Therapy Insight: Cancer Anorexia−Cachexia Syndrome-When All You Can Eat Is Yourself Alessandro Laviano; Michael M Meguid; Akio Inui; Maurizio Muscaritoli; Filippo Rossi-Fanelli Summary Tumor growth is associated with profound metabolic and neurochemical alterations, which can lead to the onset of anorexia−cachexia syndrome. Anorexia is defined as the loss of the desire to eat, while cachexia results from progressive wasting of skeletal muscle mass—and to a lesser extent adipose tissue—occurring even before weight loss becomes apparent. Cancer anorexia−cachexia syndrome is highly prevalent among cancer patients, has a large impact on morbidity and mortality, and impinges on patient quality of life. However, its clinical relevance is frequently overlooked, and treatments are usually only attempted during advanced stages of the disease. The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumor-derived factors have a significant role, thereby representing a suitable therapeutic target. Energy expenditure in anorexia is frequently increased while energy intake is decreased, which further exacerbates the progressive deterioration of nutritional status. The optimal therapeutic approach to anorectic−cachectic cancer patients should be based on both changes in dietary habits, achieved via nutritional counseling; and drug therapy, aimed at interfering with cytokine expression or activity. Our improved understanding of the influence a tumor has on the host's metabolism is advancing new therapeutic approaches, which are likely to result in better preservation of nutritional status if started concurrently with specific antineoplastic treatment. Omega-3 Fatty Acids The omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to suppress production of proinflammatory cytokines and arachidonic acid-derived mediators.[37] These in vitro effects have been exploited in the treatment of cancer patients, and it has been shown that adequate and prolonged EPA supplementation may lead to increased body weight and gain of lean body mass in cachectic cancer patients, probably due to suppression of either cytokine production or proinflammatory mediators, although this remains untested.[38] In addition, the use of an EPA-enriched, energy-dense oral supplement appears to increase physical activity, which may reflect improved quality of life.[39] Moreover, a comparison of the effects of megestrol acetate and of a caloric supplement enriched with EPA and DHA in anorectic cancer patients who had lost weight, showed that megestrol acetate and DHA/EPA supplementation are equally effective in improving appetite and body weight, although body composition was not assessed in this study.[40] A combination of both treatments did not increase response rate. The use of omega-3 fatty acids is limited by poor compliance to prolonged supplementation. Since not all cancer patients with cachexia benefit from omega-3 fatty acid supplementation,[41] further studies are needed to define the clinical and genetic subset of cancer patients most likely to derive favorable effects. Anticytokine Agents In animal models, anticytokine therapy is highly effective in counteracting cancer anorexia.[42] In humans, a number of molecules exhibiting anticytokine activity have been tested. Anti-IL-6 monoclonal antibody therapy appears promising, but clinical data are still lacking.[43] The compounds pentoxifylline, thalidomide, and suramin have been demonstrated to significantly reduce cytokine release in humans.[35] Unfortunately, pentoxifylline failed to demonstrate any clinical benefit in cancer patients with anorexia−cachexia syndrome.[35] Thalidomide showed some promise in patients with multiple myeloma, but results were modest in solid tumors.[44] Also, the potential side effects of anticytokine therapy, including suramin-induced inhibition of chemotherapy-induced apoptosis,[45] suggest it should be used with caution. Antiserotonergic Agents Cancer anorexia and cachexia can be therapeutically treated by interfering with the neurochemical events downstream of cytokine activation. Serotonergic hypothalamic neurotransmission may represent a suitable example. Synthesis of serotonin in the hypothalamus depends on the availability of its precursor, the amino acid tryptophan. Such availability is reduced by the oral administration of branched-chain amino acids (BCAA) because they compete with tryptophan for the same transport system located on the blood-brain barrier (Figure 3).[46] In a pilot study, oral supplementation with BCAA improved anorexia and energy intake in anorectic cancer patients.[47] Although not tested in larger clinical trials involving cancer patients, the prophagic effects of supplementation with BCAA have been confirmed in patients with uremia and liver cirrhosis.[48,49] Another mechanism of action of BCAA could be that they act centrally to influence appetite and energy intake, while simultaneously inhibiting peripheral muscle wasting. Serotonin has been shown to activate hypothalamic melanocortin receptors,[50] which have been linked to muscle wasting.[51] It is postulated that melanocortin receptors are less activated as a result of reducing brain serotonergic activity via BCAA, leading to reduced peripheral muscle wasting. Furthermore, recent experimental data show that leucine, one of the three BCAA, has inhibitory effects on ATP-dependent ubiquitin activity.[52] Ghrelin The role of ghrelin, an orexigenic peptide predominantly secreted from gastric cells,[53] is still controversial in cancer anorexia−cachexia syndrome. Although cachectic cancer patients appear resistant to the prophagic effects of ghrelin,[54] intravenous infusion of ghrelin to anorectic cancer patients has been shown to increase energy intake.[55] Ghrelin is a unique hormone that stimulates the release of growth hormone and increases appetite. In anorectic−cachectic cancer patients, it may simultaneously increase the intake of nutrients and favor their utilization, with the effect of preserving muscle mass. However, caution is advised with the use of ghrelin in cancer patients, because increased growth hormone production may stimulate tumor growth; although chronically administered ghrelin has not been tested in humans to ascertain whether the increased production of growth hormone is sustained. Anti-Inflammatory Agents The production of eicosanoids is involved in the pathogenesis of cancer anorexia and cachexia,[2,17] and cyclooxygenase inhibitors have been shown to decrease tumor growth and improve anorexia in animal models.[56] In humans, it was recently demonstrated that an integrated nutritional and metabolic approach, consisting of systemic anti-inflammatory treatment (indomethacin) combined with treatment to enhance erythropoietin levels, and individualized nutrition-focused patient care (oral nutritional support and/or home total parenteral nutrition), prolonged survival and increased maximum exercise capacity in cancer patients.[57] References 38. Moses AW et al. (2004) Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. Br J Cancer 90: 996-1002 39. Jatoi A et al. (2004) An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort. J Clin Oncol 22: 2469-2476 40. Burns CP et al. (2004) Phase II study of high-dose fish oil capsules for patients with cancer-related cachexia. Cancer 101: 370-378 41. Torelli GF et al. (1999) Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats. Am J Physiol 277: R850-R855 42. Trikha M et al. (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9: 4653-4665 43. Eleutherakis-Papaiakovou V et al. (2004) Thalidomide in cancer medicine. Ann Oncol 15: 1151-1160 44. Eichhorst ST et al. (2004) Suramin inhibits death receptor-induced apoptosis in vitro and fulminant apoptotic liver damage in mice. Nat Med 10: 602-609 45. 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(2004) Effect of eicosapentaenoic acid, protein and amino acids on protein synthesis and degradation in skeletal muscle of cachectic mice. Br J Cancer 91: 408-412 52. Inui A et al. (2004) Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 18: 439-456 53. Shimizu Y et al. (2003) Increased plasma ghrelin level in lung cancer cachexia. Clin Cancer Res 9: 774-778 54. Neary NM et al. (2004) Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 89: 2832-2836 55. Cahlin C et al. (2000) Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cachexia related to prostanoids. Cancer Res 60: 1742-1749 56. Lundholm K et al. (2004) Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism, and function. Cancer 100: 1967-1977 57. Inui A (1999) Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res 59: 4493-4501 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.