Combination Targeted Therapy in Advanced Renal Cell Carcinoma
Combination Targeted Therapy in Advanced Renal Cell Carcinoma
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DOI：
10.1002/cncr.24234
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发表时间：
2009-05-15
期刊：
影响因子：
6.2
通讯作者：
Puzanov, Igor
中科院分区：
文献类型：
--
作者：
Sosman, Jeffrey;Puzanov, Igor
最近已经批准了几种新的治疗晚期肾癌(RCC)的方法。这些药物抑制了von Hippel-Lindau基因VHL丢失后的下游通路。它们针对血管内皮生长因子(VEGF)配体、血管内皮生长因子受体(VEGFR)、哺乳动物雷帕霉素靶标(MTOR)和其他潜在的重要途径。即使存活率有所提高，所有患者的疾病仍会继续发展。迫切需要增加完整的反应(现在很少见)。一种这样的策略是结合几种药物来阻断不同水平的血管内皮生长因子-血管内皮生长因子受体轴(垂直阻断)。或者，将血管内皮生长因子-血管内皮生长因子受体抑制剂与mTOR抑制剂联合使用是有吸引力的。最后，用表皮生长因子受体和/或血小板衍生生长因子受体水平阻断VEGFR是另一种方法，这些信号通路都是由低氧诱导因子激活的。试验已经揭示了联合治疗的困难。通过联合用药，1或两者的毒性都可以增强。这篇文章的作者报告了他们使用索拉非尼和贝伐单抗的经验，该药物导致手足综合征、高血压和蛋白尿的增加，所有这些都是已知的毒副作用。临床活动令人印象深刻，48名患者的25个应答(52%的应答率)。其他组合也需要减少剂量(索拉非尼加替西罗莫司)或无法耐受(舒尼替尼加替西罗莫司或舒尼替尼加贝伐单抗)。以微血管病理性溶血性贫血为特征的意外毒性发生在舒尼替尼和贝伐单抗治疗的晚期。肾细胞癌患者的毒性可能更严重，他们经常患有I肾，肾功能不佳。一旦建立了联合方案的耐受性，设计信息丰富的第二阶段试验并解决联合疗法与序贯疗法的益处将是至关重要的。癌症2009；115(10补充)：2368-75。(C)2009年美国癌症协会。
Several novel therapies have been approved recently in advanced renal cell carcinoma (RCC). These agents inhibit pathways downstream of loss of the von Hippel-Lindau gene VHL. They target the vascular endothelial growth factor (VEGF) ligand, VEGF receptor (VEGFR), mammalian target of rapamycin (mTOR), and other potentially important pathways. Even with improvements in survival, disease progresses in all patients. There is a critical need to increase complete responses (now rare). One such strategy is combining several agents to block different levels of the VEGF-VEGFR axis (vertical blockade). Alternatively, combination of a VEGF-VEGFR inhibitor with an mTOR inhibitor is attractive. Finally, horizontal blockade of VEGFR with epidermal growth factor receptor and/or platelet-derived growth factor receptor, all signaling pathways activated by hypoxia-inducible factor, is another approach. Already trials have revealed difficulties with combination therapy. By combining agents, the toxicity of 1 or both can be enhanced. The authors of this article report their experience with sorafenib plus bevacizumab, which produced increases in hand-foot syndrome, hypertension, and proteinuria, all known toxic effects. Clinical activity was impressive with 25 responses in 48 patients (52% response rate). Other combinations also required dose reductions (sorafenib with temsirolimus) or were intolerable (sunitinib with temsirolimus or sunitinib with bevacizumab). Unexpected toxicity characterized by microangiopathic hemolytic anemia occurred late in treatment with sunitinib and bevacizumab. Toxicity may be more severe in patients with RCC, who frequently have I kidney and poor renal function. Once tolerability for combination regimens has been established, it will be critical to design informative phase 2 trials and address the benefit of combination versus sequential therapy. Cancer 2009;115(10 suppl):2368-75. (C) 2009 American Cancer Society.