Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia:A randomised double blind trial

Aim: N-3 fatty acids, especially eicosapentaenoic acid (EPA), may possess anticachectic properties. This trial compared a protein and energy dense supplement enriched with n-3 fatty acids and antioxidants (experimental: E) with an isocaloric isonitrogenous control supplement (C) for their effects on weight, lean body mass (LBM), dietary intake, and quality of life in cachectic patients with advanced pancreatic cancer. Methods: A total of 200 patients (95 E; 105 C) were randomised to consume two cans/day of the E or C supplement (480 ml, 620 kcal, 32 g protein ± 2.2 g EPA) for eight weeks in a multicentre, randomised, double blind trial. Results: At enrolment, patients' mean rate of weight loss was 3.3 kg/month. Intake of the supplements (E or C) was below the recommended dose (2 cans/day) and averaged 1.4 cans/day. Over eight weeks, patients in both groups stopped losing weight (Δweight E: -0.25 kg/month versus C: -0.37 kg/month; p=0.74) and LBM (ΔLBM E: +0.27 kg/month versus C: +0.12 kg/month; p=0.88) to an equal degree (change from baseline E and C, p<0.001). In view of evident non-compliance in both E and C groups, correlation analyses were undertaken to examine for potential dose-response relationships. E patients demonstrated significant correlations between their supplement intake and weight gain (r=0.50, p<0.001) and increase in LBM (r=0.33, p=0.036). Such correlations were not statistically significant in C patients. The relationship of supplement intake with change in LBM was significantly different between E and C patients (p=0.043). Increased plasma EPA levels in the E group were associated with weight and LBM gain (r=0.50, p<0.001; r=0.51, p=0.001). Weight gain was associated with improved quality of life (p<0.01) only in the E group. Conclusion: Intention to treat group comparisons indicated that at the mean dose taken, enrichment with n-3 fatty acids did not provide a therapeutic advantage and that both supplements were equally effective in arresting weight loss. Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved quality of life. Further trials are required to examine the potential role of n-3 enriched supplements in the treatment of cancer cachexia.

The role of eicoapentaenoic acid in cancer cahexia

Cachexia is a wasting syndrome often associated with malignancy, characterised by alterations in host metabolism and significant catabolism of host adipose tissue and skeletal muscle. The MAC16 murine adenocarcinoma is profoundly cachexigenic, inducing host weight-loss at relatively small tumour burden without the induction of anorexia. A 4DkDa factor capable of inducing lipolysis in vitro via an activation of adenylate cyclase (AC) has been isolated from the MAC16 tumour, and the urine of cachectic cancer patients, using a series of ion exchange and gel exclusion chromatography procedures. This lipid-mobilising factor (LMF) has been demonstrated to stimulate lipolysis in adipocytes dose-dependently via a signal transduction pathway involving, possibly, β3-adrenoceptors. Oral administration of the n-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) attenuated the progression of cachexia, but not the production of LMF, in MAC16 tumour-bearing mice, and was significantly incorporated into plasma phospholipids, skeletal muscle and adipose tissue. EPA supplemented cancer patients also demonstrated significantly increased plasma EPA concentrations. Decreased plasma membrane AC activity in response to LMF was observed in adipocytes isolated from mice receiving EPA. Incubation in vitro of adipocytes, or plasma membranes, with PUFAs significantly altered membrane fatty acid composition and attenuated the induction of both lipolysis, and AC activity, by LMF. The inhibitory actions of EPA, but not docosahexaenoic acid, are probably the consequence of an interaction with guanine nucleotide binding proteins (G-proteins). Progression of the cachectic state induced an up-regulation of adipocyte membrane expression of stimulatory G-proteins, allied with a concomitant down-regulation of inhibitory G-proteins, thus facilitating the catabolic actions of LMF, implying some tumour-mediated effect. A reversal of such alterations was observed upon oral administration of EPA, suggesting that the primary mechanism of action of this fatty acid is an inhibition of the end organ effects of LMF.

The 'cancer cachectic factor'

The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month-1. They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month-1. Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E214k), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.