Fluorouracil Combined With the Pure (6S)-Stereoisomer of Folinic Acid in High Doses for Treatment of Patients With Advanced Colorectal Carcinoma: A Phase I–II Study

• Published in: JNCI : Journal of the National Cancer Institute 1992-03, Vol.84 (5), p.321-327
• Main Authors: Machover, David, Grison, Xavier, Goldschmidt, Emma, Zittoun, Jacqueline, Lotz, Jean-Pierre, Metzger, Gerard, Richaud, Jocelyne, Hannoun, Laurent, Marquet, Jeanine, Guillot, Thierry, Salmon, Rémy, Sezeur, Alain, Mauban, Serge, Parc, Rolland, Izrael, Victor
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Chemotherapy; Colorectal Neoplasms - drug therapy; Drug Administration Schedule; Drug Evaluation; Drug Synergism; Female; Fluorouracil - administration & dosage; Humans; Leucovorin - administration & dosage; Leucovorin - pharmacokinetics; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Stereoisomerism; Survival Analysis; Treatment Outcome
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/84.5.321

Background: Potentiation of the antitumor activity of fluorouracil (5-FU) by folinic acid has been demonstrated in patients with colorectal adenocarcinoma. Modulation is due to the interaction of thymidylate synthase, fluorodeoxyuridine monophosphate, and methylene tetrahydrofolate, which leads to the formation of a stable ternary complex with concomitant enzyme inactivation. Folinic acid consists of a mixture of equal parts of two stereoisomers differing in chirality at the C-6 carbon of the pteridine ring. Only the levorotatory (6S)-stereoisomer of folinic acid is transformed into active folate cofactors. However, the (6R)-stereoisomer of folinic acid is not inert; it was shown to interfere with the (6S) form at the cellular level. Purpose: The possibility of a deleterious effect of the unnatural stereoisomer on the modulation of 5-FU led us to carry out a phase I–II study of 5-FU combined with the (6S)-stereoisomer of folinic acid given in high doses for treatment of patients with advanced colorectal carcinoma. We also determined the plasma pharmacokinetics of folates after intravenous (IV) injection of (6S)-folinic acid at the dose used in this study. Methods: Treatment consisted of 5-FU (350–550 mg/m2 per day by IV infusion for 2 hours) and(6S)-folinic acid (100 mg/m2 per day by IV bolus injection) given for 5 consecutive days; the treatment was repeated every 21 days. Twenty-five patients with advanced colorectal carcinoma, who had had no prior chemotherapy, were evaluated for antitumor activity. The quantity of folates in plasma was measured using a microbiological assay. Results: The median follow-up time was 9 months (range, 3.5–15.2 months). The response rate was 52% (complete response, 12%; partial response, 40%). The median time to disease progression for responding patients was 9.2 months (range, 5.9–15+ months). The estimated probability of survival at 12 months was 73 percnt. Palliative improvement in quality of life was achieved in most patients who had symptoms due to the tumor before the start of treatment. The dose-limiting toxic effects were grade 3 diarrhea, dermatitis, and oral mucositis. Grade 4 toxicity did not occur. Myeloid toxicity was minor. After IV injection, (6S)-folinic acid was rapidly cleared from plasma (mean half-lives: α = 7.2 minutes and β = 126 minutes). The mean concentration of the unchanged compound 2 hours after injection was 5.8 μmol/L. Conclusion: The (6S)-form of folinic acid potentiates the antitumor effect of