Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials

Abstract

Purpose: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain.

Materials and methods: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors.

Results: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses.

Conclusion: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

Trial registration: ClinicalTrials.gov NCT00275210 NCT00004931 NCT00096278 NCT00112918 NCT00079274 NCT00265811.

Figures

FIG 1.

Effect of FP-based and oxaliplatin-based adjuvant treatment according to the MSI/dMMR status. Overall survival (A) and disease-free survival (B) of patients treated with FP or FP plus oxaliplatin therapy. dMMR, mismatch repair system deficiency; FP, fluoropyrimidine; HR, hazard ratio; KM, Kaplan-Meier; MSI, microsatellite instability; OX, oxaliplatin.

FIG 2.

Forest plot for MSI effect on overall survival by baseline factors in the population treated with oxaliplatin and FP. FP, fluoropyrimidine; MSI, microsatellite instability; MSS, microsatellite stable.

FIG 3.

Outcomes of patients treated with oxaliplatin plus FP according to MSI status and N stage. Overall survival (A) and disease-free survival (B) of patients treated with FP plus oxaliplatin therapy by MSI/MSS status and N stage; overall survival (C) and disease-free survival (D) of patients treated with FP plus oxaliplatin therapy by MSI/MSS status and TN stage. FP, fluoropyrimidine; HR, hazard ratio; MMR, mismatch repair system; MSI, microsatellite instability; MSS, microsatellite stable.

FIG A1.

CONSORT flowchart.

FIG A2.

Effect of FP-based adjuvant treatment according to the MSI/dMMR status. dMMR, mismatch repair system deficiency; FP, fluoropyridimine; MSI, microsatellite instability.

FIG A3.

Forest plot for the effect of oxaliplatin on overall survival among MSI patients (C-07 and MOSAIC trials). MSI, microsatellite instability.