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Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid
  1. Andrew J Cockbain1,2,
  2. Milene Volpato1,
  3. Amanda D Race3,
  4. Alessandra Munarini4,
  5. Chiara Fazio4,
  6. Andrea Belluzzi4,
  7. Paul M Loadman3,
  8. Giles J Toogood2,
  9. Mark A Hull1
  1. 1Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK
  2. 2Department of Hepatobiliary Surgery, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UK
  3. 3Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
  4. 4Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy
  1. Correspondence to Prof Mark A Hull, Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds LS9 7TF, UK; M.A.Hull{at}leeds.ac.uk

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.

  • Angiogenesis
  • Colorectal Cancer
  • Fatty Acid Supplementation
  • Lipid Mediators
  • Liver Metastases

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