Novel approaches in adjuvant colorectal cancer therapy: the emerging role of exercise, aspirin, and immunotherapy

Summary Adjuvant treatment of colorectal cancer (CRC) has traditionally been based on fluoropyrimidine- and oxaliplatin-based chemotherapy regimens, which remain the cornerstone of care for patients with resected stage III and selected high-risk stage II disease. However, despite substantial improvements in disease-free (DFS) and overall survival (OS), a considerable proportion of patients experience disease recurrence. More recently, attention has shifted toward novel adjuvant strategies aimed at further reducing the recurrence risk, including structured exercise, biomarker-guided aspirin therapy, immune checkpoint inhibition in mismatch repair-deficient (dMMR) CRC, and circulating tumor DNA (ctDNA)-based detection of molecular residual disease. The CHALLENGE trial demonstrated that a 3-year structured exercise intervention after completion of adjuvant chemotherapy significantly improves DFS and OS in patients with stage III and high-risk stage II colon cancer. The ALASCCA trial established low-dose aspirin as a promising precision medicine strategy in patients with phosphatidylinositol 3‑kinase (PI3K) pathway alterations. The ATOMIC trial provided the first phase III evidence supporting adjuvant immunotherapy in patients with dMMR stage III colon cancer. In parallel, ctDNA has emerged as a powerful prognostic marker, although randomized studies have also demonstrated that ctDNA-guided escalation or de-escalation cannot yet be considered a universal replacement for standard clinicopathological decision-making. This review summarizes the biological rationale, clinical background, pivotal phase III data, practical implementation, and remaining uncertainties of these emerging strategies.