Oral Agents Studied for Colorectal Cancer Could Improve Efficacy of 5-FU

BIRMINGHAM, Ala—New oral agents being tested in clinical trials for the treatment of colorectal cancer show promise of improving the efficacy of 5-fluorouracil (5-FU) in combination regimens. A review of several agents under study—capecitabine (Xeloda), UFT (a combination of uracil plus ftorafur [Tegafur]), and S-1—was presented by Robert B. Diasio, MD, at a clinical investigators’ workshop.

Dr. Diasio is a member of the Department of Medicine and Pharmacology/Toxicology at the University of Alabama Comprehensive Cancer Center in Birmingham, Alabama. The workshop was sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology.

Capecitabine has been approved for chemotherapy-resistant breast cancer and is awaiting approval for use in colorectal cancer. It is an oral prodrug that is converted to 5-fluorouracil by thymidine phosphorylase, which is present in higher concentrations in tumors than in normal tissue. Toxicity is less severe than the Mayo Clinic intravenous 5-FU/leucovorin regimen, but hand-foot syndrome occurs in about 42% of patients.

How DPD Inhibitors Act

Dihydropyrimidine dehydrogenase (DPD) inhibitors decrease the variability of 5-FU bioavailability and have the effect of increasing exposure to 5-FU. The DPD inhibitors UFT, eniluracil, and S-1 are all in clinical trials. Dr. Diasio warned that preliminary data suggest that using another fluoropyrimidine within 8 weeks of eniluracil (and possibly other DPD inhibitors) can increase the risk of late 5-FU toxicity.

“Some of these new agents, including capecitabine and UFT, have shown antitumor activity at least equal to 5-FU,” Dr. Diasio said. “They also offer quality of life and economic benefits, as well as less toxicity. There may also be selective biochemical effects such as selective activation within tumors for capecitabine and the ability to overcome 5-FU resistance caused by increased tumor DPD with eniluracil,” he added.