Abstract
Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in tumor growth and progression. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessel formation and permeability. Overexpression of VEGF has been observed in a variety of cancers and has been associated with a worse relapse-free and overall survival. The antiangiogenic agent bevacizumab, a monoclonal antibody directed against VEGF, has shown clinical benefit in multiple cancers, including non-small cell lung cancer (NSCLC). Based on the favorable results of a prior randomized, phase II trial, the Eastern Cooperative Oncology Group conducted a trial (E4599) to evaluate the efficacy of bevacizumab in combination with paclitaxel and carboplatin in patients with recurrent or advanced stage IIIB or IV nonsquamous cell NSCLC. Exclusion criteria included squamous cell histology, brain metastases, significant hemoptysis, or inadequate organ function or performance status >1. The primary study end point was overall survival. The median duration of survival in the chemotherapy plus bevacizumab group was 12.3 months compared with 10.3 months in the chemotherapy alone group (P = 0.003). Significant bleeding was more frequent in the chemotherapy plus bevacizumab group, 4.4% compared with 0.9% (P = 0.001). There were 15 treatment-related deaths in the chemotherapy plus bevacizumab group, including 5 due to pulmonary hemorrhage. Future and current directions include evaluation of bevacizumab in earlier stages of NSCLC, in SCLC, and in combination with other targeted agents, such as erlotinib.
Highlights
Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in tumor growth and progression
In the only randomized trial of single-agent bevacizumab, treatment of patients with metastatic renal cell carcinoma seemed to result in a significant increase in time to progression, but no improvement was seen in overall survival [10]
Several studies in patients with metastatic colorectal, lung, and breast cancer have shown improvements in progression-free and overall survival when bevacizumab has been used in combination with chemotherapy (11 – 15)
Summary
Markers of angiogenesis have been shown to have prognostic significance in solid tumors [1]. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor acting on VEGF receptor-1 (Flt-1) and VEGF receptor-2 (KDR, Flk-1). Inhibition of VEGF has been shown to prevent tumor growth [2]. Tumor VEGF overexpression in patients with early-stage lung cancer has been associated clinically with worse relapse-free and overall survival (3 – 6). Elevated VEGF expression has been linked with development of brain metastases and pleural effusions in murine models of non – small cell lung cancer VEGF expression is elevated by diverse stimuli, which include proto-oncogene activation and hypoxia [9], the latter frequently arising in solid tumors because of inadequate perfusion
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