Angiogenesis in Non-Small Cell Lung Cancer
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Am J Respir Med 2002; 1 (5): 325-338 1175-6365/02/0005-0325/$25.00/0 © Adis International Limited. All rights reserved.
Angiogenesis in Non–Small Cell Lung Cancer A New Target for Therapy Tracy E. Kim and John R. Murren Department of Internal Medicine, Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA
Abstract
Non–small cell lung cancer (NSCLC) is cured with surgery in a minority of affected persons. Chemotherapy and radiation can palliate and extend survival of patients with disease not amenable to surgery. Consequently, new treatment options are urgently needed. In the era of molecularly targeted therapeutics, the recent direction in cancer research has been to identify and modulate specific events in tumorigenesis. Angiogenesis, or new vessel formation, is one such event elucidated to be fundamental to the development, growth, and metastasis of cancers and is one of the characteristics that differentiates tumor from host. Thus, targeting of tumor neovasculature continues to generate tremendous enthusiasm and effort in drug development. Extensive research into the role of angiogenesis in NSCLC has produced a host of novel targets; their potential inhibitors, now numbering over 40, are in various phases of clinical testing around the world. The current lead compounds include inhibitors of matrix metalloproteinases, angiogenic growth factors and their receptor tyrosine kinases. Despite their impressive activity in animal models, definitive evidence of their antitumor activity in humans is yet to be established. We face several challenges as we look to advance the field of antiangiogenesis for the treatment of cancer, namely, the need for a better understanding of the optimal timing and dosing of antiangiogenic agents, the validation of imaging and quantification methods of tumor angiogenesis, and a new clinical trials design for a more expedient evaluation of novel cytostatic target modulators.
In 2001, approximately 170 000 Americans were diagnosed with primary lung cancer and nearly 158 000 died of the disease.[1] Surgery is the treatment of choice for non–small cell lung cancer (NSCLC). Unfortunately, fewer than one-third of the patients are eligible for curative surgery. Although the tumor-nodemetastasis staging is the best predictor of outcome currently available, survival can vary widely within the same stage (table Table I. 5-Year survival rates in patients with non–small cell lung cancer[2] AJCC stage I II
TNM designation
Overall 5-year survival (%) 60-80 30-50
T1-2 N0 M0 T1-2 N1 M0 T3 N0 M0 IIIA T3 N1 M0 10-30 T1-3 N2 M0 IIIB Any T4 or any N3 M0 10%, a third investigator or blind recount a Paraffin embedding of the tumor specimen is preferred over frozen sectioning. b The immunohistochemical staining of the endothelium by anti-CD31 monoclonal antibody is recommended because it is the most sensitive pan-endothelial marker. This antibody does not distinguish between established and newly formed vessels, however, and may be inferior to more
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