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In Reply:

Haukeland University Hospital, Bergen, Norway

Bengt Glimelius

Uppsala University Hospital, Karolinska University Hospital, Stockholm, Sweden

We appreciate the comments of Yildirim et al concerning the Nordic FLOX schedule and their relevant question concerning the timing of folinic acid (FA) administration. Through the decades, fluorouracil (FU) has been administered alone, or biochemically modulated, particularly by methotrexate and FA, in a number of ways. Despite extensive research, the best schedule is not known. This uncertainty also relates to when and in what dose FA should be administered. It is true, as Yildirim et al state, that FA generally is administered before FU, and there is clinical experience and scientific rationale for that administration. However, there is strong preclinical and clinical rationale for the alternative methods used in the Nordic FU/leucovorin (FLv) combination.^1,2

Although FU has a short half-life of 10 to 20 minutes in plasma, the intratumoral peak concentrations of 5-fluorodeoxyuridine monophosphate (FdUMP) is achieved 30 to 60 minutes after an intravenous bolus injection of FU, whereas the peak concentration of the thymidylate synthetase cofactor CH₂ FH₄ is achieved 10 to 15 minutes after intravenous bolus injection of FA.³ To achieve simultaneous peak concentrations of FdUMP and the cofactor after intravenous bolus administration, FU should precede FA by about 40 minutes. When FU and FA were administered in different sequences in an experimental tumor model in rats, the best effect on reducing hepatic tumor growth was seen when FU was administered before FA.⁴

The Nordic FLv combination has, in a series of randomized phase III trials,^2,5 induced tumor regressions and yielded overall survival figures comparable to other FU schedules, including infused ones. It has also a favorable toxicity and safety profile. Because of its ease of administration, proved efficacy and minimal adverse effects, it has been used extensively in the Nordic countries. In an effort to keep the advantages of the Nordic FLv schedule, we designed the Nordic FLOX by adding oxaliplatin to the schedule. Nordic FLOX has given antitumour effects well in line with those of other more complicated schedules.⁶

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Carlsson G, Graf W, Gustavsson BG, et al: Sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic gastrointestinal cancer. Eur J Cancer 26:874-876, 1990

2. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Biochemical modulation of 5-fluorouracil: A randomized comparison of sequential methotrexate, 5-fluorouracil and leucovorin versus sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic colorectal cancer. Ann Oncol 4:235-241, 1993[Abstract/Free Full Text]

3. Spears CP, Gustavsson BG, Frosing R: Folinic acid modulation of fluorouracil: Tissue kinetics of bolus administration. Invest New Drugs 7:27-36, 1989[Medline]

4. Carlsson G, Hafstrom LO, Spears CP, et al: Sequential 5-fluorouracil and leucovorin: An experimental study in rats with hepatic metastasis of a rat colon carcinoma-clinical relevance for scheduling. Reg Cancer Treat 3:140-143, 1993

5. Jakobsen A, Berglund Å, Glimelius B, et al: Dose-effect relationship of bolus 5-fluorouracil in the treatment of advanced colorectal cancer. Acta Oncol 41:525-531, 2002[CrossRef][Medline]

6. Sørbye H, Glimelius B, Berglund Å, et al: Multicentre phase II study of Nordic 5-fluorouracil/Leucovorin bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 22:31-38, 2004[Abstract/Free Full Text]

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