A phase IIb randomized placebo-controlled trial testing the effect of MAG-EPA long-chain omega-3 fatty acid dietary supplement on prostate cancer proliferation

Abstract

Background: High prostate eicosapentaenoic fatty acid (EPA) levels were associated with a significant reduction of upgrading to grade group (GG) ≥ 2 prostate cancer in men under active surveillance. We aimed to evaluate the effect of MAG-EPA long-chain omega-3 fatty acid dietary supplement on prostate cancer proliferation.

Methods: A phase II double-blind randomized placebo-controlled trial was conducted in 130 men diagnosed with GG ≥ 2 prostate cancer and undergoing radical prostatectomy between 2015-2017 (Clinicaltrials.gov: NCT02333435). Participants were randomized to receive 3 g daily of either MAG-EPA (n = 65) or placebo (n = 65) for 7 weeks (range 4-10) prior to radical prostatectomy. The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. Additional planned outcomes at surgery are reported including plasma levels of 27 inflammatory cytokines and fatty acid profiles in circulating red blood cells membranes and prostate tissue.

Results: Cancer proliferation index measured by Ki-67 expression was not statistically different between the intervention (3.10%) and placebo (2.85%) groups (p = 0.64). In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. Secondary outcome was the changes in plasma levels of 27 cytokines, of which only IL-7 was higher in MAG-EPA group compared to placebo (p = 0.026). Men randomized to MAG-EPA prior to surgery had four-fold higher EPA levels in prostate tissue compared to those on placebo.

Conclusions: This MAG-EPA intervention did not affect the primary outcome of prostate cancer proliferation according to nuclear Ki-67 expression. More studies are needed to decipher the effects of long-chain omega-3 fatty acid dietary supplementation in men with prostate cancer.

Fig. 1. CONSORT trial flow diagram.

RCT-EPA study flow chart for the primary endpoint (n = 121). For systemic inflammation (secondary endpoint), all randomized men have been included (n = 130). For adherence to intervention and adverse events, all men who underwent radical prostatectomy have been included (n = 128). MAG-EPA eicosapentaenoic acid monoacylglyceride, FFPE Formalin-fixed paraffin-embedded, TMA Tissue Microarray.

Fig. 2. Effects of MAG-EPA on interleukin-7 (IL-7) cytokine level in enrolled men.

Difference of IL-7 level (pg/mL) after 7 weeks of intervention and study baseline. Baseline: n = 130; RP: n = 126 (2 patients in placebo group did not have blood collection at RP, 2 patients in MAG-EPA dropped out before surgery). Gray bars are the mean ± SEM. P-value from Fligner-Policello test between placebo and MAG-EPA groups. RP radical prostatectomy, MAG monoacylglyceride, EPA eicosapentaenoic acid.

Fig. 3. Effects of MAG-EPA on fatty acid profiles in enrolled men.

a Fatty acid levels of red blood cell (RBC) membranes (% of total fatty acid content). Baseline: n = 121; RP: n = 118 (2 patients did not have blood collection at RP, 1 patient withdrew consent for additional research). Left: relative level of EPA, and Right: ω6:ω3 ratio. b Fatty acid levels in prostate tissue, n = 117 (3 patients did not have tissue collected for research, 1 patient withdrew consent for additional research). Left: relative EPA level (% of fatty acid content), Middle: absolute EPA level (mg of fatty acids per gram of tissue), and Right: ω6:ω3 ratio. c DHA level of RBC membranes (% of total fatty acid content, left) and of prostate tissue at RP (mg of DHA per g of tissue, right). Error bars are ± SEM. ****p < 0.0001, student T-test between placebo and MAG-EPA group, unpaired, two-tailed. ω3 omega-3 fatty acids, ω6 omge-6 fatty acids, RP radical prostatectomy, MAG-EPA eicosapentaenoic acid monoacylglyceride, Q quartile. FA fatty acids.