeks; and nitrosoureas at 90 mg/m2 every 6 weeks. Radiological response was assessed every 6 weeks according to the Response Assessment in Neuro-Oncology (RANO) criteria. The primary endpoint was progression-free survival (PFS), progression-free survival at 6 months (PFS-6) and radiological response. The secondary endpoint was overall survival (OS). Adverse events were recorded. The indicative value of O6-methylguanine-DNA methyltransferase (MGMT) promoter, isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase (TERT) promoter were analyzed. Results: Twenty-three patients were enrolled in this study, in which the results of 20 patients were available and analyzed. The median follow-up time was 8.2 (range: 3.2 to 23.1) months. The PFS-6 was 25% and median PFS was 3.7 months (95%CI: 1.85-5.55). According to RANO criteria, 6 patients reached partial response, 9 had stable disease, and 5 patients directly got progression disease without any response. Thus objective response rate (ORR) was 30%. Median OS was 9.2 months (95%CI: 7.27-11.13). Most of treatment-related adverse events were The Common Terminology Criteria for Adverse Events (CTCAE) grade one or two. Decrease of platelet, hypertension and fatigue were common. The molecular biomarker analysis of available tissues showed TERTp wild-type patients (n=11) had longer PFS than TERTp mutated patients (n=7) (6.0 months vs 1.9 months, P=0.02). MGMTp methylated group (n=10) had better trend in response rate than MGMTp unmethylated group (n=8) (30% vs 12.5%, P=0.18), and TERTp wildtype group (n=11) had better trend in response rate compared with TERTp mutation group (n=7) (36.3% vs 14.2%, P=0.32). Conclusion: Bevacizumab plus nitrosoureas regimen could be considered effective and safe in treatment of recurrent high-grade gliomas. Wild-type TERT promoter can indicate longer PFS. MGMTp methylated group and TERTp wild-type group have better trend in response rate.

Key words: Glioma, Bevacizumab, Nitrosoureas, Molecular biomarker