Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
Brain Tumor Center and Department of Medical Psychology, VU University Medical Center, Amsterdam, Netherlands.
Lancet Oncol. 2018 Sep;19(9):1170-1179. doi: 10.1016/S1470-2045(18)30362-0. Epub 2018 Aug 13.
Bevacizumab is frequently used in the treatment of recurrent WHO grade II and III glioma, but without supporting evidence from randomised trials. Therefore, we assessed the use of bevacizumab in patients with first recurrence of grade II or III glioma who did not have 1p/19q co-deletion.
The TAVAREC trial was a randomised, open-label phase 2 trial done at 32 centres across Europe in patients with locally diagnosed grade II or III glioma without 1p/19q co-deletion, with a first and contrast-enhancing recurrence after initial radiotherapy or chemotherapy, or both. Previous chemotherapy must have been stopped at least 6 months before enrolment and radiotherapy must have been stopped at least 3 months before enrolment. Random group assignment was done electronically through the European Organisation for Research and Treatment of Cancer web-based system, stratified by a minimisation procedure using institution, initial histology (WHO grade II vs III), WHO performance status (0 or 1 vs 2), and previous treatment (radiotherapy, chemotherapy, or both). Patients were assigned to receive either temozolomide (150-200 mg/m, orally) monotherapy on days 1-5 every 4 weeks for a maximum of 12 cycles, or the same temozolomide regimen in combination with bevacizumab (10 mg/kg, intravenously) every 2 weeks until progression. The primary endpoint was overall survival at 12 months in the per-protocol population. Safety analyses were done in all patients who started their allocated treatment. The study is registered at EudraCT (2009-017422-39) and ClinicalTrials.gov (NCT01164189), and is complete.
Between Feb 8, 2011, and July 31, 2015, 155 patients were enrolled and randomly assigned to receive either monotherapy (n=77) or combination therapy (n=78). Overall survival in the per-protocol population at 12 months was achieved by 44 (61% [80% CI 53-69]) of 72 patients in the temozolomide group and 38 (55% [47-69]) of 69 in the combination group. The most frequent toxicity was haematological: 17 (23%) of 75 patients in the monotherapy group and 25 (33%) of 76 in the combination group developed grade 3 or 4 haematological toxicity. Other than haematological toxicities, the most common adverse events were nervous system disorders (59 [79%] of 75 patients in the monotherapy group vs 65 [86%] of 76 in the combination group), fatigue (53 [70%] vs 61 [80%]), and nausea (39 [52%] vs 43 [56%]). Infections were more frequently reported in the combination group (29 [38%] of 76 patients) than in the monotherapy group (17 [23%] of 75). One treatment-related death was reported in the combination group (infection after intratumoral haemorrhage during a treatment-related grade 4 thrombocytopenia).
We found no evidence of improved overall survival with bevacizumab and temozolomide combination treatment versus temozolomide monotherapy. The findings from this study provide no support for further phase 3 studies on the role of bevacizumab in this disease.
Roche Pharmaceuticals.
贝伐珠单抗常用于治疗复发性世界卫生组织（WHO）分级 II 级和 III 级胶质瘤，但缺乏来自随机试验的支持证据。因此，我们评估了贝伐珠单抗在未发生 1p/19q 共缺失的 II 级或 III 级复发性胶质瘤患者中的应用。
TAVAREC 试验是在欧洲 32 个中心进行的一项随机、开放标签的 II 期试验，入组患者为局部诊断为 II 级或 III 级胶质瘤且未发生 1p/19q 共缺失，且在初始放疗或化疗后或两者均出现对比增强复发。先前的化疗必须至少在入组前 6 个月停止，放疗必须至少在入组前 3 个月停止。通过欧洲癌症研究与治疗组织（EORTC）的基于网络的系统进行电子随机分组，采用最小化程序进行分层，使用机构、初始组织学（WHO 分级 II 与 III）、WHO 表现状态（0 或 1 与 2）和先前治疗（放疗、化疗或两者均有）。患者被分配接受替莫唑胺（150-200mg/m，口服）单药治疗，每天 1-5 天，每 4 周 1 个周期，最多 12 个周期，或相同的替莫唑胺方案联合贝伐珠单抗（10mg/kg，静脉注射）每 2 周 1 次，直至疾病进展。主要终点是方案人群中 12 个月的总生存期。安全性分析在所有开始接受分配治疗的患者中进行。该研究在 EudraCT（2009-017422-39）和 ClinicalTrials.gov（NCT01164189）注册，现已完成。
2011 年 2 月 8 日至 2015 年 7 月 31 日，共纳入 155 例患者，随机分为单药治疗组（n=77）或联合治疗组（n=78）。方案人群中 12 个月的总生存期在替莫唑胺组中达到 44 例（61%[80%CI 53-69]），在联合组中达到 38 例（55%[47-69]）。最常见的毒性是血液学毒性：单药治疗组中有 17 例（23%）和联合治疗组中有 25 例（33%）发生 3 或 4 级血液学毒性。除血液学毒性外，最常见的不良事件是神经系统疾病（单药治疗组 59 例[79%]，联合治疗组 65 例[86%]）、疲劳（53 例[70%]，61 例[80%]）和恶心（39 例[52%]，43 例[56%]）。联合治疗组感染（在与治疗相关的血小板减少症相关的 4 级颅内出血后发生的感染）比单药治疗组更常见（29 例[38%]，17 例[23%]）。联合治疗组报告了 1 例与治疗相关的死亡（在与治疗相关的血小板减少症相关的 4 级颅内出血后发生的感染）。
我们发现贝伐珠单抗联合替莫唑胺治疗与替莫唑胺单药治疗相比，总生存期没有改善的证据。本研究的结果不支持进一步开展贝伐珠单抗在该疾病中的作用的 III 期研究。
罗氏制药公司。
