Phase I trial of hepatic artery infusion of 5-iodo-2'-deoxyuridine and 5-fluorouracil in patients with advanced hepatic malignancy: biochemically based combination chemotherapy.
Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8-14 of therapy, patients received IdUrd as a separate 3-h HAI daily x 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day x 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2'deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (less than or equal to 0.1 microM). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day x 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day x 7.
Remick
S C
SC
University of Wisconsin Clinical Cancer Center, Madison.
Benson
A B
AB
Weese
J L
JL
Willson
J K
JK
Ramirez
G
G
Wirtanen
G W
GW
Alberti
D B
DB
Nieting
L M
LM
Tutsch
K D
KD
Fischer
P H
PH
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004285:Dogs; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006499:Hepatic Artery; D006801:Humans; D007065:Idoxuridine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D007261:Infusions, Intra-Arterial; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary*; D008297:Male; D008875:Middle Aged
D007065:Idoxuridine; D005472:Fluorouracil