Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
Int J Radiat Oncol Biol Phys. 2021 Jul 1;110(3):792-803. doi: 10.1016/j.ijrobp.2021.01.033. Epub 2021 Jan 29.
We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TV) and hyperperfused (TV) tumor volumes would improve outcomes in patients with glioblastoma.
This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TV/TV >1 cm, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TV/TV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TV/TV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test-Revised.
Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TV alone, and 13 patients were boosted to both TV/TV. Gross or subtotal resection was performed in 87% of patients; 22% were O-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TV/TV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TV/TV decreased to less than the median volume (3 cm) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy.
Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy.
我们假设针对不良预后的高细胞（TV）和高灌注（TV）肿瘤体积进行剂量强化的放化疗会改善胶质母细胞瘤患者的预后。
这项单臂、2 期临床试验招募了新诊断为胶质母细胞瘤的成年患者。使用高 b 值弥散加权磁共振成像（MRI）和动态对比增强灌注 MRI 识别 TV/TV >1cm 的患者，采用替莫唑胺对 TV/TV 进行 30 次分割至 75Gy 的治疗。主要目标是估计 12 个月总生存率（OS）相对于历史对照的改善。次要目标包括使用 Cox 比例风险回归评估 3 个月时 TV/TV 减少对 OS 的影响，并使用相关的 C-蛋氨酸正电子发射断层扫描（PET）对代谢肿瘤体积的覆盖（95%等剂量线）进行特征描述。通过欧洲癌症研究与治疗组织（EORTC）生活质量问卷 C30 评估生活质量的临床意义变化，通过 MD 安德森脑肿瘤症状量表评估症状负担，通过受控口头单词联想测试、连线测试 A 和 B、霍普金斯词语学习测试修订版评估神经认知功能（NCF）。
2016 年至 2018 年期间，共招募了 26 名患者。最初的患者仅接受 TV 放疗，而 13 名患者接受了 TV/TV 联合放疗。87%的患者接受了大体或次全切除术；22%的患者存在 O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）甲基化。26 个月的随访（95%CI，19 未达到），接受联合 TV/TV 放疗的患者 12 个月 OS 率为 92%（95%CI，78%-100%；P=0.03），中位 OS 为 20 个月（95%CI，18-未达到）；整个研究队列的中位 OS 为 20 个月（95%CI，14-29 个月）。3 个月时 TV/TV 降低至中位数以下（3cm）的患者具有更好的 OS（29 个月 vs 12 个月；P=0.02）。仅 5 例患者发生中心或场内失败，93%（四分位距，59%-100%）的 C-蛋氨酸代谢肿瘤体积接受了高剂量覆盖。2 例患者发生迟发性 3 级神经毒性。在非进展性患者中，1 个月和 7 个月时生活质量、症状和 NCF 的恶化发生率与标准治疗相似。
针对胶质母细胞瘤中高细胞/高灌注肿瘤区域进行剂量强化治疗可获得有前景的 OS，对 NCF、症状负担和生活质量有良好的影响，特别是在放疗后 3 个月肿瘤体积减少更大的患者中。
