A large analysis of data from twelve trials evaluating the efficacy of adjuvant fluoropyrimidine with or without oxaliplatin in patients with stage III colon cancer found that the addition of oxaliplatin to fluoropyrimidine improved survival over fluoropyrimidine alone in those patients whose tumours were N1 stage and also demonstrated microsatellite instability (MSI), deficient DNA mismatch repair (dMMR). These findings appear in an article by Romain Cohen of the Medical Oncology Department Saint-Antoine Hospital, Sorbonne Université in Paris, France and co-investigators that was published on 23 December 2020 in the Journal of Clinical Oncology.
This study was prompted by unresolved questions regarding the efficacy of adjuvant fluoropyrimidine with or without oxaliplatin in patients with stage III colon cancer whose tumors demonstrate MSI/dMMR, and whether MSI is a prognostic factor.
The investigators conducted this analysis of 12 clinical trials using the individual patient data of more than 5000 patients with stage III colon cancer who underwent fluoropyrimidine-based adjuvant therapy contained in the ACCENT database. This analysis included data from the NCCTG-78-48-52, FFCD, INT-0035, NCIC, NCCTG-87-46-51, GIVIO, MOSAIC, C07, C08, AVANT, N0147, and PETACC trials.
The effect of fluoropyrimidine with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) in these patients was evaluated using stratified Cox models that adjusted for demographic and clinicopathological factors.
The investigators identified 5,457 patients with immunohistochemistry- or PCR-confirmed MSI status; of these 609 (11.2%) patients were MSI and 4848 (88.8%) had microsatellite stable (MSS) tumours.
Oxaliplatin addition benefits patient with MSI tumours
According to two randomised controlled trials evaluating fluoropyrimidine with and without oxaliplatin in 185 patients with MSI tumours, OS was significantly improved with the addition of oxaliplatin (adjusted hazard ratio [aHR] 0.52, confidence interval [CI] 0.28-0.93).
In additional trials evaluating fluoropyrimidine plus oxaliplatin in 4,250 patients, 461 patients were MSI and 3789 were MSS. In these trials, MSI was associated with better OS in patients having N1 status compared with MSS (aHR 0.66; 95% CI 0.46-0.95). However, this result was not reflected in the N2 patient population where OS following adjuvant fluoropyrimidine plus oxaliplatin was similar between MSI and MSS patients (aHR 1.13; 95% CI 0.86-1.48; p interaction = 0.029).
Similar results were observed for DFS in all analyses.
Of the factors investigated, no interaction was observed between MSI status and T stage, primary tumour sidedness, or BRAFV600E mutational status (interaction p = 0.12). However, MSI prognostic effects were found to be dependent on the N stage category (interaction test for OS, p value = 0.029).
As compared with MSS patients, among MSI patients receiving fluoropyrimidine plus oxaliplatin the independent prognosticators for OS were T stage (aHR 2.09; 95% CI 1.29-3.38) and N stage (aHR 3.57; 95% CI 2.32-5.48). This significant interaction was confirmed for DFS, which demonstrated an excess of events in the first two years of follow-up in the MSI N2 population compared with patients with MSS N2, although the log-rank test was not significant.
Conclusions
Based on these findings, the authors concluded that the addition of oxaliplatin to fluoropyrimidine improved OS and DFS in patients with MSI stage III colon cancer. They also found that MSI was associated with better outcomes, as compared with MSS patients, in patients with N1, but not N2 disease.
The authors wrote that this meta-analysis of individual patient data demonstrates that the combination of oxaliplatin plus fluoropyrimidine should be the standard-of-care adjuvant treatment for patients with MSI/dMMR stage III colon cancer.
Furthermore, they recommended that N stage should be at least a stratification parameter in future trials involving the MSI/dMMR population.
This study was supported by the US National Cancer Institute, the ARCAD foundation, and research grants from the Nuovo-Soldati Foundation, ARC Foundation for Cancer Research, and Servier Institute.
Reference
Cohen R, Taieb, J, Fiskum J et al. Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials. Journal of Clinical Oncology; Published online 23 December 2020. DOI: https://doi.org/10.1200/JCO.20.01600.