Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease
Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease
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DOI：
10.1093/annonc/mdr011
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发表时间：
2011-12-01
影响因子：
50.5
通讯作者：
Matin, S. F.
中科院分区：
文献类型：
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作者：
Jonasch, E.;McCutcheon, I. E.;Matin, S. F.
背景：Von Hippel-Lindau（VHL）病可导致多器官血管肿瘤。我们评估了舒尼替尼在VHL患者的安全性和有效性，并检查候选受体的表达存档tissue.Methods：VHL患者给予4个周期的舒尼替尼50 mg，每天28天，然后休息14天。主要终点是毒性。采用改良RECIST进行疗效评价。我们评估了20个档案肾细胞癌（RCC）和20个血管母细胞瘤（HB）的生物标志物的表达水平，使用激光扫描细胞术（LSC）。3级毒性包括5例患者的疲劳。10例患者需要降低剂量。18个RCC和21个HB病变可评价。6例RCC（33%）部分应答，而HB无应答（P = 0.014）。LSC显示HB中磷酸化血管内皮生长因子受体-2的平均水平低于RCC内皮（P = 0.003），HB中磷酸化成纤维细胞生长因子受体底物-2（pFRS 2）的平均水平高于RCC内皮（P = 0.003）。在RCC中观察到显著反应，但在HB中未观察到。pFRS 2在HB组织中的表达高于RCC，这提出了一个假设，即用成纤维细胞生长因子通路阻断剂治疗可能使HB患者受益。
Background: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue.Methods: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC).Results: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003).Conclusions: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.