CACHEXIA IN CANCER PATIENTS Michael J. Tisdale Preface Cachexia — the massive (up to 80%) loss of both adipose tissue and skeletal muscle mass — is a significant factor in the poor performance status and high mortality rate of cancer patients. Although this metabolic defect has been known since cancer was first studied, it is only recently that major advances have been made in the identification of catabolic factors that act to destroy host tissues during the cachectic process. Although anorexia is frequently present, depression of food intake alone seems not to be responsible for the wasting of body tissues, as nutritional supplementation or pharmacological manipulation of appetite is unable to reverse the catabolic process — particularly with respect to skeletal muscle. However, recent clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise. Summary Patients with cancer cachexia show a progressive loss of body weight, which is mainly due to loss of fat and skeletal muscle. Survival of cancer patients is directly related to the total weight loss and also the rate of weight loss. Although anorexia occurs in cancer patients, the reduction in food intake alone is unable to explain the metabolic changes that are seen in cachexia. Nutritional supplementation and pharmacological manipulation of appetite are unable to restore loss of lean body mass. Resting energy expenditure is increased in patients with lung and pancreatic cancer, but not in gastric and colorectal cancer. Increased energy expenditure might be related to the upregulation of uncoupling proteins (UCPs) — particularly UCP3 in skeletal muscle. Loss of adipose tissue arises predominantly from an increase in lipolysis. Lipolysis is induced by a tumour product, lipid-mobilizing factor (LMF), which acts through a 3-adrenoceptor. Loss of skeletal muscle arises from a fall in protein synthesis and an increase in protein degradation. The decreased protein synthesis could arise from the inactivity of the patient, coupled with a reduction in the supply or balance of amino acids due to acute-phase protein production. Increased protein degradation seems to be mainly due to an increased expression of the components of the ubiquitin-proteasome proteolytic pathway in skeletal muscle. Tissue catabolism in cachexia is partially mediated by cytokines such as tumour necrosis factor- (TNF-) or interleukin (IL)-1 and IL-6. Tumour catabolic products such as LMF and proteolysis-inducing factor (PIF) directly stimulate tissue breakdown and are also correlated with human cancer cachexia. Therapy has been mainly targeted at TNF- and PIF. Agents that are directed solely at TNF- have not shown clinical activity so far. Anticatabolic agents, such as eicosapentaenoic acid (EPA), effectively downregulate the increased expression of the ubiquitin-proteasome pathway in skeletal muscle and are clinically effective in restoring loss of lean body mass in cachectic cancer patients, especially in combination with a protein and energy-dense supplement. Future therapy will consist of a combination of anabolic and anticatabolic agents. Nature Reviews Cancer 2, 862 -871 (2002); Am J Clin Nutr, 6/06 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.