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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 164 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.5607
Modulation of FU With High-Dose Folinic Acid Is Effective for Treatment of Patients With Gastric CarcinomaDepartment of Oncology and the Institut du Cancer et d’Immunogénétique (ICIG), Hospital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Villejuif; and University Paris XI, Paris, France To the Editor: The article by Lutz et al1 provides evidence that fluorouracil (FU) and high-dose folinic acid are effective for treatment of patients with advanced gastric adenocarcinoma. In this study, the antitumor activity of the combination was stronger than that of FU alone. We reported in 1982, and later in 1986, the first phase II study of FU and high-dose folinic acid for patients with advanced gastric carcinoma.2,3 In this early study, we had treated 27 patients of whom 13 (48%) responded to therapy. Median survival of responders was 11 months. However, for many years, the concept of modulation of the fluoropyrimidines by reduced folates was not further explored in this type of tumor. Hopefully, the study by Lutz et al will incite investigators to perform new studies with FU and folinic acid in gastric cancer as well as, perhaps, in all tumors where FU has shown some antitumor activity. However, the design of studies need attention because modulation of the fluoropyrimidines is a process requiring the simultaneous presence within the tumor cell of fluorodeoxyuridine monophosphate, and methylene tetrahydrofolate (CH2H4folate) in high concentrations for long periods of time, in order to stabilize the ternary complex formed with thymidylate synthase (TS), which results in sustained inhibition of the TS.4 One of the difficulties to achieve these conditions in vivo lies in the attainment of high intracellular levels of CH2H4folate. In humans, the active (6S)-stereoisomer of folinic acid is rapidly cleared from plasma with a mean half-life of only approximately 2 hours.3,5 Moreover, the intracellular concentration of CH2H4folate attained with intravenous folinic acid decreases rapidly after cessation of the infusion, as demonstrated in human tumor xenografts in mice.6 Furthermore, in most tumor models, the intracellular concentrations of CH2H4folate achieved after exposure to large amounts of folinic acid are small.7 In recent years, simplified schemas derived from older, widely used regimens of FU and folinic acid, given as single agents and in combination with other drugs, have been published.8 These new schemas of uncertain therapeutic equivalence are saddled to quickly become standard forms of therapy. In these treatments, folinic acid is given as a single short intravenous infusion before the start of a 2-day infusion of FU. However, from the pharmacologic data quoted above, it is likely that most of the time of the infusion of FU will not be accompanied by the high intracellular levels of CH2H4folate required for optimal inhibition of the TS. This may result in inadequate modulation of FU and perhaps lesser antitumor activity that might not be easy to detect in clinical studies in the short term. Phase II studies of FU and reduced folates are still lacking despite the long time passed since their initial description. At the present time, the best regimens may have not been found. Pharmacologic data should be considered as a priority for the design of treatments aiming at modulation of the fluoropyrimidines by any form of folate. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Lutz MP, Wilke H, Wagener DJT, et al: Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HD-FU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: Randomized phase II trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 25:2580-2585, 2007 2. Machover D, Schwarzenberg L, Goldschmidt E, et al: Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: A pilot study. Cancer Treat Rep 66:1803-1807, 1982[Medline] 3. Machover D, Goldschmidt E, Chollet P, et al: Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 4:685-696, 1986 4. Danenberg PV, Danenberg KD: Effect of 5,10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2'-deoxyuridylate from thymidylate synthetase: Evidence of an ordered mechanism. Biochemistry 17:4018-4024, 1978[CrossRef][Medline] 5. Machover D, Grison X, Goldschmidt E, et al: 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. J Natl Cancer Inst 84:321-327, 1992 6. Houghton JA, Williams LG, de Graaf SS, et al: Comparison of the conversion of 5-formyltetrahydrofolate and 5-methyltetrahydrofolate to 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon tumors. Cancer Commun 1:167-174, 1989[Medline] 7. Machover D, Zittoun J, Broët P, et al: Cytotoxic synergism of methioninase in combination with 5-fluorouracil and folinic acid. Biochem Pharmacol 61:867-876, 2001[CrossRef][Medline] 8. Tournigand C, Cervantes A, Figer A, et al: OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer: A GERCOR study. J Clin Oncol 24:394-400, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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