Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid.
BACKGROUND
Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM).


METHODS
We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end-point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS).


RESULTS
The median (range) duration of EPA-FFA treatment was 30 (12-65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in 'EPA-naïve' individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar.


CONCLUSIONS
EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted.
ClinicalTrials.gov NCT01070355.
Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK Department of Hepatobiliary Surgery, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK.
Andrew J
AJ
Cockbain
Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK.
Milene
M
Volpato
Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, Bradford, UK.
Amanda D
AD
Race
Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
Alessandra
A
Munarini
Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
Chiara
C
Fazio
Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
Andrea
A
Belluzzi
Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, Bradford, UK.
Paul M
PM
Loadman
Department of Hepatobiliary Surgery, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK.
Giles J
GJ
Toogood
Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK.
Mark A
MA
Hull
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004311:Double-Blind Method; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000098:blood supply / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D016588:Anticarcinogenic Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015118:Eicosapentaenoic Acid
Angiogenesis; Colorectal Cancer; Fatty Acid Supplementation; Lipid Mediators; Liver Metastases