Thymidylate synthase protein expression in colorectal cancer metastases predicts for clinical outcome to leucovorin-modulated bolus or infusional 5-fluorouracil but not methotrexate-modulated bolus 5-fluorouracil

Carlo Aschele, D. Debernardis, R. Bandelloni, S. Cascinu, V. Catalano, P. Giordani, S. Barni, D. Turci, G. Drudi, S. Lonardi, L. Gallo, F. Maley, S. Monfardini

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Different 5-fluorouracil (5-FU) schedules and/or biochemical modulators may result in different mechanisms of cytotoxicity, potentially affecting the correlation between thymidylate synthase (TS) expression and the clinical response to the fluoropyrimidine. Patients and methods: TS levels were measured immunohistochemically on archival specimens of colorectal cancer metastases from 124 patients homogeneously treated in a series of clinical trials at our institutions with: (A) leucovorin (LV)-modulated infusional 5-FU (n = 48); (B) LV-modulated bolus 5-FU (n = 41); (C) methotrexate (MTX)-modulated bolus 5-FU (n = 35). Results: A statistically significant correlation between TS levels and the clinical response was observed with the regimens involving continuous infusion and/or LV modulation (response rate in patients with low and high TS: 66% versus 24%, P = 0.003, and 50% versus 0%, P = 0.0001, in group A and B, respectively). Conversely, TS levels failed to predict the clinical response within the group of patients treated with MTX-modulated bolus 5-FU (response rate 21% versus 13%, P = 0.50, with low and high TS, respectively). Consistently, the median time to progression/overall survival time in patients with low and high TS were 9 versus 6 months/ 19 versus 14 months (P = 0.009/0-035, group A), 8 versus 2 months/12 versus 6 months (P = 0.002/0.0006, group B) and 3 versus 2 months/12 versus 13 months (P = 0. 14/0.74, group C). Conclusions: The correlation between intratumoral TS levels and the clinical response to 5-FU depends strongly on the schedule of administration/biochemical modulators that are used in different 5-FU regimens. These data strengthen the notion that different 5-FU schedules have different mechanisms of cytotoxicity.

Original languageEnglish
Pages (from-to)1882-1892
Number of pages11
JournalAnnals of Oncology
Volume13
Issue number12
DOIs
Publication statusPublished - Dec 1 2002

Keywords

  • 5-Fluorouracil
  • Biochemical modulators
  • Colorectal cancer
  • Response prediction
  • Schedule of administration
  • Thymidylate synthase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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