Cachexia in a paraneoplastic syndrome that negatively impact performance status and mortality rate of cancer patients. The symptoms include up to 80% loss of both adipose tissue and skeletal muscle mass, fatigue, skeletal muscle atrophy, anaemia as well as alterations in carbohydrate, lipid and protein metabolism. The visceral protein component remains unchanged. This waste of muscle protein results in loss of function for the cancer patients and eventually death from hypostatic pneumonia, attributable to loss of respiratory function. Clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors.
Cancer cachexia is defined as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support and that leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The weight loss experienced by cachexic patients varies greatly according to the tumour site. For example, in less aggressive forms of Hodgkin’s lymphoma, acute nonlymphocytic leukaemia and in breast cancer, the frequency of weight loss is 30-40%. More aggressive forms of non-Hodgkin’s lymphoma, colon cancer and other cancers are associated with a frequency of weight loss between 50-60%. Pancreatic cancer patients have been shown to have the highest frequency of weight loss at over 80%. Interestingly, cachexia can manifest in individuals with metastatic cancer as well as in individuals with localised disease. It also does not appear to be dependent upon tumour size, type or extent.
The consequences of cachexia are as follow:
- Reduced protein-calories intake
- Progressive wasting
- Preferential loss of somatic muscle and fat mass
- Debilitation
- Compromised immune system with possible increase of infection
- Altered hepatic glucose and lipid metabolism
- Potential medical therapy intolerance
- Death and morbidity
- Impaired quality of life
- Decreased response to chemotherapy
- More frequent and severe toxicity to chemotherapy
- Increased basic metabolic rate
- Decrease in serum albumin
- Gut barrier dysfunction
The agreed diagnostic criterion for cachexia is defined as weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height or skeletal muscle mass
An agreement was made that the cachexia syndrome can develop progressively through various stages—precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment.
The onset of anorexia-cachexia syndrome significantly influences the clinical course of the disease, and most anti-tumour therapies actually exacerbate anorexia and worsen body weight loss. As a consequence, the higher prevalence and greater severity of anorexia-cachexia is mostly due to iatrogenic causes. Cancer cachexia is associate with marked alterations in skeletal muscle protein metabolism that lead to muscle wasting. Loss of skeletal muscle in cancer patients can potentially be due to anorexia, reduced muscle protein synthesis and/or increased muscle protein breakdown. The inflammatory response elicited by cancer is one of the primary mediators of this condition, as inflammatory cytokines such as IL-6 and TNF-alpha contribute to protein muscle wasting. Cardiac muscle or proteins are also depleted, which results in alterations in heart performance.
One of the hypothesis on the nature of cancer cachexia involves the host’s production of inflammatory cytokines, which in turn orchestrate a series of complex interrelated steps that ultimately lead to a chronic state of wasting, malnourishment, and death. These cytokines are either produced by cancer or released by the cells of the immune system as a response to the presence of cancer, as well as other tumour products that induce profound lipolysis or protein degradation. Consistent with this view, inflammation-based markers have been proposed and are currently used for both the diagnosis and the prognosis of cancer cachexia. These pro-inflammatory cytokines are widely acknowledged as important players in cachexia, acting both in a paracrine and endocrine manner.
