Neoadjuvant chemotherapy did not improve disease-free survival compared with upfront surgery in patients with computed tomography–staged locally advanced colon cancer, according to results of the randomized phase 3 NeoCol trial.
Neoadjuvant approaches have improved outcomes in several solid tumors, including breast, gastroesophageal, and rectal cancers, and have been proposed in colon cancer to enable tumor downstaging, earlier systemic therapy, and risk-adapted use of postoperative chemotherapy.
The open-label trial enrolled 250 patients at nine centers in Denmark, Norway, and Sweden between 2013 and 2020. Eligible patients had colon cancer staged on computed tomography as cT3 with extramural tumor invasion of at least 5 mm or cT4, no distant metastases, and an Eastern Cooperative Oncology Group performance status of 0 to 2.
Patients were randomly assigned to upfront surgery followed by adjuvant chemotherapy as indicated or to three cycles of neoadjuvant capecitabine plus oxaliplatin followed by surgery and postoperative chemotherapy if indicated. A total of 248 patients were included in the final analysis.
At 3 years, disease-free survival—the primary end point—was 87% in the upfront-surgery group and 83% in the neoadjuvant group, with no statistically significant difference between strategies. Overall survival was also similar, with 5-year rates of 85% and 87%, respectively, and 10-year rates of 75% and 81%.
The trial was designed to detect a 10% absolute improvement in disease-free survival but observed fewer events than planned (38 vs 56), limiting statistical power and rendering the results nonconfirmatory.
Neoadjuvant chemotherapy was feasible and associated with pathologic downstaging. A complete pathologic response was observed in 4 patients (3%) in the neoadjuvant group, and nodal involvement and vascular invasion were numerically lower compared with upfront surgery. The proportion of patients meeting criteria for adjuvant chemotherapy was reduced from 73% with upfront surgery to 59% with neoadjuvant treatment, and planned postoperative chemotherapy was also less frequent (69% vs 53%).
Despite this shift in treatment timing, overall chemotherapy exposure was similar across the full study population, with a mean of 4.0 cycles in the upfront-surgery group and 4.8 cycles in the neoadjuvant group.
Surgical outcomes and safety profiles were broadly comparable. Rates of postoperative complications, including anastomotic leakage and ileus, were numerically lower in the neoadjuvant group, and quality-of-life measures at 1 year showed no clinically meaningful differences between strategies.
A key finding with direct clinical implications was the limited accuracy of computed tomography staging. Among patients undergoing immediate surgery, the positive predictive value of CT for identifying pathologic high-risk disease was 59%, indicating that a substantial proportion of patients classified as high risk preoperatively may not have had high-risk features on pathology. The positive predictive value for identifying patients who ultimately met criteria for adjuvant chemotherapy was 73%.
Exploratory post hoc analyses suggested heterogeneity by mismatch repair status. Among patients with deficient mismatch repair tumors, 3-year disease-free survival was 95% with upfront surgery and 79% with neoadjuvant chemotherapy (P = .09), a numerically large difference that raises concern about limited benefit of cytotoxic chemotherapy in this subgroup. In contrast, outcomes were similar between strategies in patients with proficient mismatch repair tumors. Mismatch repair status was not routinely assessed at trial initiation and was available for 217 patients.
These findings align with emerging evidence that mismatch repair–deficient colon cancers may respond preferentially to neoadjuvant immunotherapy rather than chemotherapy (N Engl J Med. 2024).
The NeoCol results add to a growing body of randomized evidence. The FOXTROT trial demonstrated significant tumor downstaging and a reduction in recurrence at 2 years, though without systematic disease-free survival reporting. The larger OPTICAL trial (n = 744) reported similar disease-free survival but suggested a potential overall survival benefit with neoadjuvant therapy (hazard ratio, 0.44; 95% CI, 0.25–0.77). Together, these trials suggest that although neoadjuvant chemotherapy does not clearly improve disease-free survival, it may offer advantages in selected patients and warrants further study.
The investigators noted several limitations, including the lower-than-expected number of events, the modest accuracy of CT for risk stratification, and limited generalizability beyond predominantly fit patients treated in Scandinavian health systems.
“The NeoCol trial was negative, showing that neoadjuvant chemotherapy in patients with locally advanced colon cancer is not superior to upfront surgery in terms of disease-free survival,” wrote lead researcher Lars Henrik Jensen, MD, of the Danish Colorectal Cancer Center South, Oncology, University Hospital of Southern Denmark, Vejle Hospital, and colleagues. They added that findings on feasibility, safety, downstaging, and reduced use of adjuvant chemotherapy support further evaluation of this strategy in more individualized treatment approaches.
Taken together, the data suggest that future studies may need to focus on improved patient selection using biomarkers such as mismatch repair status and circulating tumor DNA, as well as more accurate imaging techniques, to better define the role of neoadjuvant therapy in colon cancer.
Disclosures: Dr Jensen reported trial monitoring from Danish Good Clinical Practice units during the conduct of the study and institutional payments for trials from Merck, Bristol Myers Squibb, InCyte, Roche, and Pfizer outside the submitted work. Other investigators reported lecture fees, grants, travel support, speaker fees, and nonfinancial support from multiple companies. No other disclosures were reported.
Source: JAMA Surgery
