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Cancer Cachexia

Cancer cachexia, also known as cancer anorexia-cachexia syndrome (CACS), involves wasting

that is very different from that seen with simple starvation. Cachexia results from a chronic and

systemic inflammatory response in which the liver produces acute phase proteins that result in the

depletion of essential amino acids. It is estimated that 20% of cancer deaths result from cachexia.

CACS can occur in patients who meet estimated nutritional needs via oral intake or nutrition

support, and nutrition support does not always slow the progression of cachexia. CACS occursmost often in people with cancers of the upper gastrointestinal (GI) tract, including the esophagus,

stomach, and pancreas. It is also common in lung and prostate cancers. Death generally occurs

when a person has lost roughly 30% of their premorbid weight. Cachectic patients are less likely torespond to chemotherapy and are more likely to suffer toxic side effects.

It is known that anorexia, early satiety, taste changes, nausea, GI symptoms, fatigue, and anemia

contribute to the development of CACS. Cachexia causes increased lipolysis, decreased

lipogenesis, hyperlipidemia, increased circulating levels of free fatty acids and glycerol, andeventual loss of large amounts of adipose tissue.

Patients with cachexia will suffer severe loss of skeletal muscle secondary to reduced protein

synthesis and increased protein degradation. The decrease in skeletal protein synthesis results

when the available amino acids are diverted secondary to the increased synthesis of acute phaseproteins and gluconeogenesis. Protein degradation, however, is the major cause of skeletal muscle

mass loss. Patients with CACS can have both glucose intolerance and insulin resistance, although

this appears to vary according to the type of cancer. The increase in lactate production increasesenergy needs, because gluconeogenesis is very energetically expensive.

Proinflammatory cytokinesProinflammatory cytokines, including tumor necrosis factor, interleukins (IL)-1 and IL-6, andinterferon gamma, are believed to be primary mediators for development of CACS. Administration

of antibodies to these cytokines can result in some reversal of cachexia. It appears that some of

these cytokines act synergistically and are ineffective independently. All of these cytokines inhibitlipoprotein lipase, resulting in the prevention of fatty acid storage in adipocytes. Animal studies

have shown that infusion of these proinflammatory cytokines results in anorexia, weight loss,

proteolysis, lipolysis, increased energy expenditure, and elevated levels of cortisol and glucagonlevels.

Proteolysis-inducing factor (PIF)

PIF, a glycoprotein, is found in the urine of oncology patients who are losing weight and isproduced in human colon cancer. PIF induces protein degradation in skeletal muscle via

upregulation of the ubiquitin-proteasome proteolytic pathway. Both PIF and cytokines may cause

wasting by activation of nuclear factor kappa-B, which is a transcription protein that controls theexpression of several cytokines.

Changes in body composition

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Weight loss results from an increase in lipolysis and fatty oxidation and a decrease in lipogenesis.

Cytokines are thought to cause a reduction in lipogenesis. Leptin is downregulated by tumor

necrosis factor. Tumor necrosis factor also causes the expression of leptin receptors in thehypothalamus. High levels of leptin block the release of neuropeptide Y, which is the most potent

feeding-stimulatory peptide. This deregulation results in decreased energy intake and increased

metabolic demand for nutrients. Il-1 antagonizes neuropeptide Y-induced feeding in rats.

Lipid mobilizing factor (LMF) is found in the urine of cachectic patients and is tightly linked to

weight loss and induced lipolysis in murine adipocytes. LMF causes an increase in mitochondrialuncoupling proteins in brown adipose tissue, the skeletal muscle, and the liver. Mitochondrial

uncoupling proteins 1, 2, and 3 help to control energy metabolism through thermogenesis in brown

adipose tissue. These proteins generate heat by uncoupling the oxidation of fatty acids from the

generation of adenosine triphosphate (ATP). Brown adipose tissue is only found in 13% of controlsubjects, but in 80% of patients with cachexia. Tumor necrosis factor-alpha also increases the

mRNA levels of mitochondrial uncoupling proteins-2 and uncoupling proteins-3. Skeletal muscle

mitochondrial uncoupling protein-3 mRNA levels are fivefold higher in cachectic patients.

