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Existing guidelines on nutrition support in patients with cancer cachexia state limited evidence for the beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on clinical outcome. In order to report on the latest evidence for n-3 PUFAs in cancer cachexia, we conducted a systematic literature review of randomized controlled trials (RCTs), comparing the effects on clinical outcome parameters of oral or enteral supplementation of n-3 PUFAs in cancer patients receiving chemotherapy, radiotherapy, surgery or palliative care. Materials and methods In PubMed, EMBASE and the Cochrane Library, search terms on cancer, n-3 PUFAs and clinical outcome parameters (nutritional status, morbidity, mortality and quality of life) were entered on 1 April 2013, using limits for adults, humans and English language. The quality and evidence of the retrieved publications were appraised by an expert team of Australian and Dutch dieticians and nutritionists, using the ADA grading system. Fifteen RCTs were retrieved. Results Nine RCTs were of positive quality, five of neutral quality and one of negative quality and were performed in patients with various types of cancer. Fair evidence shows that supplementation of n-3 PUFAs appears to be safe and may improve the quality of life and physical activity in patients with cancer. However, supplementation of n-3 PUFAs does not improve energy or protein intake, appetite or survival and does not reduce postoperative complications. The evidence for the effect on body weight, fatfree mass and performance status remains inconclusive. Conclusion Supplementation of n-3 PUFAs may have some positive effects in patients with cancer. Introduction Cancer cachexia, a complex metabolic syndrome associated with underlying illness, characterized by an increased inflammatory status and loss of muscle mass with or without loss of fat mass, is highly prevalent among patients with cancer1–7. This syndrome is a result of complex alterations in carbohydrate, lipid and protein metabolism8,9, caused by inflammatory mediators such as cytokines and tumour-derived catabolic drivers10. Proteolysis-inducing factor (PIF) is produced by the tumour and induces protein catabolism11. As a result of the acute-phase response, the liver shows an increased protein turnover for the production of inflammatory mediators, using muscle mass to release amino acids9,10. Changes in lipid metabolism in cancer include a reduction of lipogenesis, with unchanged whole-body lipolysis and mobilization of fatty acids from fat tissue. Alterations in glucose metabolism are reflected by glucose intolerance and insulin resistance8,9,11. Thus far, conventional nutritional support has been limited in its ability to stabilize body weight and maintain fat-free mass in patients with cachexia. Pharmaceutical interventions sometimes improved appetite, body weight and quality of life, but weight gain mostly consisted of fat mass12–15. n-3 Polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA), seem to be promising agents to treat cancer cachexia. A dose of around 2 g of EPA per day (alone or combined with docosahexaenoic acid, DHA) appears to decrease the production of proinflammatory cytokines16,17 and PIF and is associated with stabilization of body weight and probably fat-free mass13,18. This has been shown in animal studies and in nonrandomized human trials in pancreatic cancer patients19,20. However, randomized controlled trials (RCTs) show contradictory results21–26. This may be due to issues related to study limitations, such as the disease severity, confounding factors and nonadherence with n-3 PUFA supplements. Also, study designs and outcome parameters differ in terms of supplementation dosage, * Corresponding author Email: b.vandermeij@vumc.nl 1 Department of Nutrition and Dietetics, Internal Medicine, VU University Medical Center Amsterdam, the Netherlands 2 Centre for Dietetics Research, School of Human Movement Studies, University of Queensland, Brisbane, Australia 3 Department of Nutrition and Dietetics, Royal Brisbane & Women’s Hospital, Brisbane, Australia 4 Department of Nutrition and Dietetic Services, Princess Alexandra Hospital, Brisbane, Australia 5 Department of Surgery, VU University Medical Center Amsterdam, the Netherlands

The effects of supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic review