Adjuvant Chemotherapy and Survival in MSI-High Stages II and III Colon Cancer: Impact of Histopathologic Risk...

Microsatellite instability-high (MSI-H) status in colorectal cancer is associated with a favorable prognosis, but its predictive value for adjuvant chemotherapy (ACT) benefit for patients with stage II disease remains controversial, particularly when histopathologic risk factors are taken into account. This study aimed to evaluate the impact of ACT on overall survival (OS) for patients with stage II MSI-H colon cancer stratified by pathologic risk and stage III MSI-H colon cancer.

A retrospective analysis of the National Cancer Database (2013-2019) was performed, identifying 8025 patients with stage II or III MSI-H colon adenocarcinoma who underwent surgical resection. The stage II patients were stratified into low- and high-risk cohorts based on adverse pathologic features including pT4 stage, lymphovascular invasion, perineural invasion, positive margins, or and fewer than 12 lymph nodes examined. Inverse probability of treatment-weighting was applied to balance the covariates, and OS was estimated using weighted Kaplan-Meier and Cox proportional hazards models.

Of the 8025 patients included in the study, 4981 had stage II disease and 3044 had stage III disease. Among the 3501 low-risk stage II patients, ACT was administered to only 5.9% and was not associated with an OS benefit (hazard ratio [HR], 0.92; 95% confidence interval [CI] 0.58-1.47; p = 0.73). In contrast, among the 1480 high-risk stage II patients, 19.1% received ACT, which was associated with a 62% reduction in mortality risk (HR, 0.38; 95% CI 0.25-0.57; p < 0.001). Increasing histopathologic risk burden correlated with higher mortality. In the stage III cohort, ACT was administered to 66.5% of the 3044 patients and significantly improved OS (HR, 0.53; 95% CI 0.45-0.62; p < 0.001). Notably, one third of the patients with stage III disease did not receive ACT despite the guideline recommendations for ACT in this population.

A patient's MSI-H status alone should not preclude the use of ACT in colon cancer. This study demonstrated a significant survival benefit of ACT for both high-risk stage II and stage III MSI-H patients. Histopathologic risk stratification should guide treatment decisions for stage II MSI-H colon cancer, and ACT may be recommended for patients with multiple adverse pathologic features.