Abstract
BACKGROUND: Evidence on the benefits of eicosapentaenoic acid (EPA) supplementation in cancer patients remains inconsistent, likely due to heterogeneity in tumor types, stages, treatment modalities, and nutritional strategies. This study aimed to assess the impact of EPA as a standalone supplement on body weight, body mass index (BMI), and muscle mass preservation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) undergoing curative-intent treatment. METHODS: We conducted a double-blind, placebo-controlled randomized trial between December 2015 and September 2018, enrolling 54 patients with advanced SCCHN. Participants received either 2.7 g/day of oral EPA or placebo, alongside standard nutritional support according to European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines. Assessments were performed at baseline (T0), post-induction chemotherapy (T1), and post-treatment (T2), including body composition, nutritional status, functionality, and inflammatory biomarkers. Plasma EPA (% of total fatty acids) was used as a biochemical marker of compliance. RESULTS: Both groups were balanced at baseline (median age 58.9 years; 46.3% malnourished). Neither the intention-to-treat nor per-protocol analyses showed statistically significant differences between groups in weight loss, BMI, or body composition (p > 0.05). In the per-protocol analysis, estimated mean weight loss was –3.81 kg (95% CI: –5.70 to –1.91) in the EPA group, compared to –7.72 kg (95% CI: –12.8 to –6.40) in the placebo group. No differences were observed in nutritional status, energy or protein intake, physical function, or treatment-related toxicity. Complete response rates after oncological treatment were comparable (77.8% EPA vs. 66.7% placebo). Only half of the patients in the EPA group reached an increase in plasma EPA levels consistent with supplementation, and 31.5% discontinued the intervention due to intolerance. CONCLUSIONS: Our study did not demonstrate a clear benefit of EPA supplementation on weight, BMI, or muscle preservation in patients with locally advanced SCCHN receiving curative-intent treatment. While EPA was safe and feasible, the findings do not provide sufficient evidence to support a clinically significant effect. Further research with larger sample sizes and more robust designs is warranted to better understand the potential role of EPA in this population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02715596 (registered on March 22, 2016 at ClinicalTrials.gov). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12937-025-01203-8.