Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: A randomized study

A. Sobrero, A. Zaniboni, G. L. Frassineti, C. Aschele, A. Guglielmi, R. Giuliani, A. Ravaioli, C. Lanfranco, C. Caroti, E. Arnoldi, S. Barni, L. Gallo, M. A. Pessi, D. Turci, E. Cortesi, F. Grossi, L. Frontini, E. Piazza, P. Bruzzi, R. Labianca

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Background: We have recently suggested that bolus 5-fluorouracil (5-FU) may work via a RNA directed mechanism while continuous infusion 5-FU may kill cells via a thymidylate synthase related pathway. It may thus be possible to selectively modulate each schedule biochemically. We have compared an alternating regimen of bolus and continuous infusion 5-FU, selectively modulated for the schedule of administration, with modulated bolus 5-FU in advanced colorectal cancer patients. Patients and methods: Two hundred fourteen patients from nineteen Italian centers were randomized to the control arm consisting of biweekly cycles of MTX, 200 mg/m2 on day 1, followed by bolus 5-FU 600 mg/m2 on day 2 and 6-S-leucovorin rescue, or to the experimental arm consisting of two biweekly cycles of the same regimen as in the control arm alternated to three weeks of continuous infusion 5-FU (200 mg/m2 day) + weekly bolus 6-S-leucovorin, 20 mg/m2. Results: Nine CR and twenty-seven PR were obtained on one hundred eleven evaluable patients treated in experimental arm (RR = 32%, 95% confidence interval (95% CI): 24%-42%), while two CR and eleven PR were observed among one hunderd three evaluable patients in control arm (RR = 13%, 95% CI: 7%-21%). WHO grade 3-4 toxicity occurred in 13% of cycles of experimental arm and in 8% of cycles in control arm. The PFS was significantly longer in experimental arm (6.2 vs. 4.3 months, odds ratio 0.66, P = 0.003), while the overall survival was similar in both arms (14.8 months in experimental arm vs. 14.1 months in control arm); quality of life was similar as well. Eighty percent of patients receiving second-line chemotherapy in control arm were treated with continuous infusion 5-FU. Conclusions: Alternating, schedule-specific biochemical modulation of FU is more active than MTX → 5-FU as first-line treatment of advanced colorectal cancer. However, the overall survival was similar suggesting that alternating bolus and infusional 5-FU upfront may be as effective as giving them in sequence as first- and second-line treatment.

Original languageEnglish
Pages (from-to)1413-1420
Number of pages8
JournalAnnals of Oncology
Issue number11
Publication statusPublished - 2000


  • 5-fluorouracil
  • Advanced colorectal cancer
  • Biochemical modulation
  • Schedule of administration

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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