Current Status of Anti-Angiogenic Therapy in the Clinical Management of Lung Cancer
Pp. 49-69 (21)
Peter M. Ellis and Abdulaziz Al Farsi
Increased angiogenic activity occurs frequently in lung cancer and results in
biologically more aggressive disease. There has been intense research into therapeutic
agents that inhibit angiogenesis and may improve treatment options for patients with
lung cancer. Bevacizumab, a monoclonal antibody directed against serum VEGF, in
combination with carboplatin and paclitaxel chemotherapy, has been shown to improve
survival for NSCLC patients. Meta-analysis of trials of bevacizumab in combination
with platinum-based chemotherapy for NSCLC, show a 10% reduction in the risk of
death (HR 0.90, 95%CI 0.81 – 0.99). However, therapy with bevacizumab is limited to
NSCLC patients with non-squamous histology, good performance status, no brain
metastases and the absence of bleeding or thrombotic disorders. Similar efficacy has
been seen also with carboplatin, pemetrexed plus maintenance pemetrexed
chemotherapy. In the second-line setting, the addition of ramucirumab to docetaxel
chemotherapy, resulted in a modest improvement in survival, adding a second antiangiogenic
treatment option for patients with NSCLC.
A large number of trials in NSCLC have been conducted evaluating oral antiangiogenic
compounds, both in first-line therapy in combination with chemotherapy, or
upon disease progression, either as combination, or single agent therapy. Some level of activity has been observed with most agents. No clear improvements in overall survival
have been observed, although a subgroup analysis of a trial evaluating the addition of nintedanib to docetaxel showed improved survival limited to patients with
adenocarcinoma. However, these findings require validation. All of the oral antiangiogenic
agents result in added toxicities. Some agents have resulted in an increased
risk of death, limiting their development. Currently, there is no established role for
anti-angiogenic therapy in SCLC, although there is some promise for sunitinib as
maintenance therapy following platinum and etoposide chemotherapy.
Despite the large number of anti-angiogenic agents evaluated in clinical trials, there is
evidence supporting a limited number of agents as treatment options for patients with
lung cancer. To date no biomarkers have been identified. It is unclear whether
treatment effects in a subpopulation, are lost among a larger unselected population of
patients. There is a need for additional translational research to identify predictive
biomarkers for anti-angiogenic therapy.
Angiogenesis, Anti-angiogenic therapy, Chemotherapy, Fibroblast
derived growth factor, Monoclonal antibodies, Non small cell lung cancer,
Overall survival, Platelet derived growth factor, Progression free survival,
Randomized clinical trials, Small cell lung cancer, Tyrosine kinase inhibitors,
Vascular endothelial growth factor.
Department of Oncology, McMaster University, Hamilton, Ontario, Canada.