Eicosapentaenoic Acid Enriched Enteral Nutrition Improves Lean Body Mass in Esophageal, Head and Neck Cancer Patients

OBJECTIVE: Cachexia is a nutrient deficient condition affecting millions of cancer patients. Cancers of the upper gastrointestinal tract, head and neck are often the most severely affected. Currently, there is no established therapy for cachexia, although several potential anti-cachectic agents are being explored. A meta-analysis was conducted to review the effect of eicosapentaenoic acid (EPA) enriched enteral nutrition on lean body mass (LBM) in esophageal, head and neck cancer patients at risk for progression of cachexia. METHODS: An evidence based review was conducted beginning with a Pubmed database literature search using the terms ‘EPA esophageal cancer’, ‘Eicosapentaenoic acid esophageal cachexia’, ‘Eicosapentaenoic acid esophageal’, ‘Eicosapentaenoic acid cachexia head and neck cancer’, and ‘EPA cachexia head and neck cancer’ for human clinical trials. The results were reviewed for relevance and the data from original research was abstracted for amount of EPA enriched formula supplemented, EPA intake, method of intake, LBM measurements, study design, intervention duration, and population characteristics. RESULTS: Three trials were identified that met the criteria and were reviewed. EPA supplementation in enteral nutrition was provided at concentrations ranging between 1.6 g/day and 2.2 g/day for a time span ranging between 3 weeks and 14 weeks. Two randomized clinical trials showed maintenance of > 1.5 kg LBM relative to the control group while a single arm trial showed a gain of 3.2 kg LBM in patients. Differences in results could be attributed to variability in the degree of cachexia, the contents of each enteral nutrition formula, duration of supplementation, and cancer treatments that subjects in each trial were undergoing. CONCLUSIONS: All three trials showed a trend in EPA enriched enteral nutrition improving the loss of LBM in esophageal, head and neck cancer patients at risk for cachexia progression. This type of formula should therefore be considered in treatment of these types of cancers and possibly, in the treatment of other seriously ill patients with cachexia. Introduction Cancer cachexia affects approximately 1.5 million patients in the United States and represents 20-30% of cancer patient deaths. Among these patients, the most severely affected are those with upper gastrointestinal tract, head and neck, or prostate cancer. In these patients, the majority of the weight lost is lean body mass (LBM). Depending on the location of the tumor and its effect on food intake functions, cachexia may progress faster in some patients than in others. Approximately 50% of head and neck cancer patients have some degree of cachexia at death with 20% dying directly from it. Metabolic changes seen in cancer cachexia cannot be attributed to starvation or reduced food intake alone. The onset of cachexia has been associated with inflammatory cytokine release by some tumors. Biochemical manifestations of cachexia include anemia, hypoalbuminemia, hypoglycemia, hyperlipidemia, and glucose intolerance. Physical manifestations of cachexia include anorexia, skeletal muscle atrophy, accelerated fat loss, and anergy. Cachectic patients may also experience physical, psychological, and social drawbacks. The severe consequences of cachexia inspire a search for anti-cachectic agents. Among these potential agents is eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid (PUFA) that can replace arachidonic acid (ω-6 PUFA) in the cell membrane. Like arachidonic acid, EPA is a substrate for synthesis of inflammatory agents such as prostaglandins and leukotrienes; however, those synthesized from EPA are less potent than those synthesized from arachidonic acid. EPA can therefore mitigate inflammatory responses. Because of cachexia’s association with inflammation, there is interest in examining whether or not EPA enriched nutrition formula can counteract the progression of cachexia. This paper reviews clinical trials on EPA enriched nutritional supplementation in esophageal, head and neck cancer patients who have or are at risk for cachexia progression. Methods To ensure coverage of all relevant trials, the following words were used in independent searches of the Pubmed database: ‘EPA esophageal cancer’, ‘Eicosapentaenoic acid esophageal cachexia’, ‘Eicosapentaenoic acid esophageal’, ‘Eicosapentaenoic acid cachexia head and neck cancer’, and ‘EPA cachexia head and neck cancer’. ‘EPA esophageal cancer’ yielded 11 studies, 9 of which were excluded due to a different end point measurement (2), the in vitro nature of the study (2), or studies that did not focus on EPA and cancer patients (5). ‘Eicosapentaenoic acid esophageal cachexia’ yielded no studies. ‘Eicosapentaenoic acid esophageal’ yielded 9 results, 6 of which overlapped with the first search and 3 of which were excluded because the study did not focus on EPA and had a different end point measurement ‘Eicosapentaenoic acid cachexia head and neck cancer’ yielded 2 studies, one of which was not a clinical trial. ‘EPA cachexia head and neck cancer’ yielded 2 studies, one of which was not focused on EPA and another of which overlapped with the prior search. The clinical trials reviewed in this paper were primary studies where changes in LBM were measured as a reflection of improvement in the cachectic condition of patients. Data extracted from these studies included amount of EPA enriched formula intake, method of intake, lean body mass measurements, study design, and population. Results The literature search identified three clinical trials that compared changes in LBM before and after EPA enriched formula supplementation in head and neck or esophageal cancer patients. In these studies, most patients had some degree of cachexia and were undergoing surgery or chemoradiotherapy, both of which exacerbate the nutritional status of patients. Ryan et al. and Weed et al. showed a statistically significant improvement in LBM in patients receiving the EPA enriched formula while Fietkau et al. showed a similar trend. Ryan et al. conducted a randomized controlled trial that examined the effects of enteral nutrition enriched with EPA in the perioperative period on esophageal cancer patients undergoing esophagectomies. 53 patients with resectable esophageal cancer were divided into a control group (n=25) or an experimental group (n=28). Prior to supplementation, 33% of patients in the control arm and 43% of patients in the experimental arm showed weight loss classified as significant or severe. Nutritional supplementation began 5 days pre-op with the experimental group receiving EPA enriched (2.2 g EPA/day) enteral feed and the control group receiving an iso-caloric and iso-nitrogenous standard nutritional feed. Supplementation lasted until 21 days post-op and was administered orally or via a feeding pump. At the end of 21 days post-op, the control group showed a statistically significant loss of -1.9 kg in LBM (p=0.03) while the EPA group showed no significant change in LBM (p=0.8). A significantly greater number of people in the control group lost >5% body weight compared to the experimental group (p=0.03). Unlike the randomized controlled trial conducted by Ryan et al., Weed et al. conducted a single arm trial investigating the effects of ‘protein and energy dense supplementation containing EPA’ on head and neck cancer patients undergoing surgery with curative intent.