Steroids and hormonal agentsMegace (megesterol acetate) is a synthetic progestin hormone (progestogen). It interferes with thenormal estrogen cycle and decreases hormone levels. It works as an appetite stimulant. The weight

gain is usually temporary, and fatty tissue and water result in weight gain, not an increase in lean

body mass. It seems that progestogen may cause a decline in response to chemotherapy and mayincrease the frequency of thromboembolic events.

Corticosteroids also are used to induce weight gain. Again, however, the results are temporary.

Furthermore, with long-term use, these medications actually interfere with muscle synthesis. Bothsteroids and hormonal agents, such as Megace, work via multiple pathways, including increasing

neuropeptide Y levels and downregulating proinflammatory cytokines. Usually these medicationsare limited to the preterminal phase of cancer cachexia. In a randomized trial involving 469patients, tetrahydrocannabinol (THC), the active ingredient in marijuana, was significantly less

effective than Megace in promoting weight gain.

Omega-3 fatty acidsOmega-3 fatty acids may reduce inflammation and protein breakdown, but more research is

warranted. Some studies have not found much benefit, while other research has determined thateicosapentaenoic acid (EPA), the major active component of fish oil, seems to interfere with the

signaling pathways of PIF and to downregulate proinflammatory cytokines. EPA combined with

beta-hydroxy-beta-methylbutyrate (HMB), a leucine metabolite, may prove more effective than

HMB given independently to reverse cachexia in animal studies.

ThalidomideUse of thalidomide, created as a sleeping aide and subsequently pulled from the market in the1960s when it was found to cause birth defects, is now permitted for people with cachexia.

Thalidomide is likely to have multiple immunomodulatory properties, including interference with

cytokine activity.

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Angiotensin-coverting enzyme inhibitorsAngiotensin-coverting enzyme inhibitors, traditionally used for hypertension, are thought to have

anti-inflammatory properties, which may help to suppress the production of cytokines. Macrolides,which are antibiotics, may work in a similar manner.

IbuprofenIbuprofen may reduce resting energy expenditure and the acute phase response. In one trial,

Megace and ibuprofen produced a greater increase in body weight when given in combination than

did Megace alone.

References and recommended readings

Gordon JN, Green SR, Goggin PM. Cancer cachexia. QJM[serial online]. 2005;98:779-788.

Available at:http://qjmed.oxfordjournals.org/content/98/11/779.full . Accessed February 19, 2012.

Maltzman JD. Developments in the fight against cancer cachexia. Available at:

http://www.oncolink.org/resources/article.cfm?c=3&s=38&ss=164&id=828. Accessed February19, 2012.

Marian M, Roberts S. Clinical Nutrition for Oncology Patients. Sudbury, MA: Jones and Bartlett;

2010:8-12.

Martignoni ME, Kunze P, Friess H. Cancer cachexia. Available at:http://www.molecular-

cancer.com/content/2/1/36. Accessed February 19, 2012.

Review Date 2/12

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http://qjmed.oxfordjournals.org/content/98/11/779.fullhttp://qjmed.oxfordjournals.org/content/98/11/779.fullhttp://www.oncolink.org/resources/article.cfm?c=3&s=38&ss=164&id=828http://www.molecular-cancer.com/content/2/1/36http://www.molecular-cancer.com/content/2/1/36http://www.molecular-cancer.com/content/2/1/36http://qjmed.oxfordjournals.org/content/98/11/779.fullhttp://www.oncolink.org/resources/article.cfm?c=3&s=38&ss=164&id=828http://www.molecular-cancer.com/content/2/1/36http://www.molecular-cancer.com/content/2/1/36