Neoadjuvant Chemotherapy in Resectable Colon Cancer: Evidence, Controversies, and an Implementation Roadmap for 2026

Neoadjuvant chemotherapy for resectable colon cancer has emerged as a potential strategy to improve systemic treatment delivery, enhance tumor downstaging, and facilitate margin-negative resection in selected patients with locally advanced disease. However, its role remains controversial because radiologic staging is imperfect and long-term survival benefits have not been uniformly demonstrated.

We performed a narrative review of the contemporary evidence on neoadjuvant chemotherapy in resectable colon cancer, focusing on randomized trials, comparative studies, meta-analyses, and implementation issues. Key trials included FOxTROT, which randomized patients 2:1 to 6 weeks of preoperative oxaliplatin-fluoropyrimidine plus 18 weeks postoperative therapy versus 24 weeks postoperative therapy; OPTICAL, which evaluated 3 months of preoperative mFOLFOX6 or CAPOX followed by surgery and 3 months postoperative chemotherapy; PRODIGE 22; and the phase III NeoCol trial. A 2024 meta-analysis of seven comparative studies including 2120 patients was also reviewed.

FOxTROT showed reduced 2-year residual or recurrent disease (16.9% vs. 21.5%; rate ratio 0.72; P = 0.037), improved downstaging, and higher complete resection rates, with fewer serious postoperative complications despite 4.3% requiring expedited surgery for obstruction. OPTICAL reported improved pathologic response and overall survival (HR 0.44; P = 0.002), although disease-free survival was not statistically significant (82.1% vs. 77.5%; HR 0.74; P = 0.08). NeoCol did not show significant DFS or OS differences. The meta-analysis suggested improved recurrence, overall survival, and incomplete resection risk without excess operative morbidity.

Neoadjuvant chemotherapy is feasible and biologically active in selected locally advanced resectable colon cancer, but benefit depends on accurate patient selection.