The cachexic patient presents marked local inflammation, however a recombinant DNA methodology has shown that only a few cytokines hold cachectic potential. The most common pro-inflammatory cytokines observed in acutely ill patients are IL-1, IL-2, INF-gamma and TNF-alpha. These cytokines, also called pre-cachectic cytokines, activate nuclear transcription factor kappa-B (NF-kB) which result in decreased muscle protein synthesis (51). NF-kB controls the expression of a large number of genes, including those encoding cytokines, chemokines, cell adhesion molecules, growth factors, immunoregulatory molecules, acute-phase and stress response, proteins, cell surface receptors and several enzymes including those involved in protein degradation by ubiquitin-proteasome system. (52).Research has shown that steroid hormones have clear effects on the NF-kB pathway, as reported for glucocorticoids and progesterone. This system has been found to be the primary regulator of protein breakdown which provide a mechanism for selective degradation of regulatory and structural proteins. Furthermore, cytokine activation is also responsible for the reduction of MyoD protein, a transcription factor that modulates signalling pathways involved in muscle development. TNF-alpha and IFN-gamma are highly specific for stimulating the proteolysis of myosin heavy-chains. TNF/cachectin is the most extensively studied cytokine because it has been found to modulate changes directly associated with cancer cachexia. Interferon-gamma appears to potentiate these effects and may also be necessary for the complete syndrome of cancer cachexia. IL-6 probably is released as another mediator, principally mediating the acute phase response seen in cancer cachexia. Interestingly, recent studies have shown that plasma concentration of leptin, vistafin, resistin and adiponectin are also impaired in cancer cachexia, possibly contributing t the development/maintenance of cachexia-related inflammation. The alterations in leptin secretion have been shown to be modulated by TNF-alpha in cancer cachexia under extensive macrophage infiltration of adipose tissues. Finally, cytokines production increases corticotrophin releasing factor which, together with prostaglandins, suppresses the production of neuropeptide Y, which regulates or increases appetite. It has also been established that cytokines modulate testosterone production, suggesting that adipose tissue-derived IL-6 plays an important role in eliciting central hypogonadism. At this stage, it is unclear whether hypogonadism is secondary to chronic systemic inflammation or an important contributor to it. What is clear, however, is that hypogonadism may be aggravated by the use of opioids which cause augmentation of plasma cortisol concentration, another feature of cancer cachexia.
Cytokines can be transported across the blood-brain barrier where they have been shown to interact with the luminal surface of brain endothelial cells to release substances that affect appetite. Receptors for TNF-alpha and IL-1 are found in the hypothalamic area of the brain which regulate food intake. Anorexia-induced by TNF-alpha and IL-6 can be modulated by inhibitors of cyclooxygenase, suggesting that a prostaglandin such as PHE2 may be the direct mediator of appetite suppression.
Semi-starvation is common in patients in hospital. Digestive disorders such as nausea, vomiting, malabsorption and obstruction as well as chemotherapy, radiation and surgery contribute to this poor nutritional status. 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. Catabolic factors are closely related to tissue acidosis, an often neglected consideration for cancer cachexia. Chronic metabolic acidosis increases whole body protein turnover, muscle protein degradation, as well as nitrogen excretion and amino acid. Metabolic acidosis promotes a higher and non-specific proteolysis of muscle proteins as well as abnormalities in the release and function of several hormones, including defects in growth hormones, insulin, glucocorticoids, thyroid hormone, parathyroid hormone and vitamin D. IGF-1, in particular, has been shown to stimulate muscle protein degradation by activating proteolytic mechanisms. In this process, the intensity of lactic fermentation and tumour aerobic glycolysis further contribute to maintain a state of chronic acidosis.
Another factor that contributes to the wasting process is the Resting Energy Expenditure (REE). The REE in cancer patients is strongly determined by the type of tumour. In fact, REE is elevated in patients with both lung and pancreatic cancer, while there is no increase in REE in patients with gastric and colorectal cancer (16). One reason for an increased REE in some cancers maybe an increased thermogenesis in brown adipose tissue or skeletal muscle, a process mediated by the presence of uncoupling protein, thus decreasing the level of coupling of respiration to ADP phosphorylation. Cytokines can increase the level of these uncoupling proteins, contributing to weight loss. Most cancer cells use the Cori cycle to generate ATP. For a tumour to grow, it will require approximately 40 times more glucose than if it were fully oxidized. In addition, the lactate passes from the tumour to the liver, where it is resynthesised into glucose, another energy-inefficient process. Tumours preferentially use glucose/protein for energy at the expense of the host.
Tumour utilise certain amino acids for glucogenesis, which results in abnormal amino acids profiles. The use of amino acids by the tumour to produce glucose for energy becomes clinically significant for the patient when protein degradation and loss exceeds synthesis. It has been noticed that protein catabolism could be interpreted as the body’s defence mechanism attempt to produces acute phase proteins. If a particular amino acid is in short supply, the body will catabolise skeletal muscle to ensure that it is available for the synthesis of these important proteins.
Several strategies have been applied in the management of cachexia and related immunodeficiency, including:
- Hypercaloric feeding
- Administration of glucocorticoids (although given their catabolic effect on skeletal muscle, they have been shown to have a limited beneficial effect on body weight)
- Progestational drugs
- Cyproheptadine and other anti-serotonergic drugs
- Branch chain amino acids
- Total parenteral nutrition (although any weight gain is transient and body composition analysis shows that this is fat and water rather than lean body mass.
