Clinical Oncology, The Christie NHS FT, Manchester, UK.
Geoffrey Jefferson Brain Research Centre, Manchester, UK.
Cochrane Database Syst Rev. 2021 May 4;5(1):CD013579. doi: 10.1002/14651858.CD013579.pub2.
Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the best treatment/s to offer people upon disease progression or recurrence. For the purposes of this review, progression and recurrence are considered as one entity.
To evaluate the effectiveness of further treatment/s for first and subsequent progression or recurrence of glioblastoma (GBM) among people who have received the standard of care (Stupp protocol) for primary treatment of the disease; and to prepare a brief economic commentary on the available evidence.
We searched MEDLINE and Embase electronic databases from 2005 to December 2019 and the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library; Issue 12, 2019). Economic searches included the National Health Service Economic Evaluation Database (NHS EED) up to 2015 (database closure) and MEDLINE and Embase from 2015 to December 2019.
Randomised controlled trials (RCTs) and comparative non-randomised studies (NRSs) evaluating effectiveness of treatments for progressive/recurrent GBM. Eligible studies included people with progressive or recurrent GBM who had received first line radiotherapy with concomitant and adjuvant temozolomide (TMZ).
Two review authors independently selected studies and extracted data to a pre-designed data extraction form. We conducted network meta-analyses (NMA) and ranked treatments according to effectiveness for each outcome using the random-effects model and Stata software (version 15). We rated the certainty of evidence using the GRADE approach.
We included 42 studies: these comprised 34 randomised controlled trials (RCTs) and 8 non-randomised studies (NRSs) involving 5236 participants. We judged most RCTs to be at a low risk of bias and NRSs at high risk of bias. Interventions included chemotherapy, re-operation, re-irradiation and novel therapies either used alone or in combination. For first recurrence, we included 11 interventions in the network meta-analysis (NMA) for overall survival (OS), and eight in the NMA for progression-free survival (PFS). Lomustine (LOM; also known as CCNU) was the most common comparator and was used as the reference treatment. No studies in the NMA evaluated surgery, re-irradiation, PCV (procarbazine, lomustine, vincristine), TMZ re-challenge or best supportive care. We could not perform NMA for second or later recurrence due to insufficient data. Quality-of-life data were sparse. First recurrence (NMA findings) Median OS across included studies in the NMA ranged from 5.5 to 12.6 months and median progression-free survival (PFS) ranged from 1.5 months to 4.2 months. We found no high-certainty evidence that any treatments tested were better than lomustine. These treatments included the following. Bevacizumab plus lomustine: Evidence suggested probably little or no difference in OS between