Anorexia and Cachexia

Etiology

Cancer-related cachexia can be broken down into 3 categories:

• Metabolic derangement
• Anorexia
• Alimentary tract dysfunction

The causes of cachexia can be related to disease, treatment, or emotional distress. Nausea, early satiety, and dysgeusia are factors in anorexia.

Cytokines

Mediators of cachexia associated with cancer include tumor necrosis factor-alpha, interleukins (IL) 1 and 6, ciliary neurotrophic factor, leukemia inhibitory factor, and interferon (IFN)-gamma. These are produced by tumor cells and host immune cells. These are procachectic factors, as they lead to anorexia, weight loss, protein and fat breakdown, an acute-phase protein response, falls in insulin levels, insulin resistance, rise in levels of cortisol and glucagon, fever, anemia, and elevated energy expenditure.[7][8]

Host immune cells, including macrophages, helper T-cells type 1, and myeloid-derived suppressor cells, produce procachectic cytokines. Many tumors cause an elevated adrenergic state that results in an increased rate of energy expenditure. Skeletal muscle is the primary site of lean body mass depletion as part of a persistent inflammatory response. Tumors only produce proteolysis-inducing (PIF) factors. Tumor necrosis factor (TNF)-alpha and PIF induce cachexia by activating the nuclear factor kappa B, a muscle transcription factor. This is secondary to increased protein turnover without equivalent protein synthesis.

The IL-6 family ligands strongly activate the Janus-associated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. STAT3 activation by IL-6 is necessary for muscle wasting. Inhibition of STAT3 pharmacologically using STAT3 or JAK inhibitors reduces muscle atrophy. This indicates that STAT3 is a primary mediator of muscle wasting when there is high IL-6 family signaling.

Anorexia and weight loss in cancer patients do not correlate with serum levels of circulating  IL-1, IL-6, IFN-gamma, and TNF-alpha. There may be a central mechanism of action producing cachexia. Cytokines postulated to be involved in cachexia include TNF-alpha, IFN-alpha, IL-1, IL-6, IL-8, and others.

Serotonin and dysfunction of neuropeptidergic circuits may be involved. Elevated plasma-free tryptophan was observed in patients with cancer and anorexia. This elevates tryptophan levels in the cerebrospinal fluid, resulting in increased serotonin synthesis. High levels of serotonin contribute to cancer anorexia.

Insulin and Ghrelin

Insulin and leptin levels are proportional to body fat content. Central nervous system (CNS) concentrations are proportional to plasma levels. Insulin secretion increases as weight increases. This occurs at the basal state and in response to meals. Leptin is more involved in CNS control of energy homeostasis than insulin. Leptin deficiency causes obesity with hyperphagia. This persists despite high insulin levels.

Ghrelin function is a peptide produced by ghrelin cells in the gastrointestinal tract and acts in the CNS. Ghrelin is secreted when the stomach is empty. The secretion stops when the stomach is stretched. Ghrelin increases hunger, gastric acid, secretion, and gastrointestinal motility centrally. The same brain cells have receptors for ghrelin and leptin, with opposing effects. 

Alimentary Tract Dysfunction

Cancer patients often have abnormalities in their taste and smell. Tumors of the mouth, neck, esophagus, and stomach may impair oral intake. Obstruction can occur in tumors of the pancreas, liver, and peritoneum. Intestinal obstruction is common. Enzymatic insufficiency secondary to pancreatic insufficiency may contribute to malabsorption. Lymphoma of the intestine or mesentery can result in issues.

Slowing of peristalsis and delayed gastric emptying contribute to early satiety. Chemotherapy commonly causes nausea, vomiting, mucositis, and abnormal perception of taste. Stomatitis, alterations in taste and smell, and xerostomia often occur secondary to radiotherapy to the head and neck. Abdominal radiation therapy can cause nausea, vomiting, anorexia, diarrhea, and malabsorption.[9][10][11]

Biochemical and Metabolic Derangement

Neoplastic cells have high levels of glucose utilization and production of lactic acid, the Warburg effect. Hexokinase is the first step of the glycolytic pathway, and overexpression in tumor cells contributes to this process. Tumor glycolysis and host gluconeogenesis may be a significant cause of cancer cachexia.

Recently, an extensive re-examination of Warburg effects shows that, unlike most cells, numerous cancer cell lines obtain a significant portion of their energy from aerobic glycolysis. Many malignant cells secrete hydrogen peroxide, and oxygen-free radicals drive mitophagy, aerobic glycolysis, and autophagy.

