Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid.

Abstract

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).

DESIGN:

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.

TRIAL IDENTIFIER:

ClinicalTrials.gov NCT01070355.

• Authors: Andrew J Cockbain, Milene Volpato, Amanda D Race, Alessandra Munarini, Chiara Fazio, Andrea Belluzzi, Paul M Loadman, Giles J Toogood, Mark A Hull
• Journal: Gut (Gut) Vol. 63 Issue 11 Pg. 1760-8 (Nov 2014) ISSN: 1468-3288 [Electronic] England
• PMID: 24470281 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• Anticarcinogenic Agents
• Platelet Endothelial Cell Adhesion Molecule-1
• Eicosapentaenoic Acid

Topics

• Adult
• Aged
• Aged, 80 and over
• Anticarcinogenic Agents (therapeutic use)
• Chromatography, Liquid
• Colorectal Neoplasms (drug therapy, pathology)
• Double-Blind Method
• Eicosapentaenoic Acid (metabolism, pharmacology)
• Female
• Humans
• Immunohistochemistry
• Liver Neoplasms (blood supply, mortality, secondary, surgery)
• Male
• Middle Aged
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Tandem Mass Spectrometry