New antiangiogenetic agents and non-small cell lung cancer

https://doi.org/10.1016/j.critrevonc.2006.01.008Get rights and content

Abstract

New blood vessel formation, known as angiogenesis is a fundamental event in the process of tumor growth and metastatic dissemination. Due to its central role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology, including the treatment of non-small cell lung cancer (NSCLC). Approaches targeting VEGF include monoclonal antibodies and vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). Bevacizumab (Avastin) is an anti-VEGF recombinant humanized monoclonal antibody. A very recent randomized phase III trial demonstrated a statistically significant advantage in median survival favouring the combination of bevacizumab plus chemotherapy versus chemotherapy alone in the treatment of advanced non-squamous NSCLC. This study represents the first evidence of superior efficacy of targeted therapy combined with chemotherapy over chemotherapy alone in the treatment of NSCLC. ZD6474 is an orally bioavailable inhibitor of VEGFR-2 tyrosine kinase. First evidences of antitumor activity and its excellent toxicity profile make it a promising targeted agent for the treatment of NSCLC. A recent phase I/II study examined the combination of Epidermal Growth Factor Receptor (EGFR)-TKI erlotinib and bevacizumab in patients with non-squamous stage IIIB/IV NSCLC. Data on antitumor activity of this combination have to be considered very promising. Clinical trials of multiple targeted therapy may represent the second generation studies in the treatment of NSCLC.

Introduction

Lung cancer is the leading cause of cancer-related mortality in both men and women [1], with 1.2 million new cases diagnosed every year and with 1 million deaths being recorded worldwide in 2001 [2]. Non-small cell lung cancer (NSCLC), accounts for approximately 80% of all lung cancers. The majority of NSCLC patients present with advanced disease at diagnosis and a large part of those diagnosed with early stage disease eventually recur, experiencing metastatic disease. For advanced disease palliation and the patients’ quality of life are still the primary goal of therapy, with total cure remaining elusive.

Although chemotherapy has recently produced promising results as neoadjuvant and adjuvant strategies for early-stage patients [3], [4] and some progress has been made in the treatment of locally-advanced and advanced disease [5], [6], treatment outcomes for NSCLC are still to be considered disappointing. Thus, clinical research of new treatment strategies is warranted. Advances in the knowledge of tumor biology and mechanisms of oncogenesis has granted the singling out of several molecular targets for NSCLC treatment. In chemotherapy refractory advanced NSCLC patients, erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), represent a further chance of survival improvement and/or symptom palliation for a subset of patients otherwise eligible only for supportive care [7]. However, erlotinib, combined with chemotherapy, failed to improve the results of chemotherapy alone in the first-line treatment of advanced NSCLC [8], [9]. New blood vessel formation, known as angiogenesis is a fundamental event in the process of tumor growth and metastatic dissemination. Thus, molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research [10], [11], and the strategy of targeting angiogenesis has very recently achieved the first clinically significant results in the treatment of NSCLC.

Section snippets

Angiogenesis and lung cancer

Generally, tumors cannot grow beyond 2 mm in diameter without developing a vascular supply [12]. Not only does neovascularization permit further growth of the primary tumor, but it also provides a pathway for migrating tumor cells to gain access to the systemic circulation and to establish distant metastases. In the absence of a functional vascular supply tumors remain dormant and unable to metastatize [13], [14]. Angiogenesis, whether physiological or pathological, is governed by a host of

Angiogenesis inhibitors

Strategies targeting angiogenesis can be classified broadly as those targeting the endothelium and those targeting the extracellular matrix. Most angiogenesis inhibitors under study act as new blood vessel formation inhibitors, while others have to be considered anti-vascular agents as they specifically target established blood vessels in tumors. Due to its central role in tumor angiogenesis, the VEGF/VEGF-Receptor (VEGFR) pathway has been a major focus of basic research and drug development in

Multiple targeted therapy: angiogenesis inhibitors combined with other biologic agents

With the exception of some rare cancers in which growth can be dependent on a single factor, selective targeted agents seem to have limited single-agent activity. This is fully in line with the concept that for most tumors there are multiple factors driving tumor growth. The complexity of the signalling process in general further supports the need to interfere at different stages to avoid an escape mechanism for the cell.

Pre-clinical evidence of synergistic antitumor activity achievable by

Conclusion

Although the progress achieved with chemotherapy, treatment outcomes for NSCLC are still to be considered disappointing. Advances in the knowledge of tumor biology and mechanisms of oncogenesis has granted the singling out of several molecular targets for NSCLC treatment. Negative results are more common to find than positive ones in the first generation of clinical trials of targeted agents in NSCLC treatment. However, angiogenesis inhibitors and specifically strategies targeting the

Reviewers

Masaaki Kawahara, MD, Director, Department of Thoracic Oncology, Clinical Research Center, National Center Hospital for Chest Disease, 1180 Nagasone-Cho, Sakai, Osaka 591-8555, Japan.

Refael Rosell, MD, PhD, Chief, Medical Oncology Service & Scientific Director of Oncology, Catalan Institute of Oncology, Hospital German Trias i Pujol, Ctra Canyet, s/n 08916 Badalona, Barcelona, Spain.

Cesare Gridelli was born in Naples on March 24, 1961. He is a medical oncologist chief of the Division of Medical Oncology and Director of Department of Onco-Hematology of “S.G. Moscati” Hospital of Avellino (Italy). He is an active member of the American Society of Clinical Oncology. He has been doing clinical research in the treatment of lung cancer for several years. He is author of about 400 publications.

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    Cesare Gridelli was born in Naples on March 24, 1961. He is a medical oncologist chief of the Division of Medical Oncology and Director of Department of Onco-Hematology of “S.G. Moscati” Hospital of Avellino (Italy). He is an active member of the American Society of Clinical Oncology. He has been doing clinical research in the treatment of lung cancer for several years. He is author of about 400 publications.

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