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. 2026 Mar 4:e260085.
doi: 10.1001/jamasurg.2026.0085. Online ahead of print.

Neoadjuvant Chemotherapy vs Upfront Surgery in Patients With Locally Advanced Colon Cancer: A Randomized Clinical Trial

Lars Henrik Jensen  1 , Monica Kjaer  2   3 , Laura Vittrup Diness  4 , Niels Henrik Hollânder  5 , Hans Bjarke Rahr  6 , Frank Pfeffer  7   8 , Finn Ole Larsen  4 , Jan Lindebjerg  9 , Søren Rafael Rafaelsen  10 , Torben Frøstrup Hansen  1 , Signe Timm  1   11 , Inger Marie Løes  12 , Ismail Gögenur  3   13 , Daniela Zitnjak  14 , Fahimeh Andersen  15 , Lone Nørgård Petersen  16 , Elinor Bexe Lindskog  17   18 , Laurids Østergaard Poulsen  19   20 , Olav Dahl  8   12
Affiliations

Neoadjuvant Chemotherapy vs Upfront Surgery in Patients With Locally Advanced Colon Cancer: A Randomized Clinical Trial

Lars Henrik Jensen et al. JAMA Surg. .

Abstract

Importance: Locally advanced colon cancer carries a high risk of recurrence. Neoadjuvant chemotherapy has been proposed to improve outcomes, but evidence from phase III trials remains limited.

Objective: To determine whether neoadjuvant chemotherapy improves disease-free survival (DFS) compared with upfront surgery in patients with locally advanced colon cancer.

Design, setting, and participants: This randomized, open-label, phase III clinical trial conducted from October 14, 2013, to November 27, 2020, with follow-up up to 3 years for DFS took place at 9 hospitals in Denmark, Norway, and Sweden. A total of 250 patients with locally advanced colon cancer staged by computed tomography, Eastern Cooperative Oncology Group performance status 0 to 2, and no distant metastases were enrolled. These data were analyzed from January 2024 to October 2024.

Interventions: Patients were randomized 1:1 to upfront surgery followed by adjuvant chemotherapy as indicated (n = 122) or 3 cycles of neoadjuvant capecitabine and oxaliplatin followed by surgery and adjuvant chemotherapy if indicated (n = 126).

Main outcomes and measures: The primary end point was DFS. Secondary end points included surgical and pathological outcomes, adjuvant chemotherapy use, adverse events, quality of life, and exploratory analysis by mismatch repair (MMR) status.

Results: A total of 248 patients were eligible and included in analyses (median age, 66 [min-max, 24-84] years; 111 women [45%] and 137 men [55%]). At 3 years, DFS was 87% in the upfront surgery arm and 83% in the neoadjuvant arm (P = .36). Neoadjuvant chemotherapy was feasible and safe, achieved tumor downstaging, and reduced the proportion of patients meeting criteria for adjuvant chemotherapy (upfront surgery 73% vs neoadjuvant group 59%; P = .02). Exploratory analyses suggested variation by MMR status, with DFS estimates higher after upfront surgery in patients with MMR-deficient tumors. Postoperative complications, adverse event profiles, and quality of life were comparable between groups.

Conclusions and relevance: Neoadjuvant chemotherapy did not improve DFS compared with upfront surgery, establishing the NeoCol trial as negative. However, feasibility, safety, downstaging effects, reduced adjuvant chemotherapy use, and MMR subgroup findings add to evidence from other randomized trials supporting further evaluation of this strategy in individualized management of locally advanced colon cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT01918527.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jensen reported trial monitoring from The Danish Good Clinical Practice units during the conduct of the study; institutional payment for trials from Merck, Bristol Myers Squibb, InCyte, Roche, and Pfizer outside the submitted work; and reported being chairman of a cross-disciplinary cancer drug committee of Danish Medicines Council and a member of the Danish Cancer Society. Dr Diness reported support for attending meetings and/or travel from the Danish Comprehensive Cancer Center and invitation to American Society of Clinical Oncology Gastrointestinal 2025 meeting. Dr Loes reported lecture fees from Bristol Myers Squibb, AstraZeneca, Servier, and PierreFabre outside the submitted work. Dr Gögenur reported grants from Pharmacosmos, Reponex, and Repoceuticals, and speaker fees from Pharmacosmos, Intuitive Surgery, and Merck. Dr Poulsen reported nonfinancial support from Merck and AstraZeneca outside the submitted work. No other disclosures were reported.

Comment in

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