CLINICAL IMPLICATIONS OF ANGIOGENESIS INHIBITION IN LUNG CANCER

Although beyond the scope of this chapter, we will mention
briefly a few of the major angiogenesis inhibitors that are in
clinical use or are being studied in lung cancer patients. This
issue is discussed comprehensively later in this manuscript by
Christian Manegold and Alan Sandler.
Bevacizumab (Avastin, Roche) is a monoclonal antibody
that is directed against the VEGF ligand. It was the first antiangiogenic
treatment to be approved for cancer. Bevacizumab
was evaluated in a phase III study of 878 patients with advanced
disease who received paclitaxel and carboplatin and was
found to result in an increased survival duration, from 10.3 to
12.3 months. 5 Bevacizumab treatment was also evaluated in
combination with cisplatinum and gemcitabine and was shown
to increase progression-free survival (http://meeting.ascopubs.
org/cgi/content/abstract/25/18_suppl/LBA7514, 2007).
Recombinant endostatin was evaluated as a treatment
for 42 neuroendocrine cancer patients, with no documented
responses. 268 Endostar, (YH-16, Medgenn Co.) is a recombinant
human endostatin modified by the addition of nine
amino acids. In a study of 493 advanced NSCLC patients, addition
of endostatin to chemotherapy led to increased time to
progression, from 3.6 to 6.3 months (http://meeting.ascopubs.
org/cgi/content/abstract/23/16_suppl/7138, 2005). These
findings suggest that endostatin has an important role in lung
cancer treatment. Endostar was recently approved for the treatment
of NSCLC patients in China. It remains to be seen if this
drug will be reevaluated in other countries.
Vandetanib (ZD6474) is a multikinase inhibitor that targets
VEGFR, EGFR, and Ret. It is being studied in several
phase II trials as a treatment for NSCLC.
Many other phase I and II studies of multikinase inhibitors
are ongoing, many of them targeting VEGFR and PDGFR.
This active clinical research is a result of the studies cited previously
that demonstrated VEGF as a major regulator of angiogenesis.
PDGFR is being evaluated as a clinical target, reflecting
the understanding that pericyte coverage is an essential part of
vascular small vessels. Many other targeted therapies are being
studied as potential antiangiogenic or vascularization- disrupting
agents. The bench-to-bedside transition of angiogenesis and vasculogenesis
inhibition is among the shortest in cancer research.
Hopefully, the combination of preclinical research and antiangiogenic
treatment development will evolve to result in effective
treatments for lung cancer patients.