The effect of eicosapentaenoic acid on biomarkers of growth and vascularity of human colorectal cancer liver metastases

Background: The omega-3 fatty acid eicosapentaenoic acid (EPA) has been demonstrated to be incorporated into tumours and inhibit tumour growth in pre-clinical models of colorectal cancer liver metastases (CRCLM). Aims: To test the safety, tolerability and effect on tumour biomarkers of growth and vascularity of orally administered EPA in patients awaiting liver resection surgery for CRCLM. Methods: In a Phase II randomised, double-blind, placebo-controlled trial, patients with CRCLM received EPA 2g daily (n=43) or placebo (n=45) prior to surgery. CRCLM tissue was analysed for fatty acid content, PGE2 content, proliferation index (Ki-67), apoptosis index and vascularity. Blood was collected for platelet function and monocyte NFkB binding studies, and urine for measurement of PGE-M. Supplementary in vitro endothelial cell studies investigated the effects of EPA on angiogenesis. Results: The two treatment groups were well matched for burden of disease and previous chemotherapy exposure. Mean duration of EPA treatment was 30 days (range 12-65 days). EPA was safe and well tolerated, with a small excess of diarrhoea (p=0.09), and no excess of post-operative complications. Tumours from the EPA group had a 40% higher EPA content (p<0.01), no difference in proliferation or apoptosis, and a trend to reduced vascularity. EPA treatment was associated with a 36% reduction in urinary PGE-M (p=0.03) compared to placebo, and reduced monocyte NFкB DNA binding compared to baseline (p=0.03). EPA inhibited angiogenesis in vitro. Conclusions: EPA 2g daily is safe and well-tolerated in patients with CRCLM before liver resection. EPA incorporates into CRCLMs, exhibits systemic anti-inflammatory effects, and may have anti-angiogenic activity. Phase III clinical evaluation of prolonged EPA treatment is warranted in patients with, or at risk of, CRCLM.