Capecitabine and radiation therapy for advanced gastrointestinal malignancies

Accumulating data indicate a beneficial effect of combining infusional fluorouracil (5-FU) with radiation therapy in gastrointestinal cancers, and phase II/III studies are under way to examine this approach in a variety of tumor types. The oral fluoropyrimidine capecitabine (Xeloda) provides a more convenient approach to radiosensitization. The agent has good single-agent activity in a variety of tumor types. The final step in activation of the drug to 5-FU occurs via activity of thymidine phosphorylase; thymidine phosphorylase activity is markedly upregulated in many tumor tissues compared with healthy tissue (Miwa M, Ura M, Nishida M, et al: Eur J Cancer 34:1274-1281, 1998), allowing greater accumulation of 5-FU in tumor tissue, and there is evidence indicating that radiation therapy results in augmented upregulation of this enzyme. A variety of data suggest benefits of 5-FU as a radiosensitizer in improving outcome of radiation therapy in a number of gastrointestinal cancers, including data indicating improved survival with this chemoradiation therapy approach. Prospective and randomized studies of 5-FU-based chemoradiation are under way in esophageal, gastric, biliary tract, pancreatic, rectal, and anal cancer. Early phase studies are planned to examine the combination of capecitabine, celecoxib (Celebrex), and radiation therapy in esophageal cancer and pancreatic cancer and to compare the effects of capecitabine and capecitabine/oxaliplatin (Eloxatin) with radiation therapy in rectal cancer. A phase III trial comparing capecitabine and infusional 5-FU in chemoradiation therapy in rectal cancer has also been planned. Additional studies should be conducted in gastric, biliary tract, and anal cancer. Capecitabine shows promise in replacing infusional 5-FU as the platform for gastrointestinal chemoradiation therapy.