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Cachexia in cancer patients

Key Points

Summary

  • Patients with cancer cachexia show a progressive loss of body weight, which is mainly due to loss of fat and skeletal muscle. Survival of cancer patients is directly related to the total weight loss and also the rate of weight loss.

  • Although anorexia occurs in cancer patients, the reduction in food intake alone is unable to explain the metabolic changes that are seen in cachexia. Nutritional supplementation and pharmacological manipulation of appetite are unable to restore loss of lean body mass.

  • Resting energy expenditure is increased in patients with lung and pancreatic cancer, but not in gastric and colorectal cancer. Increased energy expenditure might be related to the upregulation of uncoupling proteins (UCPs) — particularly UCP3 in skeletal muscle.

  • Loss of adipose tissue arises predominantly from an increase in lipolysis. Lipolysis is induced by a tumour product, lipid-mobilizing factor (LMF), which acts through a β3-adrenoceptor.

  • Loss of skeletal muscle arises from a fall in protein synthesis and an increase in protein degradation. The decreased protein synthesis could arise from the inactivity of the patient, coupled with a reduction in the supply or balance of amino acids due to acute-phase protein production. Increased protein degradation seems to be mainly due to an increased expression of the components of the ubiquitin-proteasome proteolytic pathway in skeletal muscle.

  • Tissue catabolism in cachexia is partially mediated by cytokines such as tumour necrosis factor-α (TNF-α) or interleukin (IL)-1 and IL-6. Tumour catabolic products such as LMF and proteolysis-inducing factor (PIF) directly stimulate tissue breakdown and are also correlated with human cancer cachexia.

  • Therapy has been mainly targeted at TNF-α and PIF. Agents that are directed solely at TNF-α have not shown clinical activity so far. Anticatabolic agents, such as eicosapentaenoic acid (EPA), effectively downregulate the increased expression of the ubiquitin-proteasome pathway in skeletal muscle and are clinically effective in restoring loss of lean body mass in cachectic cancer patients, especially in combination with a protein and energy-dense supplement.

  • Future therapy will consist of a combination of anabolic and anticatabolic agents.

Abstract

Cachexia — the massive (up to 80%) loss of both adipose tissue and skeletal muscle mass — is a significant factor in the poor performance status and high mortality rate of cancer patients. 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. Although anorexia is frequently present, depression of food intake alone seems not to be responsible for the wasting of body tissues, as nutritional supplementation or pharmacological manipulation of appetite is unable to reverse the catabolic process — particularly with respect to skeletal muscle. However, recent clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise.

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Figure 1: Regulation of NPY production in the hypothalamic arcuate nucleus.
Figure 2: Cori cycle with sources of gluconeogenic substrates.
Figure 3: Synthesis and degradation of proteins in skeletal muscle.

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DATABASES

Cancer.gov

colorectal cancer

gastric cancer

lung cancer

pancreatic cancer

LocusLink

cathepsin B

CNTF

CRP

E2

E3

fibrinogen

IFN-γ

IL-1

IL-6

IL-8

insulin

leptin

LMF

LPL

MC3R

MC4R

NF-κB

NPY

phospholipase-A2

POMC

PPARγ

STAT3

TNF-α

transferrin

tripeptidyl peptidase II

UCP1

UCP2

UCP3

OMIM

type IIa hyperlipidaemia

FURTHER INFORMATION

Biomedica cachexia information page

Cancernetwork.com anorexia and cachexia page

Family Practice Notebook Cachexia in Cancer

Glossary

CARCASS LIPID

The total fat content of the body when the water has been removed.

BROWN ADIPOSE TISSUE

(BAT). A special type of adipose tissue, the sole function of which is to burn off excess fat and generate heat. It is found in the interscapular region and is most important in the neonate. No BAT has been detected in adult humans, although brown adipocytes might be present in white adipose tissue.

LIPOLYSIS

The process by which triglycerides, which are stored in adipose tissue, are broken down into glycerol and non-esterified fatty acids.

ASTHENIA

Muscle weakness.

KARNOVSKY INDEX

A physician-scored performance scale ranging from 0 to 100 that determines the level of patient activity. A score of 0 means that the patient is totally inactive, a score of 50 means that the patient is just able to get out of bed, and a score of 100 means that the patient is able to function normally.

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Tisdale, M. Cachexia in cancer patients. Nat Rev Cancer 2, 862–871 (2002). https://doi.org/10.1038/nrc927

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