bevacizumab (BEV) combined with lomustine (LOM) and LOM monotherapy (hazard ratio (HR) 0.91, 0.75 to 1.10; moderate-certainty evidence), although BEV + LOM may improve PFS (HR 0.57, 95% confidence interval (CI) 0.44 to 0.74; low-certainty evidence). Bevacizumab monotherapy: Low-certainty evidence suggested there may be little or no difference in OS (HR 1.22, 95% CI 0.84 to 1.76) and PFS (HR 0.90, 95% CI 0.58 to 1.38; low-certainty evidence) between BEV and LOM monotherapies; more evidence on BEV is needed. Regorafenib (REG): REG may improve OS compared with LOM (HR 0.50, 95% CI 0.33 to 0.76; low-certainty evidence). Evidence on PFS was very low certainty and more evidence on REG is needed. Temozolomide (TMZ) plus Depatux-M (ABT414): For OS, low-certainty evidence suggested that TMZ plus ABT414 may be more effective than LOM (HR 0.66, 95% CI 0.47 to 0.92) and may be more effective than BEV (HR 0.54, 95% CI 0.33 to 0.89; low-certainty evidence). This may be due to the TMZ component only and more evidence is needed. Fotemustine (FOM): FOM and LOM may have similar effects on OS (HR 0.89, 95% CI 0.51 to 1.57, low-certainty evidence). Bevacizumab and irinotecan (IRI): Evidence on BEV + irinotecan (IRI) versus LOM for both OS and PFS is very uncertain and there is probably little or no difference between BEV + IRI versus BEV monotherapy (OS: HR 0.95, 95% CI 0.70 to 1.30; moderate-certainty evidence). When treatments were ranked for OS, FOM ranked first, BEV + LOM second, LOM third, BEV + IRI fourth, and BEV fifth. Ranking does not take into account the certainty of the evidence, which also suggests there may be little or no difference between FOM and LOM. Other treatments Three studies evaluated re-operation versus no re-operation, with or without re-irradiation and chemotherapy, and these suggested possible survival advantages with re-operation within the context of being able to select suitable candidates for re-operation. A cannabinoid treatment in the early stages of evaluation, in combination with TMZ, merits further evaluation. Second or later recurrence Limited evidence from three heterogeneous studies suggested that radiotherapy with or without BEV may have a beneficial effect on survival but more evidence is needed. Evidence was insufficient to draw conclusions about the best radiotherapy dosage. Other evidence suggested that there may be little difference in survival with tumour-treating fields compared with physician's best choice of treatment. We found no reliable evidence on best supportive care. Severe adverse events (SAEs) The BEV+LOM combination was associated with significantly greater risk of SAEs than LOM monotherapy (RR 2.51, 95% CI 1.72 to 3.66, high-certainty evidence), and ranked joint worst with cediranib + LOM (RR 2.51, 95% CI 1.29 to 4.90; high-certainty evidence). LOM ranked best and REG ranked second best. Adding novel treatments to BEV was generally associated with a higher risk of severe adverse events compared with BEV alone.
