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(Drug information on fluorouracil) (5-FU)/leucovorin or IFL (5-FU/leucovorin plus irinotecan(Drug information on 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 = .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. 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(Drug information on bevacizumab) (Avastin) and SU5416.
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(Drug information on doxorubicin), carboplatin(Drug information on 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.