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

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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

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Thymidylate Synthase
Leucovorin
Methotrexate
Fluorouracil
Colorectal Neoplasms
Neoplasm Metastasis
Proteins
Appointments and Schedules
Clinical Trials
Survival

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Annals of Oncology, Vol. 13, No. 12, 01.12.2002, p. 1882-1892.

Research output: Contribution to journalArticle

Aschele, C, Debernardis, D, Bandelloni, R, Cascinu, S, Catalano, V, Giordani, P, Barni, S, Turci, D, Drudi, G, Lonardi, S, Gallo, L, Maley, F & Monfardini, S 2002, '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', Annals of Oncology, vol. 13, no. 12, pp. 1882-1892. https://doi.org/10.1093/annonc/mdf327
Aschele, Carlo ; Debernardis, D. ; Bandelloni, R. ; Cascinu, S. ; Catalano, V. ; Giordani, P. ; Barni, S. ; Turci, D. ; Drudi, G. ; Lonardi, S. ; Gallo, L. ; Maley, F. ; Monfardini, S. / 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. In: Annals of Oncology. 2002 ; Vol. 13, No. 12. pp. 1882-1892.
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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.",
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T1 - 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

AU - Aschele, Carlo

AU - Debernardis, D.

AU - Bandelloni, R.

AU - Cascinu, S.

AU - Catalano, V.

AU - Giordani, P.

AU - Barni, S.

AU - Turci, D.

AU - Drudi, G.

AU - Lonardi, S.

AU - Gallo, L.

AU - Maley, F.

AU - Monfardini, S.

PY - 2002/12/1

Y1 - 2002/12/1

N2 - 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.

AB - 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.

KW - 5-Fluorouracil

KW - Biochemical modulators

KW - Colorectal cancer

KW - Response prediction

KW - Schedule of administration

KW - Thymidylate synthase

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