Phase 3 EMT2 trial demonstrates survival benefit for high-dose EPA

Patients assigned to receive high-dose eicosapentaenoic acid (EPA), an omega-3 fatty acid, before and after surgery for colorectal cancer liver metastases had longer overall survival than those assigned to receive placebo, according to results of the phase 3 EMT2 trial presented at the ESMO Congress 2026.

Surgery to remove colorectal cancer that has spread to the liver offers the possibility of long-term survival, but recurrence remains common. Preclinical and observational studies have suggested that EPA may have activity against colorectal cancer, while an earlier phase 2 trial indicated a possible survival benefit. 

The randomized, double-blind, placebo-controlled EMT2 trial enrolled 418 patients scheduled for liver resection with curative intent at 13 UK hepatobiliary surgery centers. Patients were assigned to 4g daily of EPA, as high-purity prescription icosapent ethyl, or mineral oil placebo. Treatment began at least one day before surgery and was planned to continue for two to four years, even after cancer progression. Other cancer treatments were broadly comparable, with 20% in each group receiving adjuvant chemotherapy.

Estimated five-year overall survival, the trial's key secondary endpoint, was 62.0% with EPA versus 45.1% with placebo. EPA was associated with a 32% lower hazard of death (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.48-0.96; p = 0.03). Median overall survival had not been reached with EPA versus 59.0 months with placebo. The survival benefit was consistent in the per-protocol analysis (HR 0.60; 95% CI 0.36-0.99). It also remained consistent after adjustment for diabetes, which was more common at baseline in the EPA group (16% versus 8%), and in other sensitivity analyses. However, median progression-free survival (PFS) was similar in the two groups (13.5 versus 12.9 months; HR 0.89; 95% CI 0.70-1.13; p = 0.33).

EPA was well tolerated, with no excess adverse events, bleeding or atrial fibrillation compared with placebo, and no negative impact on quality of life.

"The overall survival benefit seen with EPA in EMT2, if confirmed in other studies, is clinically meaningful for the group of patients who have had surgery for bowel cancer spread to the liver and in whom the cancer frequently comes back," said lead author Professor Mark Hull, Leeds Institute of Medical Research, University of Leeds, UK. "This is particularly the case as EPA is well-tolerated and safe, even when other cancer treatments are needed."

Hull suggested the survival benefit might reflect effects on the body's response to cancer, including cachexia, which can involve weight loss, reduced appetite and fatigue.

Longer overall survival but no significant improvement in progression-free survival has also been seen in trials of cancer immunotherapy, and more research is needed to work out whether EPA works by improving the body's immune response to cancer."

Mark Hull, Professor, Leeds Institute of Medical Research, University of Leeds, UK

"The results are definitely intriguing, from both a biological and a clinical point of view," said Dr Chiara Cremolini, University of Pisa, Italy, who was not involved in the study. "The lack of concordance between progression-free survival and overall survival results requires careful interpretation." She noted that PFS is a less established indicator of overall survival after surgery for liver metastases than after surgery for early-stage bowel cancer, and that additional data would help, including the treatments patients received after their cancer came back and the pattern of spread at the time of progression.

"Confirmatory results are likely needed before incorporating this treatment option into daily clinical practice," said Cremolini, noting that patients having surgery for liver metastases vary widely in the biological and molecular characteristics of their cancer and in their previous treatment, which future trials could take into account. "Acknowledging the difficulty of conducting clinical trials, and especially academic research, in this setting, the authors should be highly congratulated for their successful effort," she concluded.