In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA)
floxuridine (
FUDR) administered via an implantable pump for patients with
colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV
FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only
metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV
FUDR. The dose-limiting toxicity of IV
FUDR was
diarrhea, whereas biliary toxicity limited both the dose and duration of IA
FUDR therapy. Of the first 25 patients treated with IA
FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary
strictures, and three developed permanent
jaundice. With reduction of the initial IA
FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of
therapy for persistent elevations in
alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA
FUDR patients ultimately had
therapy terminated because of
drug toxicity rather than
disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of
FUDR against colorectal liver
metastases. Although biliary toxicity is the most serious limitation of this form of
therapy, biliary
stricture and
jaundice usually can be averted through careful monitoring of liver
enzymes and early dosage reduction.