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Targeting Vascular Endothelial Growth Factor in Colorectal Cancer

Targeting Vascular Endothelial Growth Factor in Colorectal Cancer

ABSTRACT: Recent trials have established the IFL combination (fluorouracil [5-FU], leucovorin, and irinotecan [CPT-11, Camptosar]) as a new standard first-line therapy for patients with metastatic colorectal cancer. Median survival for such patients treated with IFL still ranges from approximately 14 to 18 months, however, underscoring the need for new agents with novel mechanisms of action. Angiogenesis has become an attractive target for anticancer drug development, based on its important roles in tumor growth, invasion, and metastasis. A potent stimulus of angiogenesis is vascular endothelial growth factor (VEGF); two agents developed to inhibit VEGF activity, bevacizumab (Avastin) and SU5416, are in advanced clinical trials. Based on encouraging results in phase I and II trials with bevacizumab, a randomized trial of IFL with or without this monoclonal antibody is under way. Similarly, a randomized trial of 5-FU and leucovorin with or without the tyrosine kinase inhibitor SU5416 has recently completed accrual and results are pending. SU5416 is also being tested in a phase I/II trial combined with IFL. This article briefly reviews preclinical and clinical data leading to the current trials of these two agents in patients with colorectal cancer. [ONCOLOGY 16(Suppl 7):13-15, 2002]

Colorectal cancer is the
second leading cause of cancer death in the United States, with approximately
45,000 deaths and 130,000 newly diagnosed patients per year.[1] Recently, two
trials randomized patients to fluorouracil (5-FU)/leucovorin or IFL
(5-FU/leucovorin plus irinotecan [CPT-11, Camptosar]) as first-line therapy for
metastatic colorectal cancer. The primary end point of both trials was time to
tumor progression. One of the trials, conducted in the United States, used IFL
at a weekly × 4 schedule for each 6-week treatment cycle, and also had an
irinotecan-alone arm.[2] This trial resulted in a higher response rate and
longer time to tumor progression for IFL compared with 5-FU/leucovorin, and also
a statistically significant survival benefit (14.8 vs 12.6 months, P =
.04).

The other trial, conducted in Europe, allowed sites to choose one of two
infusion schedules (once weekly or every 2 weeks) for the 5-FU/leucovorin
regimen.[3] Patients were then randomly assigned to the 5-FU/leucovorin regimen
alone or in conjunction with irinotecan. Results of this trial also showed a
higher response rate and longer time to tumor progression for IFL compared with
5-FU/leucovorin. A survival benefit was demonstrated for IFL compared with
5-FU/leucovorin as first-line therapy (17.4 vs 14.1 months, respectively; P
= .031). However, median survival (14.8 to 17.4 months) obtained with IFL is
still limited. New active agents, ideally ones that target intracellular
mechanisms or pathways, are still needed.

VEGF and Angiogenesis

The process of angiogenesis, or new blood vessel formation, has emerged as a
novel target for development of anticancer agents. Preclinical data demonstrate
that new blood vessel formation is required for tumors to grow beyond 1 to 2
mm³. Laboratory analyses also demonstrate that, in addition to being critical
for tumor growth, angiogenesis is important for invasion and metastasis.
Angiogenesis is a complex, multistep process involving breakdown of the
extracellular matrix, invasion of tumor cells, signaling to stimulate
endothelial cell growth, and blood vessel formation. One of the most potent
stimulants of angiogenesis is vascular endothelial growth factor (VEGF).

VEGF was reported to be overexpressed in 48% to 53% of colorectal cancers.[4]
The same study suggested that VEGF expression correlated with progression of
disease and appeared to be an independent prognostic factor in colorectal
cancer. Another study suggested that high preoperative serum VEGF levels were
associated with increased likelihood of recurrence in patients with resected
colorectal malignancies.[5] Other study results have also shown correlation of
VEGF overexpression with advanced disease stage, likelihood of developing
metastases after surgery, and overall prognosis.[6-8]

The cellular receptors for VEGF are tyrosine kinases (eg, KDR or flk-1 and
FLT-1) that initiate the angiogenesis process through phosphorylation cascades.
When VEGF binds to its endothelial cell receptor, the intracellular tyrosine
kinase portion is activated, resulting in a phosphorylation cascade that
stimulates endothelial cell proliferation and new blood vessel growth.
Inhibiting VEGF effects appears to reduce angiogenesis (reduced vessel density)
in vitro, and limits tumor growth in vivo.[9-11] Two agents developed to inhibit
VEGF action have entered clinical trials, namely, bevacizumab (Avastin) and
SU5416.

Bevacizumab

Murine monoclonal antibodies have been developed to inhibit VEGF in a variety
of tumor models. However, murine antibodies can readily induce human antimurine
antibody (HAMA) responses. Bevacizumab, a recombinant humanized monoclonal
antibody to VEGF, was designed with a human IgG1 framework and a murine VEGF-binding
portion. In the first phase I trial of single-agent bevacizumab, 25 patients
were treated on five dose levels ranging from 0.1 to 10 mg/kg.[12] While no
grade 3 or 4 toxicities were clearly related to therapy, there were two episodes
of serious bleeding from tumor that were not clearly related to therapy. No
partial or complete responses occurred, but one patient had a minor response and
12 experienced stable disease during the 70-day study period. No patient
developed antibodies to bevacizumab.

Subsequently, in a phase Ib trial, 12 patients were assigned to one of three
treatment arms (four patients per arm). Treatments included bevacizumab combined
with either doxorubicin, carboplatin (Paraplatin)/paclitaxel, or
5-FU/leucovorin.[13] Results showed that bevacizumab could be safely combined
with three chemotherapy regimens. One patient with colorectal cancer responded
to 5-FU/leucovorin plus bevacizumab treatment.

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