- Fish oil helps reduce inflammation
- Cannabinoids (although it stimulates appetite, this active ingredient of marijuana has been shown to halt the progressive loss of body weight of cachexia).
- Anti-inflammatory agents
- Proteasome inhibitors and NF-kB inhibitors
- Histamine antagonist with appetitive stimulatory effects
Proteolysis-inducing factor (PIF) has also been shown to induce protein catabolism directly in isolated skeletal muscle. Researchers have isolated a PIF produced by cachexia-inducing murine and human tumours which were found to be excreted in the urine of patients with carcinoma of the pancreas, liver, rectum, colon, breast, lung and ovary where the weight loss was greater than or equal to 1 kg/month. PIF was detected in the urine of 80% of patients with pancreatic cancer. These patients had a significantly greater total weight loss and rate of weight loss than in patients without PIF in the urine.
Clinically in many patients, cancer cachexia manifests in three phases:
- The silent phase:
During the silent phase, there are no obvious symptoms of clinical disease. Biochemically, blood tests show hyper-lacticaemia, hyper-insulinaemia and alterations in the amino acid and lipid profiles. The most important factor during this phase is given by the alterations in carbohydrate metabolism which result in the excessive production of lactate through energy-inefficient anaerobic metabolism or aerobic glycolysis. This factor, in turn, give rise to increase inflammation.
- The clinical phase:
During this phase, the patient exhibits symptoms of weight loss, anorexia and lethargy. Often this phase is consistent with the start of chemotherapy, radiation or surgery.
- Third phase
During this phase, the patient presents more debilitated and biochemically shows evidence of negative nitrogen balance and hypoalbuminaemia. Cancer patients begin to lose carbohydrates and protein stores, while loss of fat deposition is generally noted in this final stage of the disease. Autonomic nervous system collapse also appears during this stage. The most relevant point during this stage is the profoundly altered carbohydrates metabolism and the subsequent conversion of lactate to glucose by the Cori cycle.
Recommended synergistic approaches to cachexia:
In order to control muscle atrophy, a synergistic combination of different nutrients is generally recommended. A study based on an integrated treatment in a population of advanced cancer patients with cancer related cachexia suggests a diet consisting of high polyphenol content (400mg), antioxidant treatment (300mg/d alpha-lipoic acid + 2.7g/d carbocysteine lysine salt + 400mg/d vitamin E + 30,000IU/d vitamin A + 500mg/d vitamin C) and pharmaconutritional support enriched with n3-PUFAs (>1·5 g/day) 500mg/d medroxyprogesterone acetate, and 200mg/d selective cyclooxygenase-2 inhibitor. This treatment was found to decrease inflammatory markers, improve appetite and increase lean body weight. Furthermore, in order to block protein loss, it is necessary to administer protein from 1.5 to 2g/kg/d, ensuring that there is sufficient intake of essential amino acids in the protein mix. Branch chain amino acids (particularly leucine) with HMB supplementation can increase body weight. Furthermore, acetyl-L-carnitine supplementation (2-4 g/d) has been found to improve fatigue in cancer patients whose dietary intake is decreased with the consequential impairment of endogenous synthesis of carnitine. The loss of adipose tissue is cachexia is associated with the liberation of stored fat-soluble toxins which need to be detoxified. Supporting liver function, reducing oxidative stress and improving waste disposal is essential. Furthermore, loss of adipose tissue is also associated with depletion of plasma phospholipids. This is likely to indicate a deficit of essential fatty acids in the periphery and supplantation with lecithin and essential fatty acids has been shown to be essential.
References:
Whitehouse AS., Smith HJ., Drake JL. Mechanism of Attenuation of Skeletal Muscle protein Catabolism in Cancer Cachexia by Eicosapentaenoic Acid. Cancer Research 2001; 61:3604-3609
Batista ML. et al. Adipose tissue inflammation and cancer cachexia: the role of steroid hormones. Horm Mol Biol Clin Invest. 2014; 17(1): 5-12
Richard F. Lamb Amino acid sensing mechanisms: an Achilles heel in cancer? The FEBS Journal. 2012, revised 27 May 2012, accepted 7 June 2012)