Cancer anorexia and cachexia

Patients with cancer cachexia experience a profound wasting of adipose tissue and lean body mass. Anorexia, although often present, is insufficient to account for tissue wasting because 1) cachexia involves massive depletion of skeletal muscle that does not occur during anorexia, 2) nutritional supplementation cannot replenish the loss of lean body mass, 3) cachexia can occur without anorexia, and 4) food intake might be normal for the lower weight of the cancer patient. Anorexia can arise from 1) decreased taste and smell of food, 2) early satiety, 3) dysfunctional hypothalamic membrane adenylate cyclase, 4) increased brain tryptophan, and 5) cytokine production. Appetite stimulants such as cyproheptadine, medroxyprogesterone acetate, and megestrol acetate do not significantly improve lean body mass. Tumor products might be more important in the development of cachexia. Cachectic patients excrete in their urine a lipid-mobilizing factor that directly stimulates lipolysis in a cyclic AMP-dependent manner and increases energy expenditure. Loss of skeletal muscle in cachexia is caused by upregulation of the ubiquitin-proteasome catabolic pathway. Cachexia-inducing tumors elaborate a sulfated glycoprotein, which directly initiates protein catabolism in skeletal muscle. The action of this proteolysis-inducing factor is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid, which is also effective in preventing loss of skeletal muscle in cancer patients. Antagonists of tumor catabolic factors will provide important new agents in the treatment of cancer cachexia.     

Cancer cachexia: from experimental models to patient management

Cachexia is frequently associated with advanced or terminal cancer states, but it can also develop early during the course of neoplastic disease. This syndrome, which is characterized by body weight loss and negative nitrogen balance, significantly affects patient survival and quality of life. Studies on experimental models have shown that a complex interplay of different factors, such as anorexia, classical hormones, cytokines and other less well defined factors, concur in causing tissue wasting. On the basis of these results, it has been possible to prevent the onset of experimental cachexia by targeting therapeutic interventions at the underlying metabolic perturbations. Anticytokine treatments, either acting centrally or peripherally, have received particular attention, and are currently reaching the stage of clinical trials.     

Cancer cachexia and its treatment with fish-oil-enriched nutritional supplementation

OBJECTIVE: Cachexia is a common condition affecting those with advanced cancer. This review explores mechanisms of cachexia and possible treatments devised with these mechanisms in mind. METHODS: Selective review of the relevant scientific literature was performed with particular emphasis on studies performed by our group over the past 10 y involving patients with advanced pancreatic cancer. RESULTS: Cancer cachexia adversely affects patient quality of life and survival. It is characterized by a lack of a normal anabolic response to the provision of apparently adequate nutrition. It appears to result from a persistent response to illness stimulated by the cancer resulting in a proinflammatory cytokine and catabolic hormonal environment. Interventions that ignore this inflammatory milieu have had little success. More promising interventions have a broad antiinflammatory component such as nonsteroidal antiinflammatory drugs or fish oil. Preliminary studies of a combination of fish oil as an antiinflammatory agent with nutritional supplementation show promise in reversing weight loss with apparent gains in lean tissue and performance status in association with normalization of the metabolic environment in patients with advanced pancreatic cancer. CONCLUSIONS: Cancer cachexia produces a metabolic environment that prevents the appropriate use of supplied nutrition. Antiinflammatory agents such as fish oil in combination with nutritional supplementation may reverse aspects of cachexia.     

Cancer cachexia: measured and predicted resting energy expenditures for nutritional needs evaluation

OBJECTIVE: Cancer cachexia is associated with weight loss, poor nutritional status, and systemic inflammation. Accurate nutritional support for patients is calculated on resting energy expenditure (REE) measurement or prediction. The present study evaluated the agreement between measured and predicted REE (mREE and pREE, respectively) and the influence of acute phase response (APR) on REE. METHODS: Thirty-six patients with cancer were divided into weight-stable (WS; weight loss <2%) and weight-losing (WL; weight loss >5%) patients. Measured REE was measured by indirect calorimetry and adjusted for fat-free mass (FFM). The Bland-Altman approach was used to assess the agreement between mREE and pREE from the Harris-Benedict equations (HBE). Blood levels of C-reactive protein were assessed. RESULTS: There was no difference in mREE between groups (WS 1677 +/- 273, WL 1521 +/- 305) even when mREE was adjusted for FFM (WS 1609 +/- 53, WL 1589 +/- 53). In WL patients, FFM-adjusted REE correlated with blood C-reactive protein levels (r = 0.471, P = 0.048). HBEs tend to underestimate REE in both groups. CONCLUSION: WL and WS patients with cancer had similar REEs but were different in terms of APR. APR could contribute to weight loss through enhancing REE. In a clinical context, HBE was in poor agreement with mREE in both groups.     

Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism

The aim of this study was to determine whether a ketogenic diet could decrease nitrogen losses in cachectic cancer patients and at the same time reduce the supply of glucose for tumor energy metabolism. Five patients with malignant disease and severe weight loss (mean 32%) were fed via a fine bore nasogastric tube. A normal diet was given for 6 d and this was followed by 7 d of an isonitrogenous, isocaloric, ketogenic diet. Both diets were well tolerated. At 7 d the mean ketone body concentration in the blood of patients fed the ketogenic diet was 1.21 +/- 0.33 mM. This ketosis was associated with a significant reduction of the concentration in blood of glucose, lactate, and pyruvate (p less than 0.05). There was, however, no significant alteration in host N balance or whole-body protein synthesis, degradation, or turnover rates. Whether the change from glucose- to fat-derived energy substrates might reduce tumor growth rates in the long term remains to be determined.     

Nutrition and cardiac cachexia

PURPOSE OF REVIEW: Congestive heart failure is a leading cause of morbidity and mortality, especially in older persons. In advanced stages of the disease, congestive heart failure can be associated with serious complications such as cardiac cachexia (defined here as weight loss of more than 6% in 6 months). This review will discuss recent insights into the pathophysiology, anthropometric predictors and potential management of cardiac cachexia. RECENT FINDINGS: Cardiac cachexia and the associated progressive weight loss are sometimes overlooked by care providers. A delay in diagnosis often results in further loss of vital tissues, progressive weakness, fall-related injuries and potentially long-term care institutionalization and/or death. Emerging data suggest that congestive heart failure is a dynamic disorder of many organ systems, including the myocardial, neurohormonal, immune, vascular, gastrointestinal, renal and musculoskeletal systems. It is becoming more widely appreciated that it is the deterioration of this interactive multisystem complex that results in the systemic inflammation and progressive wasting and atrophy of muscle and other organ tissues, which is the hallmark of cardiac cachexia. SUMMARY: Cardiac cachexia in congestive heart failure patients may be associated with a low level of physical activity. A high systemic inflammatory state is another marker of cardiac cachexia. Prudent anti-inflammatory nutrition, dietary supplements and exercise can serve to ameliorate and/or potentially prevent progressive wasting. A better understanding of factors contributing to the development of cardiac cachexia will enable us to design preventive strategies and provide improved care for individuals with this debilitating condition.     

Endocannabinoid system in cancer cachexia

PURPOSE OF REVIEW: More than 60% of advanced cancer patients suffer from anorexia and cachexia. This review focuses on the possible mechanisms by which the endocannabinoid system antagonizes cachexia-anorexia processes in cancer patients and how it can be tapped for therapeutic applications. RECENT FINDINGS: Cannabinoids stimulate appetite and food intake. Hepatocytes express functional cannabinoid type 1 receptors, activation of which increases the expression of lipogenic genes (e.g those encoding sterol regulatory element binding protein 1c, acetyl-coenzyme A carboxylase-1, and fatty acid synthase in the liver and hypothalamus) and increase de-novo fatty acid synthesis, which contributes to development of diet-induced obesity. Both ghrelin and cannabinoids stimulate AMP-activated protein kinase in the hypothalamus, whereas they inhibit it in the liver and adipose tissues. Both anandamide and synthetic cannabinoid type 1 receptor agonists such as HU210 and the plant-derived cannabinoid tetrahydro-cannabinol also significantly inhibit tumor necrosis factor-alpha. SUMMARY: Cannabinoid type 1 receptor activation stimulates appetite and promotes lipogenesis and energy storage. Further study of cancer-cachexia pathophysiology and the role of endocannabinoids will help us to develop cannabinoids without psychotropic properties, which will help cancer patients suffering from cachexia and improve outcomes of clinical antitumor therapy.     

Molecular mechanisms of cancer cachexia

Molecular mechanisms of cancer cachexia. Cancer cachexia is a complex, multifactorial syndrome characterised by a critical weight loss, anorexia, asthenia and anaemia. Most of the patients with advanced cancer suffer from cancer cachexia. The cachectic state is closely associated with progressive expansion of the tumour and leads to a malnutrition status due to the induction of anorexia and decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to malnutrition state, too, which promotes severe metabolic disturbances in the host, including hypermetabolism which leads to an increased energetic inefficiency. Although, the search for the cachectic factors has a long history, we are still far away from knowing the complete answer. The main aim of the present paper is to summarise the different catabolic mediators involved in cancer cachexia. Better understanding of the pathomechanism of cancer cachexia can lead to the discovery of new, effective strategies of the therapy for the future.     

