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

Background: 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. Methods: 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. Results: 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. Conclusions: Neoadjuvant chemotherapy is feasible and biologically active in selected locally advanced resectable colon cancer, but benefit depends on accurate patient selection. © Society of Surgical Oncology 2026.