title: Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of concurrent systemic irinotecan and hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone in patients with unresectable hepatic metastases from colorectal cancer, to determine the safety of this combination in patients who have undergone cryosurgery, and to evaluate the pharmacokinetic effects of HAI FUDR on the metabolism of irinotecan.
  
  
  METHODS
  Forty-six previously treated patients with unresectable liver metastases and no known extrahepatic disease were treated concurrently with intravenous irinotecan weekly for 3 weeks and with HAI of FUDR and dexamethasone for 14 days (both were recycled in 28 days). Parallel cohorts of patients treated with or without cryosurgery were entered at escalating dose levels.
  
  
  RESULTS
  The MTD for patients who did not undergo cryosurgery was 100 mg/m2 of irinotecan weekly for 3 weeks every 4 weeks with concurrent HAI FUDR (0.16 mg/kg/d x pump volume/flow rate) plus dexamethasone for 14 days of a 28-day cycle. The dose-limiting toxicities were diarrhea and neutropenia. The response rate (complete and partial) among all patients who did not undergo cryosurgery was 74%. All patients in the cryosurgery group responded, and seven of the eight cryosurgery patients developed normal positron emission tomography scans after chemotherapy. HAI FUDR had no effect on the metabolism of irinotecan.
  
  
  CONCLUSIONS
  Combination therapy with HAI FUDR and dexamethasone plus systemic irinotecan may be safely administered to patients with unresectable hepatic metastases from colorectal cancer. The MTD has been reached for patients with unresectable disease, and we continue to investigate the MTD for patients who have undergone cryosurgery. Although the main objective of this study was to evaluate the toxicity of the combined regimen, a high response rate (74%) was observed.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: N
authors.initials: N
authors.lastname: Kemeny
authors.forename: M
authors.initials: M
authors.lastname: Gonen
authors.forename: D
authors.initials: D
authors.lastname: Sullivan
authors.forename: L
authors.initials: L
authors.lastname: Schwartz
authors.forename: F
authors.initials: F
authors.lastname: Benedetti
authors.forename: L
authors.initials: L
authors.lastname: Saltz
authors.forename: J
authors.initials: J
authors.lastname: Stockman
authors.forename: Y
authors.initials: Y
authors.lastname: Fong
authors.forename: W
authors.initials: W
authors.lastname: Jarnagin
authors.forename: J
authors.initials: J
authors.lastname: Bertino
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.forename: P
authors.initials: P
authors.lastname: Paty
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002277:Carcinoma / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology*; D003452:Cryosurgery; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed
chemical_list: D005467:Floxuridine; D000077146:Irinotecan; D003907:Dexamethasone; D002166:Camptothecin