Eicosapentaenoic Acid: The Answers Are Not All In

Abstract

TO THE EDITOR: Jatoi et al should be congratulated in successfully performing a study comparing eicosapentaenoic acid (EPA) supplements versus megestrol acidate versus both for patients with cancer-associated wasting. The trial involved 421 patients who received EPA supplements twice a day (placebo v megestrol 600 mg per day or 2-gram EPA-containing supplements v both). The EPA arm, either alone or in combination, was found not to improve appetite or weight compared with megestrol alone. However, there are several questions surrounding the design of the trial. Weight gain may not be the best outcome to measure for either anorexia or cachexia; rather, lean body mass as measured by bioelectric impedance and functional status are more relevant outcomes. Secondly, measurement of drug absorption by plasma, red cell, or leukocyte levels of EPA would have improved the reliability of this study. It is known that a significant number of patients will take EPA off study and a certain subset of patients will not absorb EPA. Compliance and absorption factors would have influenced the results of this study. In a study by Fearon et al, a significant portion of patients had taken undisclosed EPA supplements and one fourth of patients randomly assigned to EPA did not have increases in plasma EPA. This study demonstrated significant weight stabilization and increased lean body mass correlated with plasma EPA levels. Abnormal digestive function and malabsorption are commonly seen in cancer-associated anorexia and cachexia, which influences EPA bioavailabilty. Jatoi et al evaluated response at 4 weeks. However, the benefits of EPA found by Fearon et al occurred at 8 weeks. Previous dose finding studies have demonstrated that patients tolerate higher doses of EPA when given alone. Burns et al performed a dose-finding study through the Cancer and Leukemia Group B (study 9473) and found that a dose of 0.3 g/kg per day of EPA plus decosahexaenoic acid was the maximum tolerable dose. Barber and Fearon found patients could tolerate doses as high as 18 grams of EPA per day (range, 9 to 27 grams). It may be premature to end the ongoing interest in omega-3 fatty acids. A better trial design perhaps would include a high-dose omega-3 fatty acid without nutritional supplement megestrol acetate arm to the study. Drug tolerance, weight, functional status, bioelectric impedance for lean body mass, and plasma or red cell EPA levels would help clarify potential confounding factors. This would require testing omega-3 fatty acid without nutritional supplements because it appears that EPA supplements are not well tolerated by patients and thus have a dose ceiling. It would be important to test maximum tolerable doses as demonstrated by the Cancer and Leukemia Group B study before declaring that EPA does not improve weight, appetite, or lean body mass and is not better than, nor adds to, megestrol acetate benefits.