Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity

We hypothesized that hand-foot syndrome is an inflammatory phenomenon mediated by the overexpression of cyclooxygenase 2 (COX-2). Therefore, a specific COX-2 inhibitor such as celecoxib (Celebrex) could attenuate both the incidence and severity of hand-foot syndrome. We undertook a retrospective study comparing the incidences of hand-foot syndrome in 67 patients with metastatic colorectal cancer who took capecitabine (Xeloda) with or without celecoxib. Surprisingly, celecoxib seemed to attenuate capecitabine-induced diarrhea as well. Capecitabine/celecoxib was also associated with increased tumor response, proportion of stable disease (62.5% vs 22.8%, P = .001), and increase in median time to tumor progression (6 vs 3 months, P = .002) compared with capecitabine alone, despite the fact that patients on capecitabine/celecoxib had less favorable disease characteristics (age, performance status, and prior chemotherapies). Overexpression of COX-2, implicated in promoting angiogenesis, enhanced tumor invasiveness, evasion of apoptosis, and immune suppression, is a bona fide molecular target for many solid tumors, including colorectal cancer. Combining capecitabine with celecoxib in the treatment of colorectal cancer has strong preclinical rationales. A prospective study is being designed to evaluate capecitabine and celecoxib with or without epidermal growth factor receptor antagonist ZD1839 in the frontline treatment of metastatic colorectal cancer. These regimens under study are orally based and may significantly impact quality of life in the frontline treatment of metastatic colorectal cancer.