Andrew J Cockbain1, Milene Volpato2, Amanda D Race3, Alessandra Munarini4, Chiara Fazio4, Andrea Belluzzi4, Paul M Loadman3, Giles J Toogood5, Mark A Hull2. 1. 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. 2. Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, UK. 3. Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, Bradford, UK. 4. Department of Gastroenterology, Sant'Orsola Malpighi Hospital, University of Bologna, Bologna, Italy. 5. Department of Hepatobiliary Surgery, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, 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. 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.
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. 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.
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