Neuro-Oncology Unit, Brain Tumour Centre at Erasmus MC Cancer Institute, Rotterdam, Netherlands.
Department of Radiation-Oncology (MAASTRO), Maastricht University Medical Centre (MUMC), Maastricht, Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands; Department of Radiation-Oncology, University of Münster, Münster, Germany; Paracelsus Clinic, Osnabrück, Germany.
Lancet. 2017 Oct 7;390(10103):1645-1653. doi: 10.1016/S0140-6736(17)31442-3. Epub 2017 Aug 8.
The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas.
This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990.
At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible.
Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed.
Schering Plough and MSD.
替莫唑胺化疗在新诊断的 1p/19q 非共缺失间变性神经胶质瘤中的作用尚不清楚，这类肿瘤对化疗的敏感性较低，预后较 1p/19q 共缺失肿瘤差。我们评估了放疗联合替莫唑胺辅助治疗非共缺失间变性神经胶质瘤成人患者的效果。
这是一项 3 期、随机、开放标签、2×2 析因设计的研究。符合条件的患者年龄在 18 岁及以上，新诊断为非共缺失间变性神经胶质瘤，且 WHO 体能状态评分为 0-2 分。随机分组方案采用电子 EORTC 网络 ORTA 系统生成。患者按 1:1:1:1 的比例随机分组，采用最小化技术，分别接受放疗（59.4 Gy，33 次，每次 1.8 Gy）单药治疗或放疗联合辅助替莫唑胺治疗（12 个 4 周周期，替莫唑胺剂量为 150-200 mg/m，每天 1-5 天用药）；或接受放疗联合每日 75 mg/m 替莫唑胺同步治疗，联合或不联合辅助替莫唑胺治疗。主要终点是根据体能状态评分、年龄、1p 杂合性缺失、少突胶质细胞成分和 MGMT 启动子甲基化状态进行调整的总生存，分析方法为意向治疗。在 219 例（41%）患者死亡后进行了计划的中期分析，以检验无疗效的零假设（拒绝的阈值为 p<0.0084）。该试验在 ClinicalTrials.gov 注册，编号为 NCT00626990。
在中期分析时，计划纳入的 748 例患者中已有 745 例（99%）入组。辅助替莫唑胺治疗的总生存风险比为 0.65（99.145%CI 0.45-0.93）。有和无辅助替莫唑胺治疗的 5 年总生存率分别为 55.9%（95%CI 47.2-63.8）和 44.1%（36.3-51.6）。549 例接受替莫唑胺治疗的患者中，有 8-12%出现 3-4 级不良事件，主要为血液学和可逆性不良事件。
新诊断的非共缺失间变性神经胶质瘤患者接受辅助替莫唑胺化疗可显著提高生存率。需要进一步分析同步替莫唑胺治疗和分子因素的作用。
先灵葆雅和默沙东。
