Dietary intervention with eicosapentaenoic acid combined with chemotherapy may shift inflammatory mediators toward resolution in non-resectable hepatocarcinoma and help to preserve muscle mass.
Cancer-associated cachexia is a debilitating and potentially life-threatening syndrome characterized by progressive loss of body weight, skeletal muscle, and adipose tissue, leading to functional impairment and reduced response to oncologic therapy. It is driven in part by systemic inflammation and increased pro-inflammatory cytokines, and it cannot always be reversed with conventional support. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid (PUFA), has anti-inflammatory properties and is rapidly incorporated into cell membranes, modulating lipid mediator pathways. EPA supplementation may help to attenuate systemic inflammation, alleviate cachexia symptoms, and promote the production of specialized pro-resolving mediators. A daily dose of 3 grams appears sufficient to achieve maximal incorporation into cell membranes without significant adverse events. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with most patients diagnosed at advanced stages. Cachexia is common in advanced HCC and contributes to functional decline, increased treatment toxicity, and poorer outcomes. Preclinical studies suggest that omega-3 PUFAs may also exert anti-tumor effects through modulation of COX-2 and Wnt/beta-catenin signaling pathways. For these reasons, in this proposal, the investigators aim to determine wheter supplementation with EPA in combination with chemotherapy will modify the blood profile of pro-inflammatory and pro-resolving mediators, promoting the resolution of inflammation associated with HCC, and, in turn, mitigate muscle mass loss during oncologic treatment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
18
1 sachet/day of 20 ml containing 3g EPA during 12 weeks
1 sachet/day of 20 ml of placebo during 12 weeks
Hospital Clínico Universitario Lozano Blesa. IIS Aragón
Zaragoza, Zaragoza, Spain
Effect of EPA supplementation on muscle mass
Muscle mass is assessed by calculating the skeletal muscle index using computed tomography, based on a single axial slice at the L3 level. The SliceOmatic software (TomoVision) is used for the calculations. Sarcopenia is evaluated using two criteria: Carey reference values for end-stage liver disease patients awaiting transplantation, and Martin reference values for oncology patients.
Time frame: At baseline, and at 12 weeks (study completion)
Evolution of nutritional status.
Nutritional status is assessed using the validated Patient-Generated Subjective Global Assessment tool (PG-SGA, Bauer 2002) that classify patients as well nourished (A), moderately malnourished or at risk of malnutrition (B), or severely malnourished (C).
Time frame: At baseline, at 6 weeks, and at 12 weeks (study completion)
Effect of EPA supplementation on quality of life assessed using the EORTC-QLQ-30.
Quality of life is assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30)
Time frame: At baseline, at 6 weeks, and at 12 weeks (study completion)
Change in the quality of life assessed using the EORTC-QLQ-HCC18.
Quality of life is assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18-question module (QLQ-HCC18).
Time frame: At baseline, at 6 weeks, and at 12 weeks (study completion)
Effect of EPA supplementation on plasma and serum profiles of pro-inflammatory and pro-resolving lipid mediators.
Plasma and serum concentrations of pro-inflammatory and pro-resolving lipid mediators derived from polyunsaturated fatty acids are determined using targeted LC-MS/MS.
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Time frame: At baseline, and at 12 weeks (study completion)
Change in C-reactive protein (CRP) concentration upon supplementation.
The C-reactive protein is measured using an immunoturbidimetric assay following the standard laboratory methods in the Hospital Clínico Universitario Lozano Blesa.
Time frame: At baseline, and at 12 weeks (study completion)
Change in interleukin 6 upon supplementation.
Plasma IL-6 levels are determined by enzyme-linked immunosorbent assay.
Time frame: At baseline, and at 12 weeks (study completion)
Change in interleukin 8 upon supplementation.
Plasma Il-8 is quantified using the Human XL Cytokine Luminex® Kit Performance Assay (R\&D Systems).
Time frame: At baseline, and at 12 weeks (study completion)
Change in interferon gamma (IFNγ) upon supplementation.
Plasma IFNγ is quantified using the Human XL Cytokine Luminex® Kit Performance Assay (R\&D Systems).
Time frame: At baseline, and at 12 weeks (study completion)
Change in the neutrophil-to-lymphocyte ratio (NLR) upon supplementation.
NLR is calculated by dividing the absolute neutrophil count by the absolute lymphocyte count obtained from peripheral blood samples. Both values were derived from the complete blood count (CBC) analysis.
Time frame: At baseline, and at 12 weeks (study completion)