Targeting Angiogenesis in Esophagogastric Adenocarcinoma

Learning Objectives After completing this course, the reader will be able to: Describe the receptors and ligands with identified roles in tumor angiogenesis and the mechanism of action of established and investigational antiangiogenic agents. Describe aspects of antiangiogenic agents that are incompletely understood and need further investigation to define their role in esophagogastric cancer. This article is available for continuing medical education credit at CME.TheOncologist.com The possibility of targeting tumor angiogenesis was postulated almost 40 years ago. The vascular endothelial growth factor (VEGF) family and its receptors have since been characterized and extensively studied. VEGF overexpression is a common finding in solid tumors, including esophagogastric cancer, and frequently correlates with poor prognosis. Monoclonal antibodies, soluble receptors, and small‐molecule tyrosine kinase inhibitors have been developed to inhibit tumor angiogenesis, and antiangiogenic therapy is now a component of standard treatment for advanced renal cell, hepatocellular, colorectal, breast, and non‐small cell lung carcinomas. The small‐molecule tyrosine kinase inhibitors sunitinib and sorafenib have been evaluated in phase II studies in esophagogastric cancer but appear to have only modest activity. Similarly, despite promising efficacy signals from phase II studies, the addition of the anti‐VEGF‐A monoclonal antibody bevacizumab to cisplatin plus capecitabine failed to result in a longer overall survival duration than with the chemotherapy doublet plus placebo. The response rate and progression‐free survival interval were significantly greater with bevacizumab, confirming some efficacy in advanced gastric cancer, but with inadequate benefit to justify the high cost of treatment. Evaluation of bevacizumab in the neoadjuvant and perioperative settings continues, hypothesizing that a higher response rate will translate into longer survival in patients with operable disease. Despite extensive research, the discovery of a reliable predictive biomarker for antiangiogenic therapy continues to elude the scientific and oncology communities, and mechanisms of primary and acquired resistance are incompletely understood. We are therefore currently unable to personalize antiangiogenic therapy for established indications, or use molecular selection for clinical trials evaluating novel indications. 摘要 约40年前，研究者就提出了靶向作用于肿瘤血管生成的可能性。自此血管内皮生长因子（VEGF）家族及其受体得到了和全面的研究。VEGF过度表达是包括食