Cachexia

Background¹

Cachexia is defined as the unwanted loss of at least 5% of mean body mass in the preceding six months. It is a condition which affects skeletal muscle mass and function. The word "cachexia" is derived from the Greek and means "bad condition".

For many years cachexia was viewed as an inevitable part of terminal disease, without considering it as a condition in its own right. It is increasingly being recognised as a systemic disorder as opposed to merely a secondary consequence of malnutrition or advanced disease.² Studies have shown that, alongside the obvious skeletal muscle loss, cachexia also involves:

• Striated muscle loss (which can lead to death due to cardiac and respiratory dysfunction).

• Altered mitochondrial metabolism.

• Altered fatty acid metabolism.

Pathogenesis

Cancer cachexia arises from complex and dynamic interactions between tumours and host organ systems, including immune, metabolic, endocrine, and neural networks, that collectively reshape energy balance, immune function, and tissue integrity.²

The complex systemic interplay includes:¹

• Immune system

  • Systemic inflammation and cytokine storms are drivers of cachexia.

  • Metabolic and molecular changes in skeletal muscle, caused by this, occur in patients before any evidence of weight loss.

  • Tumour necrosis factor alpha (TNF-α) was the first cytokine identified as causing cachexia.

  • Studies suggest that the development of cancer cachexia might be linked to the expansion of immature myeloid populations and decreased macrophage infiltration.

• Hepatic system

  • Liver function is significantly impacted by pro-inflammatory cytokines which lead to steatosis, insulin resistance, and cholestasis.

  • The liver is also part of the acute phase response to tissue injury and inflammation by synthesising acute phase proteins, which are strongly upregulated in cachexia.

  • Reduced ketogenesis has been shown to be occur in cachexia, reducing the physiological response to low food intake. The resultant elevated glucocorticoid levels lead to both a strong catabolysis and anti-anabolysis in skeletal muscle, ultimately leading to atrophy.

• Brain and neurological system.

  • Anorexia occurs commonly with cachexia, particularly cancer-driven cachexia.

  • There is good evidence that increased hypothalamic inflammation is involved in the disruption of homeostatic regulation of appetite.

• Gastrointestinal system

  • The gut microbiome may be another source of inflammation.

  • Gut barrier dysfunction has been shown to be associated with cachexia.

• Insulin resistance

  • A change in glucose metabolism has been known to occur in patients with cancer for over a century.

  • Recent studies have confirmed that cancers can promote insulin resistance, and that this is more significant in patients with cachexia.

• Bone density

  • Bone loss has been poorly studied in cachexia.

  • Evidence has shown that patients with 30% weight loss have lower bone mineral content.

  • Bone metastases, bone pain and hypercalcemia are often seen in cachectic patients.

Aetiology

• Many types of cancer (particularly pancreatic cancer, stomach cancer, oesophageal cancer, colorectal cancer).

• AIDS.

• Congestive heart failure.

• Rheumatoid arthritis.

• Tuberculosis.

• Chronic obstructive pulmonary disease (COPD).

• Cystic fibrosis.

• Crohn's disease.

• Chronic kidney disease (CKD).

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

The prevalence of cachexia varies depending on the diagnostic criteria used: 5-15% in cardiac disease, 5-15% in COPD, 15-32% in rheumatoid arthritis, 50-75% in CKD, and between 60% and 80% in cancer patients. The prevalence exceeds 80% in the last 1-2 weeks of life.³

Studies have suggested that cancer-related weight loss can start 12 months before any disease becomes apparent.⁴

Differential diagnosis

There are many causes of abnormal weight loss apart from cancer and cardiac failure. See the separate Abnormal weight loss article for a full list.

Management

Apart from maintaining optimal management of the underlying condition, there are currently no standardised treatments for cachexia or severe wasting. However there is a growing consensus advocating multimodal interventions to alleviate and/or stabilise cachexia and severe wasting.

General measures

Hypercaloric feeding has repeatedly been shown as ineffective in increasing lean mass. It may cause weight gain but this is due to deposition of fat.⁵

Parenteral nutritional support improves the way cancer patients tolerate treatment and has a place in the palliative care of certain patients - eg, those with intestinal obstruction.⁶

The National Institute for Health and Care Excellence (NICE) recommends oral, enteral, or parenteral support (according to need and swallowing ability) for adults when:⁷

• BMI is <18.5 kg/m³.

• There has been >10% of total body weight lost in the preceding 3-6 months.

• BMI is <20 and there has been 5% weight loss in the preceding 3-6 months.

See also the separate Enteral feeding and enteral nutrition and Nutritional support in primary care articles.

Pharmacological measures⁸

Most pharmacological measures are in the study phase and not yet approved for treatment.

• The possibility of utilising the insulin signalling system is currently being explored.⁹

• Enobosarm (a selected androgen receptor modulator) was shown to have some benefits for cachexia in phase 2 trials but its phase 3 trials did not show the same benefit. At the time of writing, it is currently undergoing trials for use in breast cancer.¹⁰¹¹

• Anamorelin (a ghrelin agonist) has not been approved for use and the company is no longer seeking approval for its use for cachexia or anorexia due to poor trial results despite early promise.¹²

• Anti-inflammatory agents such as indomethacin showed promise in animal studies but there is insufficient evidence for their use in cachexia.¹³¹⁴

• Steroids - eg, methylprednisolone - provide short-term symptomatic relief for anorexia and fatigue in palliative care but no evidence of sustained benefit or of increase in muscle mass, and their side effect profile is significant.¹²¹⁵

• There may be a role for antioxidants in combating oxidative stress.

• Nutrient supplementation has generally shown inconclusive or poor evidence of benefit, although whey protein supplementation has shown some benefit.¹⁶

Prognosis

Overall, the prognosis for the cachexia depends upon the severity of the underlying disease. However, cachexia is often a complication with a very poor prognosis, and often represents the last step of several chronic diseases.¹⁷ New studies into causative mechanisms provide some hope of treatment in the future.