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. 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. 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 =
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. 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.
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.
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. 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
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. 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. 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.
1. Greenleee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA
Cancer J Clin 51:15-36, 2001.
2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and
leucovorin for metastatic colorectal cancer. N Engl J Med 343:905-914, 2000.
3. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with
fluorouracil compared with fluorouracil alone as first-line treatment for
metastatic colorectal cancer: A multicentre randomised trial. Lancet
4. Lee JC, Chow NH, Wang ST, et al: Prognostic value of vascular endothelial
growth factor expression in colorectal cancer patients. Eur J Cancer 36:748-753,
5. Chin K-F, Greenman J, Gardiner E, et al: Pre-operative serum vascular
endothelial growth factor can select patients for adjuvant treatment after
curative resection in colorectal cancer. Br J Cancer 83:1425-1431, 2000.
6. Kumar H, Heer K, Lee PWR, et al: Preoperative serum vascular endothelial
growth factor can predict stage in colorectal cancer. Clin Cancer Res
7. Cascinu S, Graziano F, Catalano V, et al: Vascular endothelial growth
factor (VEGF), p53 and BAX expression in node-positive rectal cancer.
Relationships with tumor recurrence after adjuvant chemoradiation (abstract
595). Proc Am Soc Clin Oncol 20:150a, 2001.
8. Carmichael J, White JD, Kosuge DD, et al: Increased expression of vascular
endothelial growth factor-D (VEGF-D) is associated with poor survival in
colorectal cancer (CRC) (abstract 979). Proc Am Soc Clin Oncol 19:252a, 2000.
9. Millauer B, Longhi MP, Plate KH, et al: Dominant-negative inhibition of
Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res
10. Kim KJ, Li B, Winer J, et al: Inhibition of vascular endothelial growth
factor-induced angiogenesis suppresses tumour growth in vivo. Nature
11. Asano M, Yukita A, Matsumoto T, et al: Inhibition of tumor growth and
metastasis by an immunoneutralizing monoclonal antibody to human vascular
endothelial growth factor/vascular permeability factor 121. Cancer Res
12. Gordon MS, Margolin K, Talpaz M, et al: Phase I safety and
pharmacokinetic study of recombinant human anti-vascular endothelial growth
factor in patients with advanced cancer. J Clin Oncol 19:843-850, 2001.
13. Margolin K, Gordon MS, Holmgren E, et al: Phase Ib trial of intravenous
recombinant humanized monoclonal antibody to vascular endothelial growth factor
in combination with chemotherapy in patients with advanced cancer: Pharmacologic
and long-term safety data. J Clin Oncol 19:851-856, 2001.
14. Bergsland E, Hurwitz H, Fehrenbacher L, et al: A randomized phase II
trial comparing RhuMAb VEGF (recombinant humanized monoclonal antibody to
vascular endothelial growth factor) plus 5-fluorouracil/leucovorin (FU/LV) to
FU/LV alone in patients with metastatic colorectal cancer (abstract 939). Proc
Am Soc Clin Oncol 19:242a, 2000.
15. Fong TA, Shawver LK, Sun L, et al: SU5416 is a potent and selective
inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that
inhibits tyrosine kinase catalysis, tumor vascularization, and growth of
multiple tumor types. Cancer Res 59:99-106, 1999.
16. Shaheen RM, Davis DW, Liu W, et al: Antiangiogenic therapy targeting the
tyrosine kinase receptor for vascular endothelial growth factor receptor
inhibits the growth of colon cancer liver metastasis and induces tumor and
endothelial cell apoptosis. Cancer Res 59:5412-5416, 1999.
17. Rosen L, Mulay M, Mayers A, et al: Phase I dose-escalating trial of
SU5416, a novel angiogenesis inhibitor in patients with advanced malignancies
(abstract 618). Proc Am Soc Clin Oncol 18:199a, 1999.
18. Cropp G, Rosen L, Mulay M, et al: Pharmacokinetics and pharmacodynamics
of SU5416 in a phase I, dose escalating trial in patients with advanced
malignancies (abstract 619). Proc Am Soc Clin Oncol 18:199a, 1999.
19. O’Donnell AE, Trigo JM, Banerji U, et al: A phase I trial of the VEGF
inhibitor SU5416, incorporating dynamic contrast MRI assessment of vascular
permeability (abstract 685). Proc Am Soc Clin Oncol 19:177a, 2000.
20. Eng C, Kindler HL, Stadler WM, et al: SU5416 in advanced colorectal
cancer (CRC): A University of Chicago phase II consortium study (abstract 2215).
Proc Am Soc Clin Oncol 20:116b, 2001.
21. Rosen PJ, Amado R, Hecht JR, et al: A phase I/II study of SU5416 in
combination with 5-FU/leucovorin in patients with metastatic colorectal cancer
(abstract 5D). Proc Am Soc Clin Oncol 19:3a, 2000.
22. Rothenberg ML, Berlin JD, Cropp GF, et al: Phase I/II study of SU5416 in
combination with irinotecan/5-FU/LV (IFL) in patients with metastatic colorectal
cancer (abstract 298). Proc Am Soc Clin Oncol 20:75a, 2001.