Adding oxaliplatin to adjuvant fluoropyrimidine ups OS and DFS in MSI stage III colon cancer

Adding oxaliplatin to adjuvant fluoropyrimidine improves overall survival (OS) and disease-free survival (DFS) in patients with microsatellite instability (MSI) stage III colon cancer, a pooled analysis of 12 randomized clinical trials has shown.

Researchers analyzed data from 5,457 patients with stage III colon cancer with available microsatellite and/or DNA mismatch repair (MMR) status who were enrolled in 12 randomized trials included in the ACCENT database. Of these patients, 609 (11.8 percent) had tumours with MMR deficiency (dMMR) and/or a high level of MSI (MSI/dMMR), while 4,848 (88.8 percent) had tumours with proficient DNA mismatch repair (pMMR) and/or microsatellite stable (MSS) status or a low level of MSI (MSS/pMMR). Six of the trials evaluated surgery with or without adjuvant fluoropyrimidine, two of the trials tested adjuvant fluoropyrimidine with or without oxaliplatin, while another four trials had at least one treatment arm consisting of oxaliplatin plus fluoropyrimidine. [J Clin Oncol 2020, doi: 10.1200/JCO.20.01600]

In 185 patients with MSI/dMMR tumours enrolled in the C-07 and MOSAIC trials, adding oxaliplatin to adjuvant fluoropyrimidine was associated with significant improvements in OS (adjusted hazard ratio [aHR], 0.52; 95 percent confidence interval [CI], 0.28 to 0.93) and DFS (aHR, 0.47; 95 percent CI, 0.27 to 0,82) vs fluoropyrimidine alone.

Among 4,250 patients (MSI/dMMR, n=461; MSS/pMMR, n=3,789) treated with oxaliplatin plus fluoropyrimidine in the MOSAIC, C-07, C-08, PETACC-8, N0147 and AVANT trials, the prognostic value of MSI status was found to be dependent on N stage category. “Compared with MSS/pMMR, MSI/dMMR was associated with better OS in the N1 population [aHR, 0.66; 95 percent CI, 0.46 to 0.95], but a similar OS in the N2 population [aHR, 1.13; 95 percent CI, 0.86 to 1.48],” the researchers reported. “Similar results were observed for DFS.”

“The main independent prognosticators of MSI/dMMR patients treated with oxaliplatin plus fluoropyrimidine were T stage [aHR, 2.09; 95 percent CI, 1.29 to 3.38] and N stage [aHR, 3.57; 95 percent CI, 2.32 to 5.48],” they noted.

In MSI/dMMR patients treated with oxaliplatin plus fluoropyrimidine, estimated 3-year DFS rates were 65.0 percent vs 87.0 percent for those with N2 vs N1 disease, 60.4 percent vs 82.1 percent for those with T4 vs T1–3 disease, and 64.5 percent vs 90.1 percent for those with high-risk (T4 and/or N2) vs low-risk (T1–3 and N1) disease.

“Our individual patient data meta-analysis shows that the combination of oxaliplatin plus fluoropyrimidine should be the standard-of-care adjuvant treatment for patients with resected stage III MSI/dMMR colon cancer, and that N stage should be at least a stratification parameter in future trials dedicated to the MSI/dMMR population,” the researchers concluded.

“With one-third of patients with T4 and/or N2 MSI stage III colon cancer experiencing disease recurrence or death within 2 years after curative tumour resection, innovative therapeutic strategies should be sought for this population,” they added.

The MSI/dMMR phenotype is present in 9–10 percent of patients with stage III colon cancer. [N Engl J Med 2003;349:247-257; J Clin Oncol 2011;29:1261-1270; J Clin Oncol 2015;33:4176-4187; JAMA Oncol 2018;4:379-383; Clin Cancer Res 2014;20:5322-5330] While previous studies reported that adjuvant fluoropyrimidine may be ineffective or even detrimental in patients with MSI/dMMR localized colon cancer, the current analysis has shown no benefit or detrimental effect with adjuvant fluoropyrimidine in patients with stage III MSI/dMMR tumours. [N Engl J Med 2003;349:247-257; J Clin Oncol 2011;29:1261-1270; J Clin Oncol 2010;28:3219-3226]