Emerging therapies for metastatic colorectal cancer: focus on EGFR and VEGF inhibition.

Despite recent advances in chemotherapy, including the development of irinotecan and oxaliplatin, survival of patients with advanced colorectal cancer remains suboptimal. Thanks to an increased understanding of the biologic basis of cancer, investigators are turning to molecularly targeted therapy to further improve outcome. Current research in colorectal cancer focuses on inhibiting the epidermal growth factor receptor and vascular endothelial growth factor. Both are essential to tumor growth and frequently over-expressed in colorectal cancer cells. Epidermal growth factor receptor pathways promote survival of tumor cells through cell proliferation, differentiation, migration, adhesion, and transformation and inhibition of apoptosis, whereas the vascular endothelial growth factor is a key mediator of angiogenesis and may have other biologic roles. Recent phase II and III results show the feasibility and activity of inhibiting both by using monoclonal antibodies in combination with chemotherapy in patients with advanced colorectal cancer. Cetuximab (an epidermal growth factor receptor antibody) plus irinotecan yields an increased overall response in patients with irinotecan-refractory colorectal disease. In previously untreated patients, irinotecan/5-fluoruoracil/leucovorin plus cetuximab also generates an increased overall response rate. Randomized trials of the humanized anti-vascular endothelial growth factor antibody (rhuMAb vascular endothelial growth factor) plus chemotherapy yielded increased overall response rates and median survival times compared with chemotherapy alone. The primary toxicity of cetuximab is an acneform skin rash; rhuMAb vascular endothelial growth factor causes mild hypertension and may cause perturbations in coagulation. Treatment with either does not appear to exacerbate chemotherapy-related toxicity.