Cardiovascular Toxicity Profiles of Vascular‐Disrupting Agents

• Published in: The oncologist (Dayton, Ohio) Ohio), 2011-08, Vol.16 (8), p.1120-1130
• Main Authors: Subbiah, Ishwaria M., Lenihan, Daniel J., Tsimberidou, Apostolia M.
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - therapeutic use; Bibenzyls - adverse effects; Bibenzyls - therapeutic use; Cardiovascular System - drug effects; Cardiovascular toxicity; Clinical Pharmacology; Clinical Trials as Topic; Combretastatin; Humans; Hypertension; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Organophosphorus Compounds - adverse effects; Organophosphorus Compounds - therapeutic use; Phase 1; Quinazolines - adverse effects; Quinazolines - therapeutic use; Serine - adverse effects; Serine - analogs & derivatives; Serine - therapeutic use; Vascular‐disrupting agent; Xanthones - adverse effects; Xanthones - therapeutic use
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2010-0432

Background. Vascular‐disrupting agents (VDAs) represent a new class of chemotherapeutic agent that targets the existing vasculature in solid tumors. Preclinical and early‐phase trials have demonstrated the promising therapeutic benefits of VDAs but have also uncovered a distinctive toxicity profile highlighted by cardiovascular events. Methods. We reviewed all preclinical and prospective phase I–III clinical trials published up to August 2010 in MEDLINE and the American Association of Cancer Research and American Society of Clinical Oncology meeting s of small‐molecule VDAs, including combretastatin A4 phosphate (CA4P), combretastatin A1 phosphate (CA1P), MPC‐6827, ZD6126, AVE8062, and ASA404. Results. Phase I and II studies of CA1P, ASA404, MPC‐6827, and CA4P all reported cardiovascular toxicities, with the most common cardiac events being National Cancer Institute Common Toxicity Criteria (version 3) grade 1–3 hypertension, tachyarrhythmias and bradyarrhythmias, atrial fibrillation, and myocardial infarction. Cardiac events were dose‐limiting toxicities in phase I trials with VDA monotherapy and combination therapy. Conclusions. Early‐phase trials of VDAs have revealed a cardiovascular toxicity profile similar to that of their vascular‐targeting counterparts, the angiogenesis inhibitors. As these agents are added to the mainstream chemotherapeutic arsenal, careful identification of baseline cardiovascular risk factors would seem to be a prudent strategy. Close collaboration with cardiology colleagues for early indicators of serious cardiac adverse events will likely minimize toxicity while optimizing the therapeutic potential of VDAs and ultimately enhancing patient outcomes. 摘要 背景血管阻断剂（VDAs）是一类以实体瘤现存血管结构为治疗靶点的新型化疗药物，临床前和早期临床研究已显示VDAs的治疗前景，但同时也发现了其特有的毒性谱，以心血管不良事件尤为明显。 方法综述2010年8月前发表并收录于MEDLINE，或是发表于美国癌症研究学会（AACR）及美国临床肿瘤学会（ASCO）的相关会议摘要中，所有小分子VDAs相关的临床前与前瞻性I~III期临床研究结果，VDAs包括考布他汀A4磷酸盐（CA4P）、考布他汀A1磷酸盐（CA1P）、MPC‐6827、ZD6126、AVE8062和ASA404。 结果CA1P、ASA404、MPC‐6827和CA4P的I、II期研究均报告了心血管毒性，最常见的心脏事件为国立癌症研究院常见毒性标准（NCIC‐CTC，第3版）界定的1~3级高血压、心动过速、心动过缓、房颤和心肌梗死。I期研究中，心脏事件是VDA单药治疗和联合治疗的剂量限制性毒性。 结论早期临床研究结果显示，VDAs的心血管毒性谱与其他靶向血管生成的抑制剂相似。由于这些药物多与主流化疗方案联合使用，因此仔细确认基线心血管危险因素是谨慎的策略。与心脏科同行密切合作，监控心脏严重不良事件的早期指标，有可能在获得VDAs最佳治疗作用的同时，使毒性最小化，并最终改善患者转归。 The cardiovascular adverse events noted in clinical trials of vascular‐disrupting agents and their potential ramifications are examined.