AUTHORS' CONCLUSIONS: For treatment of first recurrence of GBM, among people previously treated with surgery and standard chemoradiotherapy, the combination treatments evaluated did not improve overall survival compared with LOM monotherapy and were often associated with a higher risk of severe adverse events. Limited evidence suggested that re-operation with or without re-irradiation and chemotherapy may be suitable for selected candidates. Evidence on second recurrence is sparse. Re-irradiation with or without bevacizumab may be of value in selected individuals, but more evidence is needed.
胶质母细胞瘤（GBM）是一种高度恶性的脑肿瘤，在接受标准治疗（Stupp 方案）后几乎不可避免地会进展或复发。对于疾病进展或复发后的最佳治疗方案，尚无共识。出于本综述的目的，进展和复发被视为一个实体。
评估在接受标准治疗（原发性疾病的 Stupp 方案）后患有胶质母细胞瘤（GBM）的人进一步治疗/治疗进展或复发的有效性；并对现有证据进行简要的经济评论。
我们检索了 MEDLINE 和 Embase 电子数据库，检索时间为 2005 年至 2019 年 12 月，以及 Cochrane 中央对照试验注册库（Cochrane 图书馆，第 12 期，2019 年）。经济检索包括截至 2015 年（数据库关闭）的国家卫生服务经济评估数据库（NHS EED）和 2015 年至 2019 年 12 月的 MEDLINE 和 Embase。
随机对照试验（RCT）和比较非随机研究（NRS）评估进展性/复发性 GBM 治疗效果的研究。合格研究包括接受一线放疗联合替莫唑胺（TMZ）治疗后发生进行性/复发性 GBM 的患者。
两位综述作者独立选择研究并使用预设计的数据提取表格提取数据。我们进行了网络荟萃分析（NMA），并使用随机效应模型和 Stata 软件（版本 15）根据每种结果的有效性对治疗方法进行排名。我们使用 GRADE 方法评估证据的确定性。
我们纳入了 42 项研究：这些研究包括 34 项随机对照试验（RCT）和 8 项非随机研究（NRS），涉及 5236 名参与者。我们判断大多数 RCT 存在低偏倚风险，而 NRS 存在高偏倚风险。干预措施包括化疗、再手术、再放疗和单独使用或联合使用的新型疗法。对于首次复发，我们在网络荟萃分析（NMA）中包括了 11 项干预措施的总生存期（OS），8 项干预措施的无进展生存期（PFS）。洛莫司汀（LOM；也称为 CCNU）是最常见的比较剂，被用作参考治疗。没有研究在 NMA 中评估手术、再放疗、PCV（丙卡巴肼、洛莫司汀、长春新碱）、TMZ 再挑战或最佳支持性治疗。由于数据不足，我们无法进行第二次或以后复发的 NMA。质量生活数据很少。首次复发（NMA 结果）纳入 NMA 的研究中，中位 OS 范围从 5.5 到 12.6 个月，中位无进展生存期（PFS）范围从 1.5 个月到 4.2 个月。我们没有发现任何治疗方法比洛莫司汀更好的高确定性证据。这些治疗方法包括：贝伐单抗加洛莫司汀：贝伐单抗（BEV）联合洛莫司汀（LOM）和 LOM 单药治疗的 OS 之间的证据可能表明两者之间可能没有差异（HR 0.91，0.75 至 1.10；中等确定性证据），尽管 BEV+LOM 可能改善 PFS（HR 0.57，95%置信区间（CI）0.44 至 0.74；低确定性证据）。贝伐单抗单药治疗：低确定性证据表明，贝伐单抗（BEV）与洛莫司汀（LOM）单药治疗的 OS（HR 1.22，95%CI 0.84 至 1.76）和 PFS（HR 0.90，95%CI 0.58 至 1.38；低确定性证据）之间可能没有差异；需要更多关于 BEV 的证据。瑞戈非尼（REG）：REG 可能比 LOM 改善 OS（HR 0.50，95%CI 0.33 至 0.76；低确定性证据）。PFS 的证据非常低确定性，需要更多关于 REG 的证据。替莫唑胺（TMZ）联合 Depatux-M（ABT414）：对于 OS，低确定性证据表明 TMZ 联合 ABT414 可能比 LOM（HR 0.66，95%CI 0.47 至 0.92）和 BEV（HR 0.54，95%CI 0.33 至 0.89；低确定性证据）更有效，这可能是由于 TMZ 成分所致，需要更多证据。福莫司汀（FOM）：FOM 和 LOM 可能对 OS 有相似的影响（HR 0.89，95%CI 0.51 至 1.57，低确定性证据）。贝伐单抗和伊立替康（IRI）：贝伐单抗+伊立替康（IRI）与 LOM 对 OS 和 PFS 的证据非常不确定，贝伐单抗+IRI 与贝伐单抗单药治疗之间可能没有差异（OS：HR 0.95，95%CI 0.70 至 1.30；中等确定性证据）。当对治疗方法进行 OS 排名时，FOM 排名第一，BEV+LOM 排名第二，LOM 排名第三，BEV+IRI 排名第四，BEV 排名第五。排名不考虑证据的确定性，这也表明 FOM 和 LOM 之间可能没有差异。其他治疗方法三项研究评估了手术与不手术、有或无再放疗和化疗的比较，这些研究表明，在能够选择适合手术的患者的情况下，手术可能具有生存优势。早期评估的一种大麻素治疗方法与 TMZ 联合使用，值得进一步评估。第二次或以后复发有限的证据来自三项异质性研究表明，放疗联合或不联合贝伐单抗可能对生存有益，但需要更多的证据。证据不足，无法得出关于最佳放疗剂量的结论。其他证据表明，与医生的最佳治疗选择相比，肿瘤治疗场可能对生存没有差异。我们没有发现关于最佳支持性治疗的可靠证据。严重不良事件（SAEs）贝伐单抗+LOM 联合治疗与 LOM 单药治疗相比，严重不良事件（RR 2.51，95%CI 1.72 至 3.66，高确定性证据）的风险显著增加，与西地尼布+LOM 联合治疗（RR 2.51，95%CI 1.29 至 4.90；高确定性证据）并列最差。LOM 排名最好，REG 排名第二。将新型治疗方法添加到 BEV 中通常与 BEV 单药治疗相比，严重不良事件的风险更高。
对于胶质母细胞瘤首次复发患者，在接受过手术和标准放化疗治疗的患者中，与 LOM 单药治疗相比，联合治疗方案并未改善总生存期，且通常与严重不良事件风险增加有关。有限的证据表明，在合适的患者中，再手术联合或不联合再放疗可能是合适的。关于第二次复发的证据很少。在选定的个体中，再放疗联合或不联合贝伐单抗可能有价值，但需要更多的证据。
