Nutritional therapy for cancer cachexia

The process of inflammation has a paradoxical effect. This is mostly due to the metabolic responses triggered by the release of the three proinflammatory cytokines, interleukin 1β (IL-1β), tumour necrosis factor α (TNF-α), and interleukin 6 (IL-6). As an integral part of the body’s response to infection and injury, these mediators release substrate, from host tissues, to support T and B lymphocyte activity, create a hostile environment for invading pathogens, via a raised body temperature and oxidant production, and initiate downregulation of the process once invasion has been defeated.¹ All of these metabolic effects come at considerable cost to the host, as witnessed by the extensive tissue depletion, anorexia, and anaemia seen in severely infected and injured patients.² However, the cost is of great biological value if recovery from infection and injury are achieved. The inflammatory process contains elements which inherently upregulate the response. Oxidants will increase proinflammatory cytokine production by activating nuclear factor κB (NFκB). A wide range of genes associated with the inflammatory process have NFκB response elements in their structure. These include genes for proinflammatory cytokines and adhesion molecules.¹

Tumour cells may initiate the inflammatory response as effectively as invading pathogens. However, while the inflammatory process may be effective in dealing with single malignant cells, once cancer is established the inflammatory process becomes a cause of the patient’s demise, rather than a means of destroying the tumour. In addition to stimulating the cytokine mediated and hormonal aspects of the inflammatory response, tumour specific products also add to the level of inflammatory stress in the patient.

The tissue depletion that occurs during inflammation is different qualitatively to that seen during starvation and forms part of the syndrome of cancer cachexia. While starvation results primarily in fat loss, with secondary loss in muscle and visceral protein mass, cachexia results almost equally in fat and protein loss. Losses of up to 75% of body stores can occur.³ Furthermore visceral protein mass is relatively preserved. While the desire to eat is strong in starvation, in cachexia severe anorexia occurs. The precise mechanism for the appetite loss in cachexia is unclear. However, proinflammatory cytokines, raised serotoninergic activity in the hypothalamus, and leptin have been implicated.³ Chemotherapy unfortunately imposes oxidant stress on the patient, thereby providing a further boost to the inflammatory process.⁴

A number of approaches have been taken to improve nutritional status in cancer patients. Attempts to raise energy and protein intake by counselling have been successful, but despite improvements over a three month period, no improvement in weight, anthropometric measures, response rate, survival, or quality of life have been demonstrated.^5,6 Disappointing results were also obtained when nutrient intake was increased by the parenteral route. The deleterious effects of parenteral nutrition (for example, increased infective complications) led the American College of Physicians, in a position paper, to conclude “parenteral nutritional support was associated with net harm, and no conditions could be defined in which such treatment appeared to be of benefit”.³

While the precise mechanism(s) of cachexia is unclear it is self evident that the inflammatory process is exceedingly strong in weight losing cancer patients. Thus the patient’s nutrient intake is dissipated by the hypermetabolism induced by the inflammatory state. Thus nutritional therapy, to improve survival in cancer patients, must make the inflammatory process its prime target.⁷ Among nutrients that may be effective in this respect are n-3 or omega-3, polyunsaturated fatty acids (n-3PUFA) and antioxidants. The former have been shown to be particularly effective anti-inflammatory agents in rheumatoid arthritis.⁸ Moreover, the effectiveness of n-3 PUFA in modulating the inflammatory process has been demonstrated in a diverse range of clinical situations ranging from surgery⁹ to adult respiratory distress syndrome.¹⁰ Fearon’s group have pioneered the use of fish oil in the treatment of pancreatic cancer. The results of a number of small trials have been reported in which the oil, or the main n-3 PUFA that it contains (eicosapentaenoic acid (EPA)), has been demonstrated to reduce the high rates of weight loss in such patients.^11,12

As a logical extension to this work, an international, multicentre, double blind, randomised trial¹³ is reported in this issue of Gut [see pages 1479–86]. The study examined the effects of an n-3 PUFA and antioxidant enriched oral supplement on loss of weight and lean tissue loss in pancreatic cancer patients. In the study, 95 patients received the enriched supplement and 105 received the control diet. The former diet contained an amount of n-3 PUFA equivalent to 6 g fish oil per day, and vitamin C and E at over four and eight times the recommended amount for healthy subjects, respectively. This level of antioxidant vitamin supplementation was similar to that used by Pacht and colleagues¹⁰ who successfully used a combination of n-3 PUFA and antioxidant, in an enteral formulation, to reducing severe lung inflammation in adult respiratory distress syndrome patients.

The large number of patients in the multicentre study¹³ permitted subgroup analysis to determine whether the dose of supplement exerted an effect. Some interesting insights were achieved by this strategy. There was a linear relationship between change in lean body weight and enrichment of plasma phospholipids with EPA, indicating that the greater the intake of n-3 PUFA, the greater the protein accretion in the patients. Furthermore, when body weight change was related to dietary protein intake, only those patients consuming the n-3 PUFA enriched formulation showed a positive relationship. In other words, a synergistic effect was obtained by consumption of protein in the presence of n-3 PUFA. Disappointingly, the authors do not mention any indices of inflammation (for example, plasma IL-6, C reactive protein) in their paper. It is not therefore possible to judge whether a concomitant reduction in inflammatory stress occurred during the time that n-3 PUFA was facilitating accretion of lean body mass.

In the clinical setting, n-3 PUFA are often given in immunonutrient mixtures (as in the present study¹³) and thus it is difficult to determine whether the n-3 PUFA per se are achieving the observed effect or whether there is some synergistic interaction within the body between the components of the clinical feed. It is likely that oxidant/antioxidant status had a part to play in the response observed in the multicentre study.¹³ Experimental studies have shown that antioxidants can decrease NFkκB activation and reduce muscle protein loss in animal cachexia models and during cell culture.^14–16 Indeed, in a randomised double blind study on weight losing acquired immunodeficiency syndrome patients, an antioxidant-glutamine supplement increased body cell mass.¹⁷ It should be noted that glutamine, by acting as a source of glutamate, may provide one of the three amino acids (glycine, cysteine, glutamate) required for the synthesis of the key antioxidant glutathioine (GSH). Denno et al noted, in a rat model, that glutamine administered parenterally enhanced plasma and hepatic GSH concentrations.¹⁸ Cysteine acts as the rate limiting amino acid in GSH synthesis and studies in rat models show that, during low protein intakes, addition of the amino acid restores GSH to normal levels following injection with TNF-α or endotoxin.¹⁹ In the multicentre study,¹³ accretion of lean body mass in patients receiving fish oil was positively related to protein intake. While the amino acid composition of protein in the supplement is not quoted in the paper, it is feasible that it may have indirectly improved antioxidant status by providing the three necessary amino acids for GSH synthesis, thereby indirectly reducing inflammatory stress in the patients.

While there are a number of unanswered questions posed by the study it does illustrate that in cancers where high inflammatory stress is usual, protein rich supplements containing n-3 PUFA and high levels of antioxidant vitamins, can reverse severe weight loss. It remains to be seen whether this effect is achieved by an anti-inflammatory mechanism and whether cancers in which cachexia is not as severe as in pancreatic cancer will respond favourably to similar nutritional therapy.