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.

Inclusion Criteria:

• Participants diagnosed with unresectable HCC, candidates for systemic treatment with Sorafenib or similar agents.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Life expectancy > 8 weeks.
• Not eligible for curative treatment (surgical resection/ablative therapy/liver transplantation).
• Not having a history of previous or concomitant malignancy except when a disease-free interval > 5 years had been documented.
• Not receiving any other systemic antitumor agents (docetaxel, doxorubicin, irinotecan).

Exclusion Criteria:

• Allergy to omega-3 acid or fish-derived products.
• Psychological or medical conditions that can interfere with study participation or the ability to provide informed consent.
• Drug abuse (except for alcohol).
• Any experimental therapy within 30 days prior to study entry.
• Recurrent epistaxis

The statistician responsible for analysing the data was also blinded. Only the nurse in charge of recruiting participants and releasing the products was non-blinded.