Modulators of FUDR May Improve Outcomes in Patients Receiving Hepatic Artery Infusion

CHICAGO—Hepatic artery infusion of fluorodeoxyuridine (floxuridine or FUDR) theoretically should benefit colorectal cancer patients with metastases in the liver because it delivers chemotherapy directly into the tumors. This not only raises intratumoral drug levels but also prolongs the duration of exposure of the tumors to chemotherapy without increasing toxicity.

In prospective randomized trials in the 1980s, however, hepatic artery infusion not only failed to improve survival, it also frequently caused toxic complications such as biliary sclerosis.

Now, researchers may have found ways of improving survival and reducing the toxic complications of hepatic artery infusion by manipulating the dose and duration of FUDR or by using FUDR in combination with other drugs that modulate its actions, said Mark Talamonti, MD, assistant professor of surgery, Lurie Cancer Center, Northwestern University, at the annual scientific meeting of the American College of Surgeons.

He described four phase II trials using these new approaches. In one study at the University of California, San Francisco, in 1991, the dose and duration of FUDR were reduced. Rather than two 14-day courses of chemotherapy at doses of FUDR as high as 0.3 mg/kg/day, the investigators gave 0.1 mg/kg/day of FUDR for 7 days, followed by a bolus injection of fluorouracil on days 15, 22, and 29.

In two studies at Memorial Sloan Kettering Cancer Center, the actions of FUDR were modulated by adding other agents to the regimen. In one study, researchers mediated the inflammatory response to FUDR by administering dexamethasone; in the other, the cytotoxicity of the drug was enhanced by giving leucovorin as a potentiator.

“Preliminary results from these trials were so good, the researchers initiated another trial in which FUDR, dexametha-sone, and leucovorin were combined,” Dr. Talamonti said. The three-drug combination produced response rates of at least 78%, increased median survival up to 2 years, and caused only a 3% rate of biliary sclerosis.

These studies have led to a Cancer and Leukemia Group B (CALGB) trial that is comparing survival, response rates, patient tolerance, cost effectiveness, and toxicity of hepatic artery infusion and systemic chemotherapy.

In the CALGB trial, all patients in the experimental group receive FUDR, dex-amethasone, and leucovorin for 14 days, and the cycle is repeated every 28 days. These patients are compared with a control group treated with IV bolus fluorouracil. “Hopefully, we’ve got the right study, the right drugs, and we’ll get the right answer,” Dr. Talamonti said.