5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer

Abstract

Background & aims: 5-Fluorouracil (5-FU)-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy.

Methods: We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP positive if at least 3 promoters were methylated.

Results: Tumors from 29.5% of patients (89/302) were CIMP positive; CIMP status did not influence disease-free survival (DFS; log-rank = 0.3). Of tumors of TNM stages II-III (n = 196), 32.7% were CIMP positive. Among patients with stages II-III CRC who did not receive adjuvant 5-FU chemotherapy, those with CIMP-positive tumors had longest times of DFS (log-rank = 0.04); In patients who received chemotherapy, those with CIMP-positive tumors had shorter times of DFS (log-rank = 0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of DFS (log-rank = 0.00001). However, in patients with CIMP-positive tumors, adjuvant 5-FU chemotherapy did not affect time of DFS (log-rank = 0.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.5-0.8). Among patients with CIMP-positive tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR, 0.8; 95% CI, 0.3-2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR, 2.0; 95% CI, 1.1-3.8).

Conclusions: Patients with CIMP-positive colorectal tumors do not benefit from 5-FU-based adjuvant chemotherapy.

Conflict of interest statement

Conflict of Interest: None of the authors have any potential conflicts to disclose.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

(A)Kaplan-Meier survival curves depicting the effect of CIMP status on disease-free survival (DFS) in the entire series of CRCs. Vertical tick marks indicate censored events. (B) Kaplan-Meier survival curves illustrating the effect of CIMP status on disease-free survival (DFS) in patients with TNM stage II and III CRCs. Vertical tick marks indicate censored events.

Figure 1

(A)Kaplan-Meier survival curves depicting the effect of CIMP status on disease-free survival (DFS) in the entire series of CRCs. Vertical tick marks indicate censored events. (B) Kaplan-Meier survival curves illustrating the effect of CIMP status on disease-free survival (DFS) in patients with TNM stage II and III CRCs. Vertical tick marks indicate censored events.

Figure 2

Kaplan-Meier survival curves demonstrating the effect of CIMP status on survival according to 5-FU based chemotherapy treatment. In patients with CIMP-negative tumors (panel A), adjuvant chemotherapy clearly provides a survival benefit with a higher probability of disease-free survival (DFS). In patients with CIMP-positive tumors (panel B), the use of 5-FU based adjuvant chemotherapy does not improve DFS. Vertical tick marks indicate censored events.

Figure 3

Kaplan-Meier survival curves indicating the effect of chemotherapy on survival according to CIMP status. In patients who received 5-FU based adjuvant chemotherapy (panel A), the existence of a CIMP-positive tumor confers a worse prognosis, with lower disease-free survival (DFS). In contrast, in patients who did not receive adjuvant chemotherapy (panel B) the situation reverses, and those with CIMP-positive tumors had a better prognosis. Vertical tick marks indicate censored events.