Targeting Angiogenesis in Esophagogastric Adenocarcinoma

Abstract

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 http://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.

A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

“…Furthermore, as in many other cancers, it has been demonstrated the reliance of GC on angiogenesis, with the arrest of tumor growth in the absence of neovascularization. 39 In particular, 3 phase II studies that investigated the effect of bevacizumab-based therapy showed an encouraging RR (65-68%), subsequently confirmed in a phase III trial in the absence, however, of significant benefit in OS. [39][40][41] Recently, a meta-analysis confirmed the benefit of anti-VEGF target therapy in aGC on all endpoints evaluated (OS, PFS, RR).…”

“…39 In particular, 3 phase II studies that investigated the effect of bevacizumab-based therapy showed an encouraging RR (65-68%), subsequently confirmed in a phase III trial in the absence, however, of significant benefit in OS. [39][40][41] Recently, a meta-analysis confirmed the benefit of anti-VEGF target therapy in aGC on all endpoints evaluated (OS, PFS, RR). 42 Despite EGFR overexpression is observed in 27-44% of all GC, different trials evaluating the role of anti-EGFR agents failed to demonstrate any improvement in either PFS, OS, or RR.…”

Gastric cancer: past progress and present challenges

“…Without neovascularisation, it is thought that tumour growth will be arrested, with many solid tumours known to overexpress vascular endothelial growth factor (VEGF), which stimulates angiogenesis through a complex signalling cascade. Several isoforms of VEGF exist (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E), along with multiple receptors [VEGF receptor (VEG-FR) 1, VEGFR-2, and VEGFR-3], mediators (placental growth factor) and coreceptors (neuropilin 1 and neuropilin 2) [29]. Increased expression of VEGF by tumours is associated with poorer prognosis, and agents targeting one or more of these receptors have been evaluated in clinical studies in gastric cancer, with mixed results.…”

“…It has been hypothesised that the increased use of second-line chemotherapy in patients treated in Asia (66 % vs 21 % in pan-America) may explain why the pan-American patients appeared to derive an overall survival benefit which was not seen in those treated in Asia in a post hoc subgroup analysis. Despite extensive exploration, no predictive biomarker has yet been identified to determine which patients may benefit from bevacizumab therapy [29].…”

Targeting Angiogenesis in Gastroesophageal Cancer: Industry‐Sponsored Trials are not the Answer

“…Okines et al, in a recent review [6], pleaded for ''parallel prospective translational research in current trials'' to ''bridge'' gaps in our knowledge. I would argue that translational or benchside research, such as the current study by Liu et al, is an essential first step prior to the institution of further industry-sponsored clinical trials because of the tendency of such trials, even when randomized, to produce biased results [10].…”