Theorized Causes of Cancer Anorexia

Cancer anorexia may be caused by:

• Cytokines, TNF-alpha, IL-1, IL-6
• Serum lactate
• Neuropeptides
• Glucagon and similar peptides
• Bombesin
• Serotonin
• Cisplatin, nitrogen mustard, doxorubicin, and other chemotherapeutic agents
• Hypercalcemia
• Satietins
• Toxohormone-L

Orexigenic and Anorexigenic Neuropeptides

Orexigenic molecules

Orexigenic molecules that may play a role in cancer-related cachexia include:

• Hypocretin 1 and 2 
• Cocaine and amphetamine-regulated transcript 
• Agouti-related protein 
• Galanin
• Ghrelin
• Neuropeptide Y 
• Melanin-concentrating hormone 

Anorexigenic molecules

Anorexigenic molecules that may play a role in cancer-related cachexia include:

• a-Melanocyte-stimulating hormone 
• Bombesin
• Calcium-gene related peptide
• Cholecystokinin
• Cocaine and amphetamine-regulated transcript 
• Corticotropin-releasing hormone 
• Urocortin 
• Dopamine
• Glucagon-like peptide 1 
• Histamine
• Insulin
• Neurotensin
• Leptin
• IL-1b
• Oxytocin
• Pro-opiomelanocortin 
• Serotonin
• Thyrotropin-releasing hormone 

Epidemiology

The cachexia prevalence ranges from 5% to 15% in congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) to 60% to 80% in advanced cancer. Mortality rates of patients with COPD and cachexia are 10% to 15% per year. In patients with cachexia and CHF or chronic kidney disease, mortality is 20% to 30% per year, and it is 80% in patients with cachectic cancer patients.[12]

Pathophysiology

Signaling Pathways

The multiple signaling pathways that cause muscle atrophy are interdependent; these include:  

• Autophagic-lysosomal pathway
• IGF-1 pathway
• Dystrophin-glycoprotein complex 
• Calcium-dependent proteolysis system
• Mitogen-activated protein kinases
• IL-6, JAK/STAT pathway
• Myostatin/activin pathway
• Poly(ADP-ribose)polymerase
• NF-kB-dependent pathway (including tumor necrosis factor-like weak inducer of apoptosis)
• Ubiquitin-proteasome pathway 

Inhibition or activation of a single path often causes a cascade affecting muscle protein balance. Cancer-related cachexia results in the metabolic reprogramming of muscle and fatty tissues. Fatty acids are catabolized by cancer cells to provide energy for tumor growth. Invasion of adipose tissue by cancer cells induces the release of free fatty acids from adjacent adipocytes. Autophagy and lysosomal degradation result in muscle wasting. HSL and ATGL knockdown studies reveal that they mediate muscle degradation.

Selective Parasitism

There is selective parasitism by the tumor of the host. There is competition for substrates, with tumors acting as nitrogen traps independent of protein intake. Given that the total tumor mass in most patients is usually less than 550 g and that patients with tiny tumors can have cachexia, it is doubtful that simple competition for nitrogen is responsible for cachexia.

History and Physical

The definition of cancer cachexia includes weight loss of more than 5% over 12 months, BMI of less than 20, or sarcopenia, as evidenced by dual-energy X-ray absorptiometry.

Evaluation

Evaluating a patient with cachexia includes monitoring blood chemistry and body weight. Bioelectrical impedance has also been used.[13][14]

Stages of Cancer Cachexia

• Pre-cachexia: There is anorexia and metabolic change with a weight loss of 5% or less.
• Cachexia: The BMI is less than 20, and weight loss is more than 2%, or systemic sarcopenia and weight loss is more than 2%.
• Refractory cachexia: The cancer is usually unresponsive, the performance score is low, and the predicted survival is less than 3 months.

Treatment / Management

Removal of the tumor is the best treatment for cancer cachexia. When definitive treatment is not possible, there has been some success with multiple treatment modalities.[15][16][17]

Supportive Care

Intervention from the stage of precachexia is best. Early nutritional intervention can improve nutritional status. This may reduce the inflammatory response. Body weight stabilization during chemotherapy often reduces toxicity and better overall survival. The following have all shown limited success:

• Antiemetics
• Exogenous pancreas extract 
• Frequent small feedings
• Homemade food supplements may be better tolerated
• Oral and parenteral nutritional supplements
• Treatment of stomatitis 
• Transfusions of blood components

Exercise

Exercise is safe during active cancer treatments. It improves muscle strength, bone health, and quality of life while decreasing depression, fatigue, and psychosocial distress. Physical activity can reduce the risk of comorbidities negatively affecting cancer survivors. Evidence indicates that exercise is associated with a reduction in overall mortality. Physical exercise can improve insulin sensitivity, modulate muscle metabolism, and reduce inflammation. Exercise has anti-inflammatory benefits. It up-regulates anti-inflammatory cytokines in skeletal muscle and adipose tissue. Recommendations should be made to exercise early in the treatment of cancer. Physical therapy evaluation can be helpful. Caregiver participation improves compliance.

