Dj. Kerr et al., PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF LEUCOVORIN AND INFUSIONAL HEPATIC ARTERIAL FLUOROURACIL, Journal of clinical oncology, 13(12), 1995, pp. 2968-2972
Purpose: A phase I and pharmacokinetic trial wets performed between Oc
tober 1993 and June 1994 to determine the maximum-tolerated dose of he
patic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (
IV) leucovorin (folinic acid; FA) in patients with hepatic metastases
from colorectal cancer. Patients and Methods: Forty-three patients rec
eived 310 courses of HAI chemotherapy administered over 48 hours every
2 weeks, The regimen consisted of FA 200 mg/m(2) by IV infusion over
2 hours, followed by a loading dose of 5-FU 400 mg/m(2) by HAI over 15
minutes, followed by a 22-hour infusion of 5-FU at doses ranging from
0.8 to 1.84 g/m(2), with identical chemotherapy on day 2. Pharmacokin
etic studies were performed to determine peak and steady-stare plasma
concentrations (C-ss) of 5-FU. Results: Severe diarrhea and cardiac an
d neurologic toxicity were dose-limiting at 1.84 g/m(2), The recommend
ed dose for the 22-hour component of the schedule was 1.6 g/m(2) and w
ets associated with tolerable toxicity. A C-ss of 2.2 +/- 0.8 mu mol/L
for 5-FU was achieved on the recommended schedule, which compares fav
orably with conventional IV 5-FU regimens, Among 30 patients assessabl
e for response, there were four complete responses and seven partial r
esponses, and 12 patients with stable disease and seven with progressi
ve disease, reported after 3 months (ie, six cycles) of therapy. Concl
usion: A regimen that combines 5-FU and FA has been identified for reg
ional chemotherapy in patients with hepatic metastases from colorectal
cancer, The systemic levels of 5-FU achieved are similar to the conve
ntional IV de Gramont regimen using an identical schedule of 5-FU and
FA, which implies that this chemotherapy py has the best of both world
s, ie, a regional advantage in delivering high drug concentrations to
the target organ with adequate systemic cover for extrahepatic microme
tastases. (C) 1995 by American Society of Clinical Oncology.