A pilot study investigating specific immune regulatory cells and microRNA in patients with advanced Pancreatic Adenocarcinoma treated with intravenous omega-3 fish oil infusion and Gemcitabine.

Introduction: Pancreatic adenocarcinoma (PAC) is a devastating disease and the majority of patients have advanced pancreatic cancer (APC) and incurable disease at the time of presentation, and die within a few months. The overall survival of pancreatic cancer has not changed significantly in the past forty years with multiple trials demonstrating disappointing results. PAC features a profound inflammatory response and immune dysregulation, both systemically and locally that contributes to tumour progression. Immune modulatory cells particularly myeloid derived suppressor cells (MDSCs), T regulator cells (Tregs), endothelial progenitor cells (EPCs) in addition to micro RNAs are important mediators in PAC. Omega 3 fatty acids (ω-3FAs) have been shown to have anti-inflammatory and anti-cancer properties. There is good evidence demonstrating the benefit of ω-3FAs in PAC including growth inhibition, induction of apoptosis, inhibition of proliferation and invasion, augmentation of the effect of gemcitabine, reduced pro inflammatory mediators and growth factors and an improved quality of life. Methods: This was a single centre cohort study investigating intravenous ω-3FAs and gemcitabine chemotherapy versus gemcitabine therapy only in patients with APC. The primary outcome measures were the levels of specific immune modulatory cells and micro RNAs in trial versus control patients. The secondary outcome measure was the correlation of demonstrated changes with progression free and overall survival. Results: Eighteen trial and nine control patients were recruited. There was significant benefit in progression free survival in trial compared to control patients (P=0.0003). Median survival in trial patients was 5.65 months compared to 1.8 months in control patients. There was no significant benefit in overall survival in trial compared to control patients (P=0.13). Medial survival in trial patients was 7 months compared to 2.9 months in control patients. There was a significant benefit in progression free survival in trial compared to control patients (P=0.0003). MDSCs were significantly decreased in trial patients (P=0.0001) but not control patients. Tregs were significantly increased in control patients (P=0.005) but not in trial patients. Three EPC phenotypes (CD45-, CD31+, CD133+ (P=0.04), CD45-, CD31+, CD34+ (P=0.001), and CD45-, CD34+, CD31+ and CD133+(P=0.006) were significantly increased in the trial patients but not control patients. In addition EPCs (CD45-, CD31+, CD34+ (P=0.0001) and CD45-, CD34+, CD31+ and CD133+ (P=0.0001)) were significantly increased compared to controls on comparison regression analysis over treatment. There was no significant change seen in any micro RNA measured in either cohort. Conclusion: Administration of ω-3FAs with gemcitabine chemotherapy in APC results in a significant decrease of MDSCs and stability of Tregs. This may be secondary to the reduction of pro inflammatory mediators. A phase three randomised trial is indicated to further validate these results.