“As the current work is the largest ever published on adjuvant [fluoropyrimidine; FP] for patients with MSI stage III [colon cancer], it suggests that FP alone should not be recommended as adjuvant treatment for these patients,” wrote the study authors, who were led by Romain Cohen, MD, PhD.
A meta-analysis of individual patient data from the ACCENT database demonstrated that the combination of oxaliplatin plus fluoropyrimidine (FP) should be considered standard-of-care adjuvant therapy for patients with microsatellite instability or mismatch repair deficient (MSI/dMMR) stage III colon cancer.1
The study, published in the Journal of Clinical Oncology, also indicated that patients with colon cancer and MSI experienced better outcomes in the N1 group when compared with those with microsatellite stable (MSS) disease; however, both groups saw similar survival in the N2 group. Given these findings, the investigators suggested that N stage should be a stratification parameter in future trials dedicated to the MSI/dMMR population.
“As the current work is the largest ever published on adjuvant FP for patients with MSI stage III [colon cancer], it suggests that FP alone should not be recommended as adjuvant treatment for these patients,” wrote the study authors, who were led by Romain Cohen, MD, PhD.
Using the ACCENT database, the investigators assessed the impact of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III colon cancer. In addition, the prognostic value of MSI was evaluated in regard to FP plus oxaliplatin therapy by stratified Cox models adjusted for demographic and clinicopathological factors.
Notably, for the purposes of statistical analysis, T stage and N stage were combined in a comprehensive TN variable (T1-3 and N1: low risk; T4 and/or N2: high risk).
Of 12 randomized clinical trials identified for the study, MSI status was available among a total of 5457 patients (609 MSI, 11.2%; 4848 MSS, 88.8%). Among patients with MSI colon cancer from 2 randomized clinical trials testing FP with or without oxaliplatin, the addition of oxaliplatin was revealed to induce significantly improved OS (n = 185; adjusted HR [aHR], 0.52; 95% CI, 0.28-0.93).
“These results bring contrast to the negative results of the FoxTrot trial, which showed a very low rate of pathological responses (73.6% with no regression) and no survival benefit from neoadjuvant FOLFOX in the 106 MSI/dMMR patients treated in that trial,” the authors noted.2
Moreover, of 4250 patients treated with FP plus oxaliplatin, MSI status (n = 461) was found to be associated with better OS in the N1 group when compared with patients considered to be MSS (n = 3789; aHR, 0.66; 95% CI, 0.46-0.95); however, similar survival was reported in the N2 population (aHR, 1.13; 95% CI, 0.86-1.48; P interaction = .029). The main independent predictive characteristics of patients with MSI treated with FP plus oxaliplatin were T stage (aHR, 2.09; 95% CI, 1.29-3.38) and N stage (aHR, 3.57; 95% CI, 2.32-5.48). Three-year DFS rate estimates of 65.0% (95% CI, 6.0%-70.0%) for patients with N2, MSI/dMMR tumors and 60.4% (95% CI, 52.9%-68.9%) for patients with T4, MSI/dMMR were reported.
“With one-third of T4 and/or N2 high-risk stage III MSI/dMMR [colon tumors] patients experiencing disease recurrence or death within 2 years after curative tumor resection, therapeutic innovations should be sought for this patient population,” explained the authors.
Notably, 2 phase 3 randomized trials have already been launched for patients with resected MSI/dMMR stage III colon cancer. These include the ATOMIC trial (NCT02912559), which is evaluating FOLFOX with or without atezolizumab (Tecentriq); and the POLEM trial (NCT03827044), which is evaluating the use of 24 weeks of FP or 12 weeks of FP plus oxaliplatin, with or without avelumab (Bavencio), for patients who have MSI/dMMR or polymerase epsilon–mutated colon cancer.
1. 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. J Clin Oncol. Published online December 23, 2020. doi: 10.1200/JCO.20.01600
2. Morton D. FOxTROT: An international randomised controlled trial in 1053 patients evaluating neoadjuvant chemotherapy (NAC) for colon cancer. On behalf of the FOxTROT Collaborative Group. Ann Oncol. 2019:30(Suppl 5):v198-v252. doi: 10.1093/annonc/mdz246