Cell cycle-specific with activity in the S-phase.
Requires transport into the cell via a nucleoside transport protein.
Requires activation to cytotoxic metabolite forms. Metabolized to 5-FU metabolite FdUMP, which inhibits thymidylate synthase (TS). This results in inhibition of DNA synthesis, function, and repair.
Incorporation of 5-FU metabolite FUTP into RNA, resulting in alterations in RNA processing and/or mRNA translation.
Incorporation of 5-FU metabolite FdUTP into DNA, resulting in inhibition of DNA synthesis and function.
Inhibition of TS leads to accumulation of dUMP, which becomes misincorporated into DNA in the form of dUTP, resulting in inhibition of DNA synthesis and function.
Increased expression of thymidylate synthase.
Decreased levels of reduced folate substrate 5, 10-methylenetetrahydrofolate.
Decreased incorporation of 5-FU into RNA.
Decreased incorporation of 5-FU into DNA.
Increased activity of DNA repair enzymes, uracil glycosylase and dUTPase.
Increased salvage of physiologic nucleosides, including thymidine.
Increased expression of dihydropyrimidine dehydrogenase.
Decreased expression of mismatch repair enzymes (hMLH1, hMSH2).
Alterations in TS, with decreased binding affinity of enzyme for FdUMP.
After IV administration, floxuridine is rapidly extracted by the liver via first-pass metabolism. After hepatic IA administration, greater than 90% of drug is extracted by hepatocytes. Binding to plasma proteins has not been well characterized.
Metastatic colorectal cancer—Intrahepatic arterial treatment of colorectal cancer metastatic to the liver.
Metastatic GI adenocarcinoma—Patients with metastatic disease confined to the liver.
Leucovorin—Leucovorin enhances the toxicity and antitumor activity of floxuridine. Stabilizes the TS-FdUMP-reduced folate ternary complex, resulting in maximal inhibition of TS.
Thymidine—Rescues against the toxic effects of floxuridine.
Vistonuridine (PN401)—Rescues against the toxic effects of floxuridine.
Contraindicated in patients with poor nutritional status, depressed bone marrow function, or potentially serious infection.
No dose adjustments are necessary in patients with mild and moderate liver dysfunction or abnormal renal function. However, patients should be closely monitored, as they may be at increased risk of toxicity.
Patients should be placed on an H2-blocker, such as ranitidine 150 mg PO bid, to prevent the onset of peptic ulcer disease while on therapy. Onset of ulcer-like pain is an indication to stop therapy, as hemorrhage and/or perforation may occur.
Patients who experience unexpected, severe grades 3 or 4 toxicities with initiation of therapy may have an underlying deficiency in dihydropyrimidine dehydrogenase (DPD). Therapy must be discontinued immediately. Further testing to identify the presence of this pharmacogenetic syndrome should be considered.
Pregnancy category D. Breastfeeding should be avoided.
Hepatotoxicity is dose-limiting. Presents as abdominal pain and elevated alkaline phosphatase, liver transaminases, and bilirubin. Sclerosing cholangitis is a rare event. Other GI toxicities include duodenitis, duodenal ulcer, and gastritis.
Nausea and vomiting are mild. Mucositis and diarrhea also observed.
Hand-foot syndrome (palmar-plantar erythrodysesthesia). Characterized by tingling, numbness, pain, erythema, dryness, rash, swelling, increased pigmentation, and/or pruritus of the hands and feet.
Myelosuppression. Nadir occurs at 7-10 days, with full recovery by 14-17 days.
Neurologic toxicity manifested by somnolence, confusion, seizures, cerebellar ataxia, and rarely encephalopathy.
Cardiac symptoms of chest pain, ECG changes, and serum enzyme elevation. Rare event but increased risk in patients with prior history of ischemic heart disease.
Blepharitis, tear-duct stenosis, acute and chronic conjunctivitis.
Catheter-related complications include leakage, catheter occlusion, perforation, dislodgement, infection, bleeding at catheter site, and thrombosis and/or embolism of hepatic artery.
