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)

• Type of Material: Article
• Authors: Neal J. Meropol, Case Western Reserve University; Yang Feng, Dana Farber Cancer Institute; Jean L. Grem, University of Nebraska; Mary F. Mulcahy, Northwestern University; Paul J. Catalano, Dana Farber Cancer Institute; John Kauh, Emory University; Michael J. Hall, Fox Chase Cancer Center; Joel N. Saltzman, Lake University; Thomas J. George, University of Florida; Jeffrey Zangmeister, Mt. Carmel Health Center West; Elena G. Chiorean, Indiana University; Puneet S. Cheema, Abbott Northwestern Hospital; Peter J. O'Dwyer, University of Pennsylvania; Al B. Benson, lll., Northwestern University
• Language: English
• Date: 2018-02-15
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Cancer Society
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.30967
• Title of Journal or Parent Work: Cancer
• ISSN: 0008-543X
• Volume: 124
• Issue: 4
• Start Page: 688
• End Page: 697
• Grant/Funding Information: This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs); and supported in part by Public Health Service Grants CA180794, CA180820, CA180853, CA180864, CA180847, CA189954, CA180795, CA189863; and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services.; Cooperative Group funding was provided by Sanofi-Aventis
• Keywords: predictive factors; COLON-CANCER; prognostic factors; Oncology; FLUOROURACIL; Science & Technology; oxaliplatin; QUANTITATION; bevacizumab; CHEMOTHERAPY; PROGNOSTIC VALUE; thymidylate synthase; PROGRESSION; 5-fluorouracil; SURVIVAL; COMBINATION; irinotecan; LEUCOVORIN; colorectal cancer; Life Sciences & Biomedicine; P53
• Research Categories: Health Sciences, Oncology

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.