Hydrazine sulfate and cancer cachexia

Hydrazine sulfate, a gluconeogenic blocking agent designed to inhibit cancer cachexia, has produced significant subjective response in late‐stage cancer patients as well as a degree of accompanying “objective”; response, while at the same time inducing little or no important clinical side effects. In addition the drug has been demonstrated to inhibit tumor growth and potentiate the action of cytostatics in a variety of experimental animal tumors. The mechanism of action for these latter responses is indicated to be indirect and not a function of tumor cytotoxicity. It is suggested that new indices of subjective response replace standard cytotoxic criteria in the evaluation of a non‐cytotoxic drug.     

Computational modeling of cancer cachexia

PURPOSE OF REVIEW: Measurements of whole-body energy expenditure, body composition, and in-vivo metabolic fluxes are required to quantitatively understand involuntary weight loss in cancer cachexia. Such studies are rare because cancer cachexia occurs near the end of life when invasive metabolic tests may be precluded. Thus, models of cancer-associated weight loss are an important tool for helping to understand this debilitating condition. RECENT FINDINGS: A computational model of human macronutrient metabolism was recently developed that simulates the normal metabolic adaptations to semi-starvation and re-feeding. Here, this model was used to integrate data on the metabolic changes in patients with cancer cachexia. The resulting computer simulations show how the known metabolic disturbances synergize with reduced energy intake to result in a progressive loss of body weight, fat mass, and fat-free mass. The model was also used to simulate the effects of nutritional support and investigate inhibition of lipolysis versus proteolysis as potential therapeutic approaches for cancer cachexia. SUMMARY: Computational modeling is a new tool that can integrate clinical data on the metabolic changes in cancer cachexia and provide a conceptual framework to help understand involuntary weight loss and predict the effects of potential therapies.     

Eicosanoid-dependent cancer cachexia and wasting

The reversal of catabolic processes remains a significant challenge related, in part, to their complexity and our incomplete understanding of the mechanisms involved. The eicosanoids are key players in the inflammatory process and have been implicated in the process of cancer cachexia. They are unsaturated C20 fatty acids which can be separated into two main groups: the lipoxygenase products including leukotrienes and lipoxins, and the prostanoids including prostaglandins, prostacyclin and thromboxane. This review examines the biology of the eicosanoids and the evidence of a role for the eicosanoids in cancer cachexia and wasting.     

Role of intestinal function in cachexia

PURPOSE OF REVIEW: Cachexia is a prominent feature in many chronic diseases, but its pathogenesis is still not fully understood. This article reviews recent research into the role of the gut barrier in the pathogenesis of inflammation and cachexia with special emphasis on two potentially catabolic diseases: liver cirrhosis and chronic heart failure. RECENT FINDINGS: There is increasing evidence that catabolic diseases such as liver cirrhosis and chronic heart failure are associated with increased gut permeability, endotoxemia and enhanced expression of proinflammatory cytokines. In liver cirrhosis normalization of portal hypertension by insertion of a transjugular intrahepatic portosystemic stent shunt obviously causes improvement not only of gut barrier function, but also of nutritional status. SUMMARY: Although its pathogenesis is not yet completely understood, proinflammatory cytokines have been implicated in the onset and progression of cachexia. Recent data support the hypothesis that impaired gut barrier function and increased permeability further translocation of endotoxins. Increased endotoxemia might be a potent trigger of systemic inflammatory response which is involved in the pathogenesis of the cachexia syndrome. Thus, it is tempting to speculate that therapeutic strategies for the improvement of gut barrier function will concomitantly improve nutritional status.     

Cytokines and cancer anorexia cachexia syndrome

Cancer anorexia cachexia syndrome is frequent yet still a not well understood cancer-related problem. The pathophysiology of cancer cachexia is multifactorial. It is suggested to be the result of tumor-host interactions and studies of the disturbances seen during cancer anorexia cachexia syndrome, such as anorexia, hyper-metabolism, tissue wasting, metabolic abnormalities, and hormonal changes, all point to the involvement in one way or another of one key factor: cytokines. The purpose of this review is to summarize the latest developments in the field of cytokines and their role in cancer anorexia cachexia syndrome. The emphasis is on the role of cytokines in anorexia and tissue wasting.