Effect of Supplementary Omega-3 Fatty Acids on the Biochemical, Radiological and Clinical Outcome of Patients with Metastatic Oesophago-Gastric Cancer Receiving Palliative Chemotherapy

Background: Omega-3 polyunsaturated fatty acids (PUFAs) have reported anti-cancer effects. Few studies have assessed oesophago-gastric cancer, either in vitro or in vivo. Aims: To evaluate whether addition of omega-3 PUFAs (Omegaven) to palliative chemotherapy would influence the clinical and biochemical outcome of patients with oesophago-gastric cancer, and to assess the response of oesophageal adenocarcinoma cell lines to omega-3 PUFAs compared to oxaliplatin. Methods: Participants in a phase II trial received palliative chemotherapy and Omegaven infusion. Clinical and radiological outcome were assessed. Comparison was made to historical patients who received chemotherapy alone. Serum cytokine concentrations and uptake of PUFAs in plasma and red cell membrane were assessed in trial patients. The in vitro response of cell lines to omega-3 PUFAs or oxaliplatin were evaluated. Results: Participants who received chemotherapy and Omegaven had a higher radiological response rate than those who received chemotherapy alone ((overall response: 73% (95% CI 51 to 95) vs 43% (95% CI 25 to 61), p=0.05; partial response 73% (95% CI 51 to 95) vs 39% (95% CI 21 to 57), p=0.03)). . Grade 3/4 toxicity was observed less frequently in those who received Omegaven (thromboembolism, gastrointestinal side-effects). This translated into fewer hospital admissions. There were significant reductions in the concentrations of TNF-α (p<0.0001, 95% CI -0.0121 to -0.0046) & VEGF (p=0.002, 95% CI -0.0161 to -0.0034) following each treatment. Participants with low baseline IL-6 & TNF-α expression had a superior survival. Each infusion of Omegaven resulted in a short lived increase in plasma EPA and DHA. The serial infusions of Omegaven caused a sustained increase in the EPA content of the red cell membrane. DHA, EPA and oxaliplatin had an anti-proliferative effect on the oesophageal cancer cell lines at all concentrations. Omegaven had a more concentration dependent anti-proliferative effect. Reduction in VEGF expression was the most consistently observed cytokine effect. The anti-proliferative effect was associated with reduction in anti-apoptotic protein and an increase in pro-apoptotic protein. Conclusions: Infusion of omega-3 PUFAs resulted in a more favourable chemotherapy side-effect profile and an improved radiological response rate. Treatment resulted in a reduction in serum pro-inflammatory cytokines. Repeated Omegaven infusion resulted in a gradual and sustained uptake of EPA in the red cell membrane. The anti-proliferative effect of omega-3 PUFAs on oesophageal cancer was demonstrated in vitro.