Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil.
OBJECTIVE
A phase I and pharmacokinetic trial was performed between October 1993 and June 1994 to determine the maximum-tolerated dose of hepatic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (IV) leucovorin (folinic acid; FA) in patients with hepatic metastases from colorectal cancer.


METHODS
Forty-three patients received 310 courses of HAI chemotherapy administered over 48 hours every 2 weeks. The regimen consisted of FA 200 mg/m2 by IV infusion over 2 hours, followed by a loading dose of 5-FU 400 mg/m2 by HAI over 15 minutes, followed by a 22-hour infusion of 5-FU at doses ranging from 0.8 to 1.84 g/m2, with identical chemotherapy on day 2. Pharmacokinetic studies were performed to determine peak and steady-state plasma concentrations (Css) of 5-FU.


RESULTS
Severe diarrhea and cardiac and neurologic toxicity were dose-limiting at 1.84 g/m2. The recommended dose for the 22-hour component of the schedule was 1.6 g/m2 and was associated with tolerable toxicity. A Css of 2.2 +/- 0.8 mumol/L for 5-FU was achieved on the recommended schedule, which compares favorably with conventional IV 5-FU regimens. Among 30 patients assessable for response, there were four complete responses and seven partial responses, and 12 patients with stable disease and seven with progressive disease, reported after 3 months (ie, six cycles) of therapy.


CONCLUSIONS
A regimen that combines 5-FU and FA has been identified for regional chemotherapy in patients with hepatic metastases from colorectal cancer. The systemic levels of 5-FU achieved are similar to the conventional IV de Gramont regimen using an identical schedule of 5-FU and FA, which implies that this chemotherapy has the best of both worlds, ie, a regional advantage in delivering high drug concentrations to the target organ with adequate systemic cover for extrahepatic micrometastases.
University of Birmingham Cancer Research Campaign Institute for Cancer Studies, Queen Elizabeth Hospital, United Kingdom.
D J
DJ
Kerr
J A
JA
Ledermann
C S
CS
McArdle
J
J
Buckels
J
J
Neoptolemos
M
M
Seymour
J
J
Doughty
J
J
Budden
I
I
Taylor
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000556:secondary*; D008297:Male; D008875:Middle Aged
D002955:Leucovorin; D005472:Fluorouracil