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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3862 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.341
Controversy in Folinic Acid Administration After FluorouracilBaskent University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey To the Editor: We read with interest the paper by Sorbye et al1 on Nordic fluorouracil (FU) and folinic acid (FA) bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer, recently published in the Journal of Clinical Oncology. This schedule in general seems to be beneficial and easy to apply in outpatient clinics. FU and FA are administered in a few minutes, so hospitalization is not needed. Decrease in hospitalization rate results in decrease in cost of chemotherapy. We are planning to use this schedule in metastatic colorectal patients. However there is a controversy in FA administration. In this schedule FA was administered 30 minutes after FU bolus. In contrast to this, in Mayo regimen or in FOLFOX 4 (biweekly oxaliplatin in combination with infusional FU + FA), FA was used before the FU infusion.2,3 It is well known that FU is a false primidine base. Intracellulary FU is converted to fluoruridinemonophosphate (FdUMP), fluorotriphosphate (FUTP) and fluorodeoxiuridinetriphospate (FdUTP).4 FU cytotoxicity is related to inhibition of thymidilate synthase (TS) with FdUTP, incorporation of FUTP into cellular RNA and incorporation of FdUTP into cellular DNA. Since FA can increase intracellular levels of reduced folates, modulation of FU dose is achieved by FA. Reduced folates, FdUMP and TS form a ternary complex. Increased stability of this complex results in prolong inhibition of TS and enhanced cytotoxicity. FA can be used to rescue organisms from adverse effects of chemotherapy; however, the objective of FA usage in this schedule is to enhance cytotoxicity. Besides this, FU has a short half-life of about 10 to 20 minutes. Therefore, presence of FA in the cell before FU administration seems to be feasible to enhance the cytotoxicity of FU. This schedule is practical and economic. We are planning to use FA before FU administration in contrast to Nordic FLOX (oxaliplatin combined with the bolus Nordic schedule of FU + FA) schedule because the rationality of FA administration after FU bolus remains unclear. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Sorbye H, Glimelius B, Berglund A, et al: Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 22:31-38, 2004 2. Buroker TR, O’Connell MJ, Wieand HS, et al: Randomized comparison of two schedule fluorouracil and leucoverin in the treatment of colorectal cancer. J Clin Oncol 12:14-20, 1994[Abstract]
3. De Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 4. Gutheil C, Finucane DM: Antimetabolites, in Perry MC (ed): The Chemotherapy Source Book. Philadelphia, PA, Lippincot, Williams & Wilkins 2001, pp 27-29
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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