Ameratunga Malaka, Pavlakis Nick, Wheeler Helen, Grant Robin, Simes John, Khasraw Mustafa
Medical Oncology, Alfred Hospital, Commercial Road, Melbourne, Victoria, Australia, 3004.
Cochrane Database Syst Rev. 2018 Nov 22;11(11):CD008218. doi: 10.1002/14651858.CD008218.pub4.
This is an updated version of the original Cochrane Review published in September 2014. The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma and carries a median survival in treated patients of about 15 months. Glioblastomas are rich in blood vessels (i.e. highly vascular) and also rich in a protein known as vascular endothelial growth factor (VEGF) that promotes new blood vessel formation (the process of angiogenesis). Anti-angiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several anti-angiogenic agents have been investigated in clinical trials, both in newly diagnosed and recurrent HGG, showing preliminary promising results. This review was undertaken to report on the benefits and harms associated with the use of anti-angiogenic agents in the treatment of HGGs.
To evaluate the efficacy and toxicity of anti-angiogenic therapy in people with high-grade glioma (HGG). The intervention can be used in two broad groups: at first diagnosis as part of 'adjuvant' therapy, or in the setting of recurrent disease.
We conducted updated searches to identify published and unpublished randomised controlled trials (RCTs), including the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE and Embase to October 2018. We handsearched proceedings of relevant oncology conferences up to 2018. We also searched trial registries for ongoing studies.
RCTs evaluating the use of anti-angiogenic therapy to treat HGG versus the same therapy without anti-angiogenic therapy.
Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles.
After a comprehensive literature search, we identified 11 eligible RCTs (3743 participants), of which 7 were included in the original review (2987 participants). There was significant design heterogeneity in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to glioblastomas and there were no eligible studies evaluating other HGGs. Ten studies were available as fully published peer-reviewed manuscripts, and one study was available in abstract form. The overall risk of bias in included studies was low. This risk was based upon low rates of selection bias, detection bias, attrition bias and reporting bias. The 11 studies included in this review did not show an improvement in overall survival with the addition of anti-angiogenic therapy (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88 to 1.02; P = 0.16; 11 studies, 3743 participants; high-certainty evidence). However, pooled analysis from 10 studies (3595 participants) showed improvement in progression-free survival with the addition of anti-angiogenic therapy (HR 0.73, 95% CI 0.68 to 0.79; P < 0.00001; high-certainty evidence).We carried out additional analyses of overall survival and progression-free survival according to treatment setting and for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone. Pooled analysis of overall survival in either the adjuvant or recurrent setting did not show an improvement (HR 0.93, 95% CI 0.86 to 1.02; P = 0.12; 8 studies, 2833 participants; high-certainty evidence and HR 0.99, 95% CI 0.85 to 1.16; P = 0.90; 3 studies, 910 participants; moderate-certainty evidence, respectively). Pooled analysis of overall survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy also did not clearly show an improvement (HR 0.92, 95% CI 0.85 to 1.00; P = 0.05; 11 studies, 3506 participants; low-certainty evidence). The progression-free survival in the subgroups all showed findings that demonstrated improvements in progression-free survival with the addition of anti-angiogenic therapy. Pooled analysis of progression-free survival in both the adjuvant and recurrent setting showed an improvement (HR 0.75, 95% CI 0.69 to 0.82; P < 0.00001; 8 studies, 2833 participants; high-certainty evidence and HR 0.64, 95% CI 0.54 to 0.76; P < 0.00001; 2 studies, 762 participants; moderate-certainty evidence, respectively). Pooled analysis of progression-free survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone showed an improvement (HR 0.72, 95% CI 0.66 to 0.77; P < 0.00001; 10 studies, 3464 participants). Similar to trials of anti-angiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events, although generally, the rate of grade 3 and 4 adverse events was low (< 14.1%) and in keeping with the literature. The impact of anti-angiogenic therapy on quality of life varied between studies.
AUTHORS' CONCLUSIONS: The use of anti-angiogenic therapy does not significantly improve overall survival in newly diagnosed people with glioblastoma. Thus, there is insufficient evidence to support the use of anti-angiogenic therapy for people with newly diagnosed glioblastoma at this time. Overall there is a lack of evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent glioblastoma. When considering the combination anti-angiogenic therapy with chemotherapy compared with the same chemotherapy alone, there may possibly be a small improvement in overall survival. While there is strong evidence that bevacizumab (an anti-angiogenic drug) prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, the impact of this on quality of life and net clinical benefit for patients remains unclear. Not addressed here is whether subsets of people with glioblastoma may benefit from anti-angiogenic therapies, nor their utility in other HGG histologies.
这是2014年9月发表的原始Cochrane系统评价的更新版本。成人大脑中最常见的原发性脑肿瘤是胶质瘤。胶质瘤范围从低级别到高级别，根据世界卫生组织（WHO）分类，病理上按1至4级分级。高级别胶质瘤（HGG）预后较差。IV级胶质瘤即胶质母细胞瘤，接受治疗患者的中位生存期约为15个月。胶质母细胞瘤血管丰富（即高度血管化），并且还富含一种称为血管内皮生长因子（VEGF）的蛋白质，该蛋白质可促进新血管形成（血管生成过程）。抗血管生成药物可抑制新血管形成过程并促进现有血管消退。在新诊断和复发性HGG的临床试验中，已经对几种抗血管生成药物进行了研究，显示出初步的有前景的结果。本系统评价旨在报告使用抗血管生成药物治疗HGG的益处和危害。
评估抗血管生成疗法对高级别胶质瘤（HGG）患者的疗效和毒性。该干预措施可用于两大类人群：在初次诊断时作为“辅助”治疗的一部分，或用于复发性疾病的情况。
我们进行了更新检索，以识别已发表和未发表的随机对照试验（RCT），包括截至2018年10月的Cochrane对照试验中心注册库（CENTRAL；2018年第9期）、MEDLINE和Embase。我们手工检索了截至2018年的相关肿瘤学会议论文集。我们还在试验注册库中检索正在进行的研究。
评估使用抗血管生成疗法治疗HGG与不使用抗血管生成疗法的对照试验。
综述作者筛选了检索结果，并在检索符合条件文章的全文之前，审查了潜在相关文章的摘要。
经过全面的文献检索，我们确定了11项符合条件的RCT（3743名参与者），其中7项纳入了原始综述（2987名参与者）。纳入研究中存在显著的设计异质性，尤其是在使用的反应评估标准方面。所有符合条件的研究均限于胶质母细胞瘤，没有评估其他HGG的符合条件的研究。10项研究以完全发表的同行评审手稿形式提供，1项研究以摘要形式提供。纳入研究中的总体偏倚风险较低。该风险基于选择偏倚、检测偏倚、失访偏倚和报告偏倚的发生率较低。本综述纳入的11项研究未显示添加抗血管生成疗法可改善总生存期（合并风险比（HR）为0.95，95%置信区间（CI）为0.88至1.02；P = 0.16；11项研究，3743名参与者；高确定性证据）。然而，10项研究（3595名参与者）的合并分析显示，添加抗血管生成疗法可改善无进展生存期（HR 0.73，95%CI 0.68至0.79；P < 0.00001；高确定性证据）。我们根据治疗情况以及抗血管生成疗法联合化疗与单纯化疗相比，对总生存期和无进展生存期进行了额外分析。辅助或复发情况下总生存期的合并分析未显示改善（HR 0.93，95%CI 0.86至1.02；P = 0.12；8项研究，2833名参与者；高确定性证据和HR 0.99，95%CI 0.85至1.
