Stephen E. and Catherine Pappas Center for Neuro-Oncology, Yawkey 9E, Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston, MA 02114, USA.
J Clin Oncol. 2010 Jun 10;28(17):2817-23. doi: 10.1200/JCO.2009.26.3988. Epub 2010 May 10.
PURPOSE: Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. METHODS: Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. RESULTS: Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. CONCLUSION: Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
目的：胶质母细胞瘤是一种无法治愈的实体肿瘤，其特征是血管内皮生长因子 (VEGF) 表达增加。我们对复发性胶质母细胞瘤患者进行了西地尼布的 II 期研究。
方法：西地尼布是一种口服泛血管内皮生长因子受体酪氨酸激酶抑制剂，用于治疗复发性胶质母细胞瘤患者，直至疾病进展或出现不可接受的毒性。主要终点是 6 个月时无进展生存（APF6）的患者比例。我们在多个时间点进行了磁共振成像（MRI）和血浆及尿液生物标志物评估。
结果：共纳入 31 例复发性胶质母细胞瘤患者。西地尼布治疗后的 APF6 为 25.8%。30 例可评估患者中，17 例（56.7%）采用三维测量，8 例（27%）采用二维测量，MRI 观察到放射性部分缓解。对于 15 例入组时正在服用皮质类固醇的患者，减少了剂量（n=10）或停用了药物（n=5）。毒性是可控的。3 级/4 级毒性包括高血压（31 例中有 4 例；12.9%）；腹泻（31 例中有 2 例；6.4%）；疲劳（31 例中有 6 例；19.4%）。31 例患者中有 15 例（48.4%）至少需要减少一次剂量，15 例患者因毒性需要暂时中断药物治疗。药物中断与结果无关。西地尼布治疗后血浆胎盘生长因子、碱性成纤维细胞生长因子、基质金属蛋白酶 (MMP)-2、可溶性血管内皮生长因子受体 1、基质细胞衍生因子-1alpha 和可溶性 Tek/Tie2 受体以及尿液 MMP-9/中性粒细胞明胶酶相关脂质运载蛋白活性的变化与放射学反应或生存相关。
结论：西地尼布单药治疗复发性胶质母细胞瘤与令人鼓舞的放射学反应比例、6 个月无进展生存率和皮质类固醇节省效应相关，且毒性可控。我们发现循环分子的早期变化可能是对西地尼布反应的生物标志物。西地尼布的疗效和这些候选生物标志物的预测价值将在前瞻性试验中进行探索。
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