NeoCol trial: Neoadjuvant chemotherapy does not improve disease-free survival in patients with locally advanced colon cancer

1. Neoadjuvant capecitabine-oxaliplatin chemotherapy did not improve three-year disease-free survival compared to upfront surgery in locally advanced colon cancer.

2. An exploratory subgroup analysis revealed that neoadjuvant chemotherapy may reduce overall survival in patients with deficient mismatch repair tumors.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Two prior randomized controlled trials demonstrated that neoadjuvant chemotherapy for colon cancer safely achieved measurable downstaging despite no improvement in disease-free survival (DFS). The NeoCol trial was another attempt to investigate the impact of neoadjuvant chemotherapy in adult patients with locally advanced colon cancer. NeoCol randomized patients to a neoadjuvant capecitabine-oxaliplatin (CAPOX) arm or an upfront surgery arm. Although three cycles of neoadjuvant chemotherapy proved feasible, there was no significant difference in three-year DFS, five-year OS, and ten-year OS between the groups. There was also no between-group difference in quality of life measures. However, post hoc stratified analyses based on mismatch repair (MMR) status revealed several numerical differences that did not reach significance: upfront surgery improved DFS in deficient mismatch repair (dMMR) tumors, while OS was slightly augmented in patients receiving neoadjuvant chemotherapy with proficient mismatch repair (pMMR) tumors. Strengths of this study include its generalizability as a multicenter, international trial. Limitations include potentially suboptimal tumor staging via computed tomography and the exploratory nature of the MMR subgroup finding, which ultimately should not guide practice without confirmatory prospective data. Overall, the findings of this negative trial remain valuable for demonstrating the feasibility and safety of neoadjuvant CAPOX in locally advanced colon cancer. This study also suggests that neoadjuvant chemotherapy may result in nodal downstaging and reduced vascular invasion at the time of surgery, as well as lower rates of certain postoperative complications and an overall survival benefit in patients with pMMR tumor characteristics, warranting individualized therapy decisions and further research.

Click to read the study in JAMA Surgery

Relevant Reading: Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer

In-Depth [randomized controlled trial]: NeoCol was a phase III international, multicenter open-label randomized controlled trial. Eligible patients had CT-staged, histologically-confirmed, locally-advanced colon cancer and no distant metastases. A total of 248 participants were randomized 1:1 to an upfront surgery group (n = 122), which underwent surgery followed by up to eight cycles of adjuvant chemotherapy, or to a neoadjuvant CAPOX group (n = 126), which underwent up to three cycles of preoperative chemotherapy followed by surgery and an additional up to five cycles of adjuvant chemotherapy. The primary endpoint was three-year DFS, defined as the time from randomization to recurrence or death from any cause. Secondary endpoints included overall survival (OS), rate of patients meeting criteria for adjuvant chemotherapy, and quality of life. Patients in the intervention arm underwent a median of 2.7 cycles of neoadjuvant chemotherapy. Ultimately, 99% of patients underwent surgery, with a right hemicolectomy being the most common procedure performed. Postoperative ileus was observed in 8% of upfront surgery patients and 3% of neoadjuvant patients; anastomotic leakage occurred in 8% of patients in the upfront surgery arm and 2% in the neoadjuvant chemotherapy arm. At three years, DFS was 87% in the upfront surgery group and 83% in the neoadjuvant group (log-rank P = .36), a non-significant difference that rendered the trial negative for its primary endpoint. Five-year OS was 85% in the upfront arm and 87% in the neoadjuvant group (log-rank P = .83). At ten years, OS was 75% in the upfront arm and 81% in the neoadjuvant arm (log-rank P = .36). Neoadjuvant chemotherapy achieved tumor downstaging, with 73% of patients in the upfront arm vs. 59% of patients in the neoadjuvant arm meeting criteria for and undergoing adjuvant treatment (P = .02). Adverse events and quality-of-life measures were comparable between the two arms. MMR status was collected postoperatively in an exploratory fashion, with 18% of upfront surgery patients and 27% of neoadjuvant patients expressing the deficient MMR (dMMR) genotype. Post hoc stratified analyses based on MMR status revealed numerically higher DFS after upfront surgery in patients with dMMR tumors, suggesting that neoadjuvant CAPOX might be less effective in patients with deficient mismatch repair tumor characteristics. Although this finding did not reach statistical significance, it motivates prospective MMR-stratified evaluation.

Image: PD

©2026 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.