Hart Michael G, Garside Ruth, Rogers Gabriel, Stein Ken, Grant Robin
Academic Division of Neurosurgery, Department of Clinical Neurosciences, Department of Neurosurgery, Cambridge, UK.
Cochrane Database Syst Rev. 2013 Apr 30;2013(4):CD007415. doi: 10.1002/14651858.CD007415.pub2.
High grade glioma (HGG) is an aggressive form of brain cancer. Treatment of HGG usually entails biopsy, or resection if safe, followed by radiotherapy. Temozolomide is a novel oral chemotherapy drug that penetrates into the brain and purportedly has a low incidence of adverse events.
To assess whether temozolomide has any advantage for treating HGG in either primary or recurrent disease settings.
The following databases were searched: CENTRAL (Issue 10, 2012), MEDLINE, EMBASE, Science Citation Index, Physician Data Query and the Meta-Register of Controlled Trials in October, 2012. Reference lists of identified studies were searched. The Journal of Neuro-Oncology and Neuro-oncology were handsearched from 1999 to 2012 including conference abstracts. We contacted neuro-oncologists regarding ongoing and unpublished trials.
Randomised controlled trials (RCTs) where the interventions were the use of temozolomide during primary therapy or for recurrent disease. Comparisons included no chemotherapy, non-temozolomide chemotherapy or different dosing schedules of temozolomide. Patients included those of all ages with histologically proven HGG.
Two review authors undertook the quality assessment and data extraction. Outcome measures included: overall survival (OS); progression-free survival (PFS); quality of life (QoL); and adverse events.
For primary therapy three RCTs were identified, enrolling a total of 745 patients, that investigated temozolomide in combination with radiotherapy versus radiotherapy alone for glioblastoma multiforme (GBM). Temozolomide increased OS (hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.46 to 0.79, P value 0.0003) and increased PFS (HR 0.63, 95% CI 0.43 to 0.92, P value 0.02), when compared with radiotherapy alone, although these benefits only appear to emerge when therapy is given in both concomitant and adjuvant phases of treatment. A single RCT found that temozolomide did not have a statistically significant effect on QoL. Risk of haematological complications, fatigue and infections were increased with temozolomide.In recurrent HGG, two RCTs enrolling 672 patients in total found that temozolomide did not increase OS compared to standard chemotherapy (HR 0.9, 95% CI 0.76 to 1.06, P value 0.2) but it did increase PFS in a subgroup analysis of grade IV GBM tumours (HR 0.68, 95% CI 0.51 to 0.90, P value 0.008). Adverse events were similar between arms.In the elderly, 2 RCTs of 664 patients found OS and PFS was similar with temozolomide alone versus radiotherapy alone. QoL did not appear to differ between arms in a single trial but certain adverse events were significantly more common with temozolomide.
AUTHORS' CONCLUSIONS: Temozolomide when given in both concomitant and adjuvant phases is an effective primary therapy in GBM compared to radiotherapy alone. It prolongs survival and delays progression without impacting on QoL but it does increase early adverse events. In recurrent GBM, temozolomide compared with standard chemotherapy improves time-to-progression (TTP) and may have benefits on QoL without increasing adverse events but it does not improve overall. In the elderly, temozolomide alone appears comparable to radiotherapy in terms of OS and PFS but with a higher instance of adverse events.
高级别胶质瘤（HGG）是一种侵袭性脑癌。HGG的治疗通常需要进行活检，若安全则进行切除，随后进行放疗。替莫唑胺是一种新型口服化疗药物，可穿透血脑屏障，据称不良事件发生率较低。
评估替莫唑胺在原发性或复发性疾病中治疗HGG是否具有任何优势。
检索了以下数据库：Cochrane系统评价数据库（2012年第10期）、医学期刊数据库、荷兰医学文摘数据库、科学引文索引、医师数据查询以及2012年10月的对照试验元注册库。检索了已识别研究的参考文献列表。手工检索了1999年至2012年的《神经肿瘤学杂志》和《神经肿瘤学》，包括会议摘要。我们联系了神经肿瘤学家，了解正在进行和未发表的试验。
随机对照试验（RCT），干预措施为在原发性治疗期间或复发性疾病中使用替莫唑胺。比较包括不进行化疗、非替莫唑胺化疗或替莫唑胺的不同给药方案。患者包括所有年龄组、经组织学证实为HGG的患者。
两位综述作者进行了质量评估和数据提取。结局指标包括：总生存期（OS）；无进展生存期（PFS）；生活质量（QoL）；以及不良事件。
对于原发性治疗，共识别出3项RCT，纳入了745例患者，研究了替莫唑胺联合放疗与单纯放疗治疗多形性胶质母细胞瘤（GBM）的疗效。与单纯放疗相比，替莫唑胺提高了总生存期（风险比（HR）0.60，95%置信区间（CI）0.46至0.79，P值0.0003），并提高了无进展生存期（HR 0.63，95%CI 0.43至0.92，P值0.02），尽管这些益处似乎仅在治疗的同步和辅助阶段给予时才会出现。一项RCT发现，替莫唑胺对生活质量没有统计学上的显著影响。替莫唑胺增加了血液学并发症、疲劳和感染的风险。在复发性HGG中，两项RCT共纳入672例患者，发现与标准化疗相比，替莫唑胺并未提高总生存期（HR 0.9，95%CI 0.76至1.06，P值0.2），但在IV级GBM肿瘤的亚组分析中，它确实提高了无进展生存期（HR 0.68，95%CI 0.51至0.90，P值0.008）。两组之间的不良事件相似。在老年人中，两项共664例患者的RCT发现，单独使用替莫唑胺与单独放疗的总生存期和无进展生存期相似。在一项试验中，两组之间的生活质量似乎没有差异，但替莫唑胺的某些不良事件明显更常见。
与单纯放疗相比，替莫唑胺在同步和辅助阶段给药时是GBM有效的原发性治疗方法。它延长了生存期并延迟了进展，而不影响生活质量，但确实增加了早期不良事件。在复发性GBM中，与标准化疗相比，替莫唑胺改善了至进展时间（TTP），可能对生活质量有益，且不增加不良事件，但总体上并未改善。在老年人中，单独使用替莫唑胺在总生存期和无进展生存期方面似乎与放疗相当，但不良事件发生率较高。
