Future Directions in Vascular
Endothelial Growth Factor–Targeted
Therapy for Metastatic Colorectal Cancer
Axel Grothey
Bevacizumab, the first approved vascular endothelial growth factor (VEGF)–targeted agent
for metastatic colorectal cancer, continues to be developed in phase III trials in other tumor
types. Its use is being explored not only in advanced disease, but also in earlier-stage
disease in the adjuvant setting. Preclinical and clinical research is also addressing several
potential strategies for maximizing the benefits of bevacizumab and other VEGF-targeted
agents, including (1) dual inhibition of VEGF and platelet-derived growth factor signaling to
target both the endothelial and the pericyte components of tumor vasculature; (2) combin-
ing VEGF-targeted agents with other targeted agents, such as inhibitors of HER2 or
epidermal growth factor receptor signaling, which affect several angiogenic pathways; and
(3) combining VEGF-targeted agents with low-dose, metronomic chemotherapy. The opti-
mal dose and schedule of VEGF-targeted agents is another unanswered question. Further
investigation of the mechanism of action and vascular effects of VEGF-targeted agents in
humans will help to address these questions. Mechanistic studies in humans will be aided
by the development and validation of surrogate clinical end points such as noninvasive
assessment of hemodynamics and vascular changes within tumors, using imaging studies.
Semin Oncol 33:S41–S49 © 2006 Elsevier Inc. All rights reserved.
I
n 2004, bevacizumab became the first vascular endothelial
growth factor (VEGF)–targeted agent to be approved by
the US Food and Drug Administration. This humanized
monoclonal antibody to VEGF is indicated for the first- or sec-
ond-line treatment of metastatic colorectal cancer (mCRC) in
combination with intravenous 5-fluorouracil (5-FU)–based
chemotherapy.
1
Since the approval of bevacizumab, two
other antiangiogenic agents, sorafenib and sunitinib, have
also been approved in different indications. Sorafenib, a mul-
tikinase inhibitor with activity against VEGF receptor 2
(VEGFR-2), similarly structured receptor tyrosine kinases,
and some signaling molecules, is indicated for the treatment
of metastatic renal cell cancer.
2
Sunitinib, a tyrosine kinase
inhibitor with activity against VEGFR-1 and VEGFR-2 and a
number of other receptor tyrosine kinases, is indicated for the
treatment of metastatic renal cell cancer and gastrointestinal
stromal tumors.
3
The availability of these agents culminates a
century of research that began with the observation in 1907
that malignant tumors induce the growth of abnormal blood
vessels.
4
The availability of bevacizumab, sorafenib, and sunitinib,
and the ongoing development of a number of other antian-
giogenic agents presents opportunities for improving and
optimizing the clinical results with VEGF-targeted antineo-
plastic therapy. This article reviews ongoing trials with bev-
acizumab, the development of other antiangiogenic agents,
and ongoing research that will help optimize VEGF-targeted
therapies.
Clinical Trials of
Antiangiogenic Therapies
Bevacizumab is in late-stage clinical development for the
treatment of mCRC in combination with oxaliplatin-based
regimens.
5,6
It is also being evaluated as monotherapy or in
combination with chemotherapy for the treatment of non–
small cell lung cancer,
7
metastatic breast cancer,
8
ovarian
cancer,
9,10
advanced pancreatic cancer,
11,12
non-Hodgkin’s
lymphoma,
13
liver cancer,
14
and metastatic renal cell can-
cer
15,16
(Table 1).
Division of Medical Oncology, Mayo Clinic College of Medicine,
Rochester, MN.
Dr Grothey has served as a consultant to Pfizer, Genentech, and AstraZeneca.
Address reprint requests to Axel Grothey, MD, Division of Medical Oncol-
ogy, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN
55905; e-mail: Grothey.axel@mayo.edu
S41
0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1053/j.seminoncol.2006.08.004