Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study
Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study
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DOI：
10.1200/jco.2008.20.9908
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发表时间：
2009-06-20
影响因子：
45.3
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
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作者：
Zhu, Andrew X.;Sahani, Dushyant V.;Jain, Rakesh K.
目的评估舒尼替尼在晚期肝细胞癌 (HCC) 患者中的安全性和有效性，并探索舒尼替尼反应的生物标志物。患者和方法我们对舒尼替尼（一种抗血管内皮生长因子受体酪氨酸激酶抑制剂）在晚期 HCC 中进行了一项多学科 II 期研究。患者接受舒尼替尼 37.5 mg/d 治疗 4 周，然后每个周期休息 2 周。主要终点是无进展生存期（PFS）。我们使用功能磁共振成像来评估舒尼替尼治疗后 HCC 的血管变化。在舒尼替尼治疗前和治疗后的六个时间点评估循环分子和细胞生物标志物。结果 34 名患者入组。客观缓解率为2.9%，50%的患者病情稳定。中位 PFS 为 3.9 个月（95% CI，2.6 至 6.9 个月），总生存期为 9.8 个月（95% CI，7.4 个月至不可用）。 3 级或 4 级毒性包括白细胞减少/中性粒细胞减少、血小板减少、转氨酶升高和疲劳。舒尼替尼迅速减少血管渗漏，这种效果在延迟进展的患者中更为明显。当早期（基线和第 14 天）以及超过三个治疗周期进行评估时，较高水平的炎症分子（例如，白细胞介素 6、基质衍生因子 1 α、可溶性 c-KIT）和循环祖细胞与不良结果相关。 结论 证据显示，舒尼替尼在晚期 HCC 中具有适度的抗肿瘤活性，且副作用可控。肿瘤血管通透性和循环炎症生物标志物的快速变化是 HCC 中舒尼替尼反应和耐药的潜在决定因素。我们的研究表明，控制炎症可能对于改善晚期 HCC 的治疗结果至关重要。 J 临床肿瘤学杂志 27：3027-3035。 (C) 2009 年美国临床肿瘤学会
PurposeTo assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.Patients and MethodsWe conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment.ResultsThirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1 alpha, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome.ConclusionSunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC. J Clin Oncol 27: 3027-3035. (C) 2009 by American Society of Clinical Oncology