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Annals of Oncology 13:1882-1892, 2002
© 2002 European Society for Medical Oncology

Original Paper

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

C. Aschele1,+, D. Debernardis1, R. Bandelloni1, S. Cascinu2, V. Catalano3, P. Giordani3, S. Barni4, D. Turci5, G. Drudi6, S. Lonardi7, L. Gallo1, F. Maley8 and S. Monfardini7

1 Departments of Medical Oncology and Pathology, EO Ospedali Galliera, Genoa; 2 Azienda Ospedaliera di Parma, Parma; 3 Ospedale San Salvatore, Pesaro; 4 Azienda Ospedaliera Treviglio–Caravaggio, Treviglio; 5 Ospedale S Maria delle Croci, Ravenna; 6 Ospedale Infermi, Rimini; 7 Azienda Ospedaliera di Padova, Padua, Italy; 8 Wadsworth Center, New York State Department of Health, Albany, NY, USA

Received 14 January 2002; revised 30 April 2002; accepted 17 May 2002

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.

Key words: biochemical modulators, colorectal cancer, 5-fluorouracil, response prediction, schedule of administration, thymidylate synthase


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