Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities. Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/Medline and American Society of Clinical Oncology databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts. 摘要 概要. 分子靶向抗癌治疗的引入有望延长某些既往无法治疗的恶性肿瘤的生存期，但同时也带来需要认识并管理的新毒性，某些将持续较长时间。血管内皮生长因子抑制剂可能发生许多不良反应，尤其是血管毒性。本综述着重阐述晚期癌症患者血管毒性的（高血压、出血和血栓栓塞）病理生理和发病机制的最新知识，探讨其发生、严重程度及当前临床治疗手段。在疾病早期即引入抗血管生成治疗将改变其相关毒性对临床实践的影响。 检索策略和选择标准. 本综述所用资料检索自PubMed/Medline和美国临床肿瘤学会摘要数据库。所用的医学主题术语有：毒性、高血压、血栓栓塞、出血、肠穿孔、危险因素、药物代谢和代谢动力学，并与下列自由文本检索术语相结合：VEGF抑制剂、贝伐珠单抗、舒尼替尼、索拉非尼，但并不局限于这些术语。除源自病例报告和药物说明书的信息外，2010年3月之前用英文发表的文献也入选。 This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism) of molecularly targeted anticancer therapies, their incidence and severity, the current clinical management, and implications in the advanced cancer setting.