The combination of
leucovorin [(6d,l)-5-formyl-
tetrahydrofolate] and
5-fluorouracil (5-FU) has increased efficacy compared to
5-FU alone as treatment of advanced
colorectal cancer.
Leucovorin is metabolized to methylene
tetrahydrofolate, which potentiates the antitumor actions of
5-FU by forming a ternary complex of
thymidylate synthase,
fluorodeoxyuridine and methylene
tetrahydrofolate. Only l-
leucovorin is metabolized to methylene
tetrahydrofolate and forms this ternary complex. However, d-
leucovorin may not be inert. d-
Leucovorin may impair cellular uptake and metabolism of l-
leucovorin, thereby inhibiting the actions of l-
leucovorin. Because of this possible limitation to the effectiveness of racemic
leucovorin, we have begun to explore the effects of the pure, biologically active isomer, l-
leucovorin. In this phase I trial, patients with advanced gastrointestinal
malignancies were treated with a 5-day continuous infusion of l-
leucovorin and daily intravenous boluses of
5-FU at 370 mg/m2. The dose of l-
leucovorin was escalated in groups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 per day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeated every 28 days. Seventeen patients with advanced
gastrointestinal cancers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for
leucovorin plus
5-FU. The most common severe toxicities (and the number of patents affected) were:
diarrhea (2),
mucositis (2),
nausea/
vomiting (1), and abdominal/rectal
pain (2). The maximum tolerated dose of l-
leucovorin was 700 mg/m2 per day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with
colorectal carcinomas. The combination of l-
leucovorin and
5-FU is well tolerated by patients and appears active for treatment of advanced
colorectal carcinomas. Additional clinical trials are necessary to determine if l-
leucovorin is more effective than d,l-
leucovorin for modulating the effectiveness of
5-FU.