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JNCI Journal of the National Cancer Institute 1992 84(5):321-327; doi:10.1093/jnci/84.5.321
© 1992 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 84, No. 5, 321-327, March 4, 1992
© 1992 Oxford University Press

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

David Machover*,, Xavier Grison, Emma Goldschmidt, Jacqueline Zittoun, Jean-Pierre Lotz, Gerard Metzger, Jocelyne Richaud, Laurent Hannoun, Jeanine Marquet, Thierry Guillot, Rémy Salmon, Alain Sezeur, Serge Mauban, Rolland Parc, Victor Izrael

Department of Oncology, J. Richaud (Service of Radiology), Hospital Tenon Paris, France.
Service of Radiology, Hospital Tenon Paris, France
Service of Hematology and Immunology, Hospital Henri Mondor Créteil France
Service of Surgery, Hospital Saint Antoine Paris
Lederle Laboratories Rungis France
Service of Surgery, Institut Curie Paris
Service of Surgery, Hospital Rothschild Paris
Service of Hematology and Oncology, Hospital Paul Brousse Villejuif, France

* Correspondence to David Machover, M. D., Service d'Oncologie médicale Hopital Tenon, 4, rue de la Chine, 75020 Paris, France.

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: {alpha} = 7.2 minutes and beta = 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 5-FU given concomitantly. Implication: Our results justify a more complete exploration of the pure active stereoisomer as a modulator of the fluoropyrimidines. [J Natl Cancer Inst 84: 321–327, 1992]


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