Pharmacologic Management

Multiple agents with different mechanisms of action can be used alone or in combination, including:

• Olanzapine, a selective monoaminergic antagonist, has a strong affinity for dopamine and serotonin receptors. It has been used at low doses, showing improved weight and nutritional status and low incidence of side effects.
• Ghrelin and its analogs, including anamorelin, are helpful in some patients with cachexia. Side effects included nausea and hyperglycemia.
• Recombinant-human GH with insulin has been evaluated and showed improved whole-body protein net balance. 
• Anabolic-androgenic steroids have been used to promote muscle growth and strength. Nandrolone decanoate was studied in patients with non-small cell lung cancer. The treated group had less weight loss, but survival was comparable. Fluoxymesterone, an anabolic steroid, was found to be inferior to megestrol acetate or dexamethasone.
• Enobosarm (GTx-024) is an androgen receptor modulator. It has tissue-selective anabolic effects in muscle and bone. One study showed an increase in lean body mass.
• Thalidomide suppresses TNF production in patients with cancer. It has been combined with medroxyprogesterone or megestrol acetate, oral eicosapentaenoic acid, and L-carnitine, resulting in a significant increase in lean body mass, decreased fatigue, and improved appetite.
• MABp1 (Xilonix; Xbiotech, Inc., Austin, TX) is a fully humanized, monoclonal anti-IL-1a antibody. It is a receptor antagonist that results in partial remission or stabilization of cachexia.
• Corticosteroids have been found in uncontrolled studies to diminish anorexia, asthenia, and pain in patients with cancer. The improvements did not persist, and all nutritional status returned to baseline with no differences in the mortality rate.
• Megestrol acetate has been used historically. It improves appetite and increases body fat more than lean body mass. There is a reduction of serum levels of IL-1a and b, IL-2, IL-6, and TNF-a.
• Medroxyprogesterone acetate is a synthetic progestagen that also has been used. It reduces the production of cytokines and serotonin. It increases appetite in cancer patients but does not cause weight gain.
• Metoclopramide can be used for patients with delayed gastric emptying or gastroparesis. 
• Dronabinol and Marijuana Dronabinol (Delta 9-tetrahydrocannabinol, THC) have been studied. Cannabinoids have not shown to be more effective than megestrol despite improved appetite. 
• The anti-TNF antibody has been studied with conflicting results.
• Eicosapentaenoic acid was found to have antitumor and anti-cachexia activities in animal cachexia models, but randomized clinical studies show no unique benefit of EPA.
• Myostatin inhibitors may be a new potential therapeutic target. Activin type-2 receptor (ActRIIB) has been used to treat muscle wasting. ActRIIB is a high-affinity activin type 2 receptor known to mediate the signaling via a subset of TGF-b family ligands, including myostatin, activin, GDF11, and others.
• Bimagrumab is a fully humanized anti-ActRII monoclonal antibody that is to be studied for non-small cell lung cancer-associated cachexia.
• NSAIDs, including indomethacin and celecoxib, have not been shown to improve nutritional status.
• Hydrazine sulfate is an inhibitor of the enzyme phosphoenolpyruvate carboxykinase. It interrupts gluconeogenesis in animals. Studies have shown no benefit.
• Beta-hydroxy-beta-methyl butyrate with L-arginine and L-glutamine has been used for cachexia. HMB is a metabolite of leucine and interferes with the activation of NF-kB. In tumor-bearing mice, it inhibited PIF-induced protein degradation and attenuated the increased protein degradation.  
• OHR/AVR118 (OHR Pharmaceuticals, Inc., New York, NY) is a broad-spectrum peptide-nucleic acid immunomodulator theorized to have cytoprotective properties. A study in patients with cancer showed stabilization of body mass and muscle mass, increased appetite, and enhanced quality of life.
• Total parenteral nutrition has not been shown to significantly benefit patients undergoing chemotherapy or radiation therapy regarding tolerance, response, or survival.
• Cyproheptadine is a serotonin and histamine receptor antagonist. It can help with weight gain in carcinoid tumor patients.

Differential Diagnosis

The differential diagnoses for anorexia and cachexia include the following:

• Achalasia
• Avoidant restrictive food intake disorder
• Binge eating disorder 
• Cancer
• Constipation
• Crohn disease
• Cystic fibrosis
• Dementia, tuberculosis
• Hypothyroidism
• Irritable bowel syndrome 
• Multiple sclerosis
• Panhypopituitarism
• Protein-losing enteropathy
• Rheumatoid arthritis