Cancer Chemotherapy and Pharmacology

, Volume 32, Issue 3, pp 215–220 | Cite as

Phase I trial of a 5-day infusion ofL-leucovorin plus daily bolus 5-fluorouracil in patients with advanced gastrointestinal malignancies

  • Frank H. Valone
  • David R. Gandara
  • Judith A. Luce
  • Susan Wall
  • Edith A. Perez
  • Natalie Braham
  • Martine George
  • Laurie Letvak
Original Articles L-Leucovorin, 5-Fluorouracil, Advanced Gastrointestinal Malignancies

Abstract

The combination of leucovorin [(6d,l)-5-formyltetrahydrofolate] 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. Onlyl-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 ofl-leucovorin, thereby inhibiting the actions ofl-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 ofl-leucovorin and daily intravenous boluses of 5-FU at 370 mg/m2. The dose ofl-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 patients affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/rectal pain (2). The maximum tolerated dose ofl-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 ofl-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 ifl-leucovorin is more effective thand,l-leucovorin for modulating the effectiveness of 5-FU.

Keywords

Colorectal Carcinoma Ternary Complex Leucovorin Advanced Colorectal Cancer Methylene Tetrahydrofolate 

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Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Frank H. Valone
    • 1
  • David R. Gandara
    • 2
  • Judith A. Luce
    • 3
  • Susan Wall
    • 4
  • Edith A. Perez
    • 2
  • Natalie Braham
    • 1
  • Martine George
  • Laurie Letvak
  1. 1.Department of MedicineVA Medical CenterSan FranciscoUSA
  2. 2.VA Medical CenterMartinezUSA
  3. 3.San Francisco General HorspitalSan FranciscoUSA
  4. 4.Department of RadiologyVA Medical CenterSan FranciscoUSA

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