Adjuvant Oxaliplatin Added to Fluoropyridine Improves Survival in Stage III MSI-High Colon Cancer

The addition of adjuvant oxaliplatin to fluoropyridine improves overall survival (OS) and disease-free survival (DFS) compared with fluoropyridine alone in patients with stage III colon cancer with microsatellite instability (MSI), according to findings from a pooled analysis of randomized clinical trials using individual patient data.

In addition, among patients treated with fluoropyridine and oxaliplatin, MSI predicted improved survival compared with microsatellite stable (MSS) disease in patients with stage N1 disease, but not in those with N2 disease.

Results of the pooled analysis, led by Romain Cohen, MD, PhD, of Sorbonne Université, Saint-Antoine Hospital, AP-HP, in Paris, France, found that oxaliplatin plus fluoropyridine improved OS compared with fluoropyridine alone in patients with MSI/deficient mismatch repair (dMMR) stage III colon cancer (HR, 0.52; 95% CI, 0.28-0.93) as well as in those with microsatellite stable (MSS)/proficient mismatch repair (pMMR) disease (HR, 0.89; 95% CI, 0.74-1.06). There was no significant interaction found for the effect of oxaliplatin between MSI/dMMR status (P = .11 for interaction).

Similarly, on the end point of DFS, adding oxaliplatin was associated with a significant 53% improvement compared with fluoropyridine monotherapy in the MSI/dMMR subcohort (HR, 0.47; 95% CI, 0.27-0.82) and a significant 18% improvement in DFS in the MSS/pMMR subgroup (HR, 0.82; 95% CI, 0.70-0.97; P = .14 for interaction).

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

The analysis pooled data from 12 randomized trials included in the ACCENT database that included 5457 patients with stage III colon cancer. A total of 609 (11.2%) had MSI/dMMR disease and 4848 (88.8%) had MSS/pMMR disease. Six trials tested surgery with or without fluoropyridine, 2 tested fluoropyridine with or without oxaliplatin, and 4 had at least 1 treatment arm consisting of oxaliplatin plus fluoropyridine.

Individual patient data from 6 randomized trials testing surgery with or without fluoropyridine as adjuvant treatment were pooled. The effect of fluoropyridine plus oxaliplatin on outcomes was analyzed based on a pooled analysis of 2 randomized trials: the C-07 and the MOSAIC trials.

MSI/dMMR had different prognostic effects depending on N stage. Compared with MSS/pMMR, MSI/dMMR was associated with better OS in those with stage N1 (HR, 0.66; 95% CI, 0.46-0.95) but a similar OS in those with stage N2 disease (HR, 1.13; 95% CI, 0.86-1.48). The interaction test was significant (P = .029).

“This significant interaction was confirmed for DFS, with an excess of events in the first 2 years of follow-up in the MSI/dMMR N2 population compared with patients with MSS/pMMR N2 [disease],” the investigators wrote.

In a multivariable model, prognosticators for patients with MSI/dMMR stage III colon cancer who were treated with oxaliplatin plus fluoropyridine were N stage (N2 vs N1; HR, 3.10; 95% CI, 2.13-4.50), T stage (T4 vs T1-3; HR, 2.39; 95% CI, 1.56-3.66), and sex (male vs female; HR, 1.71; 95% CI, 1.14-2.58).

In the MSI/dMMR population treated with oxaliplatin plus fluoropyridine, the 3-year estimates of DFS were:

• 65.0% (95% CI, 6-70.0%) for the N2 subcohort versus 87.0% (95% CI, 84.3-89.9%) for the N1 subgroup
• 60.4% (95% CI, 52.9-68.9%) for patients with stage T4 disease versus 82.1% (95% CI, 79.5-84.9%) for those with T1 to T3 disease
• 64.5% (95% CI, 60.1-69.2%) for high-risk patients versus 90.1% (95% CI, 87.5-92.8%) for low-risk patients

Reference

Cohen R, Taieb J, Fiskum J, et al. Microsatellite instability in patients with stage III colon cancer receiving fluoropyridine with or without oxaliplatin: an ACCENT pooled analysis of 12 adjuvant trial. J Clin Oncol. Published online December 23, 2020. doi.org/10.1200/JCO.20.01600