Phase 2 study of treatment selection based on tumor thymidylate synthase expression in previously untreated patients with metastatic colorectal cancer: A trial of the ECOG-ACRIN Cancer Research Group (E4203)

Neal J. Meropol, Yang Feng, Jean L. Grem, Mary F. Mulcahy, Paul J. Catalano, John S. Kauh, Michael J. Hall, Joel N. Saltzman, Thomas J. George, Jeffrey Zangmeister, Elena G. Chiorean, Puneet S. Cheema, Peter J. O'Dwyer, Al B. Benson

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Abstract

BACKGROUND: The authors hypothesized that patients with metastatic colorectal cancer (mCRC) who had tumors with low thymidylate synthase (TS-L) expression would have a higher response rate to combined 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (FOLFOX/Bev) than those with high TS (TS-H) expression and that combined irinotecan and oxaliplatin (IROX) plus bevacizumab (IROX/Bev) would be more effective than FOLFOX/Bev in those with TS-H tumors. METHODS: TS protein expression was determined in mCRC tissue. Patients who had TS-L tumors received FOLFOX/Bev, and those who had TS-H tumors were randomly assigned to receive either FOLFOX/Bev or IROX/Bev. The primary endpoint was the response rate (complete plus partial responses). RESULTS: In total, 211 of 247 patients (70% TS-H) were registered to the treatment phase. Efficacy analyses included eligible patients who had started treatment (N = 186). The response rates for patients who received IROX/Bev (TS-H), FOLFOX/Bev (TS-H), and FOLFOX/Bev (TS-L) were 33%, 38%, and 49%, respectively (P = nonsignificant). The median progression-free survival (PFS) was 10 months (95% confidence interval [CI], 9-12 months; 10 months in the IROX/Bev TS-H group, 9 months in the FOLFOX/Bev TS-H group, and 13 months in the FOLFOX/Bev TS-L group). The TS-L group had improved PFS compared with the TS-H group that received FOLFOX/Bev (hazard ratio, 1.6; 95% CI, 1.0%-2.4%; P =.04; Cox regression). The median overall survival (OS) was 22 months (95% CI, 20 29 months; 18 months in the IROX/Bev TS-H group, 21 months in the FOLFOX/Bev TS-H group, and 32 months in the TS-L group). OS comparisons for the 2 TS-H arms and for the FOLFOX/Bev TS-H versus TS-L arms were not significantly different. CONCLUSIONS: TS expression was prognostic: Patients with TS-L tumors who received FOLFOX/Bev had a longer PFS than those with TS-H tumors, along with a trend toward longer OS. Patients with TS-H tumors did not benefit more from IROX/Bev than from FOLFOX/Bev. Cancer 2018;124:688-97.

Original languageEnglish (US)
Pages (from-to)688-697
Number of pages10
JournalCancer
Volume124
Issue number4
DOIs
StatePublished - Feb 15 2018

Keywords

  • 5-fluorouracil
  • bevacizumab
  • colorectal cancer
  • irinotecan
  • oxaliplatin
  • predictive factors
  • prognostic factors
  • thymidylate synthase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Meropol, N. J., Feng, Y., Grem, J. L., Mulcahy, M. F., Catalano, P. J., Kauh, J. S., Hall, M. J., Saltzman, J. N., George, T. J., Zangmeister, J., Chiorean, E. G., Cheema, P. S., O'Dwyer, P. J., & Benson, A. B. (2018). Phase 2 study of treatment selection based on tumor thymidylate synthase expression in previously untreated patients with metastatic colorectal cancer: A trial of the ECOG-ACRIN Cancer Research Group (E4203). Cancer, 124(4), 688-697. https://doi.org/10.1002/cncr.30967