Cachexia

• Many types of cancer (particularly of the pancreas, stomach, oesophagus, colon and rectum)
• HIV/AIDS
• Congestive heart failure
• Rheumatoid arthritis
• Tuberculosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis
• Crohn's disease

It is also seen in the elderly without any apparent associated disease.

Cancer cachexia describes a syndrome of progressive weight loss, anorexia, and persistent erosion of host body cell mass in response to a malignant growth. Although often associated with preterminal patients with disseminated disease, it may also be present in the early stages of tumour growth before any signs or symptoms of malignancy.

It is present in approximately 50% of cancer patients during treatment, and nearly 100% of treated cancer patients at death.¹ It accounts for at least 20% of deaths in neoplastic patients.²
Cancer cachexia impairs quality of life and response to therapy, increasing morbidity and mortality of cancer patients.

Mediators of cancer anorexia and associated abnormalities are unknown. Cachectin/TNF or other host-derived cytokines (produced as a defense against malignancy) have been implicated as signal molecules in cachexia, based upon similar metabolic derangements produced by these cytokines in other chronic wasting illnesses.

This is a common complication of chronic heart failure (CHF) which is associated with poorer prognosis. It is independent of functional disease severity, age, measures of exercise capacity and left ventricular ejection fraction.³

Patients have generalised loss of lean tissue and fat tissue, as well as bone tissue. They tend to be weaker and become fatigued earlier. This is due to both reduced skeletal muscle mass and impaired skeletal muscle quality. In patients with heart failure, the usual association between obesity and reduced survival appears to be reversed.⁴

Cachexia represents the clinical consequence of a chronic, systemic inflammatory response. The changes seen in cachexia are complex and highly co-ordinated. It is characterised by an accelerated loss of skeletal muscle, often accompanied by loss of appetite and altered taste.

• Muscle wasting is the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways.
• There is also an increase in the synthesis of proteins involved in the response to tissue injury; the so-called 'acute-phase response'.
• Pathological changes occur in response to the body's acute-phase response to tissue damage, including synthesis by the liver of large amounts of proteins, e.g. C-reactive protein, complement factors, fibrinogen and many others.
• This response consumes large amounts of energy and amino acids which are obtained by breaking down skeletal muscle.
• In acute conditions this is an effective response, as skeletal muscle can be replaced later.

In a chronic condition, it adds to morbidity and can prove fatal.

Raised resting energy expenditure is typical of cachexia, but not starvation. However, this is not the cause of weight loss because it is compensated for by a reduction in energy used for voluntary activity, which further adds to loss of skeletal muscle from immobility.

Nutritional support is effective in maintaining body weight of cachectic cancer patients, but ineffective in maintaining lean body mass. Cachexia has repeatedly been associated with adverse clinical outcomes.

Starvation.

Treatment of the underlying condition is important.

General measures

• Hypercaloric feeding has repeatedly shown to be ineffective in increasing lean mass. However, may confer other benefits on the patients.
  May cause weight gain but due to deposition of fat.⁵The metabolic adaptations, notably the increase in the rate of protein catabolism, limit the ability of hypercaloric feeding to reverse the depletion of lean mass.
• Resistance exercise training benefits have been reported.⁶
• In one study, parenteral nutritional support improved operative morbidity and mortality in cancer patients⁷ but it has not been seen to improve response to chemotherapy or radiation therapy.⁷
• A Cochrane review (2005) failed to demonstrate any benefit on the healing of decubitus ulcers with protein-rich nutritional supplements.⁸

NICE recommends oral, enteral or parenteral support (according to need and swallowing ability) for adults when:⁹

• BMI is <18.5 kg/m³.
• There has been >10% of total body weight lost on last 3-6 months.
• BMI is <20 and there has been 5% weight loss in last 3-6 months.

Trials that have looked into nutritional support are small and underpowered. They also tend to be hospital based. Ethical considerations exclude a large number of patients. Elective entry into the trials may make results difficult to generalise into the community.

Pharmacological measures

• Insulin: insulin resistance is observed in cachexia. Treatment appears to preserve lean mass by preferential feeding of the host at the expense of the tumour.
• Corticosteroids and semi-synthetic progestational steroids (e.g. megestrol - but lays down fat not muscle) commonly used:
  • Anabolic steroids oxandrolone/nandrolone/testosterone used off-label with high protein diet and exercise has been shown to increase lean body mass (LBM).¹⁰
  • Nandrolone administration was associated with a greater increase in LBM than placebo.
  • However, the change in LBMs with nandrolone was not significantly different from human growth hormone.
• Where patients have a functioning GI tract, enteral feeding is found to be superior to parenteral.¹¹
  
  
• Because of metabolic derangements seen in cancer cachexia, effective nutritional treatment regimens will probably require manipulation of host intermediary metabolism in addition to feeding:
  • Anti-inflammatory agents indomethacin and prednisolone reduce C-reactive protein and with erythropoietin improve exercise capacity. The benefits of anti-inflammatory agents may be more apparent in non-malignant conditions.
  • Omega-3 fatty acids (eg eicosapentanoic acid) have been studied for their ability to reduce cytokine release but their benefits are not clearly established.
  • Other agents tried include antiserotogenic drugs, gastroprokinetic agents, branched chain amino acids, cannabinoids, melatonin, and thalidomide.

If future studies can define the role of signal molecules in producing cancer cachexia syndrome, it may lead to new treatment strategies, possibly involving modulation of the effects of such molecules on host metabolism.

Overall the prognosis for the cachexia depends upon the severity of the underlying disease.