Cyclooxygenase-2 inhibition in colorectal cancer: boom or bust?

Currently, combination chemotherapy represents the standard of care treatment for patients with metastatic colorectal cancer in the United States. Despite recent improvements with the addition of biologic agents, novel treatment approaches are needed to further benefit patients. Cyclooxygenase (COX)-2 inhibition represents one such possibility. COX-2 is highly expressed in colorectal tumor neovasculature and nodal and liver metastases, and expression of COX-2 correlates with tumor stage and patient survival in selected series. COX-2 may be related to colorectal cancer development and propagation through multiple mechanisms, including stimulation of growth, migration, and invasiveness, resistance to apoptosis, and enhancement of angiogenesis. Epidemiologic data suggest nonsteroidal anti-inflammatory drugs (NSAIDs) might prevent development of colorectal cancers, and preclinical data suggest selective COX-2 inhibitors might be additive or synergistic with specific chemotherapeutic agents used in the treatment of colorectal cancer. Despite the lack of published phase I data and the limited, preliminary results of phase II studies, combinations of celecoxib and standard colorectal cancer chemotherapy have entered randomized trials. It is too early to definitively state whether COX-2 inhibition represents a major breakthrough in the treatment of colorectal cancer. Pending the results of ongoing and planned phase III studies, use of COX-2 inhibitors as single agents or incorporation of COX-2 inhibition into combined modality therapy of colorectal cancer should be limited to the setting of clinical trials.