Title: Weight Loss in Cancer

Key words: cachexia, anorexia, muscle wasting, body cell mass (BCM), tumor necrosis factor (TNF), cytokines

Date: July 2000

Category: 13. Specific Conditions

Type: Article

Author: Dr Van Rhijn

 

Weight Loss in Cancer

 

 

Introduction

Weight loss and cachexia, associated with increased morbidity and mortality1, is a frequent complication of cancer, due to wasting of both fat mass and body cell mass (BCM)2. The latter is an important determinant of performance status and survival3, 4. Anorexia plays a central role in the weight loss, but cancer cachexia is more complex than pure chronic starvation. This article will explore the complex underlying pathophysiology.

Mechanisms

In contrast to simple starvation, the predominant manifestations of cancer cachexia are an elevated basal metabolic rate5 and increased energy expenditure6 (BCM-adjusted resting energy expenditure) combined with an equal systemic catabolism of muscle and adipose tissues7. Mounting evidence suggests that cancer cachexia is related to a chronic, low-grade tumour-induced activation of the host immune system8, 9, very similar to the acute-phase response found in trauma and infection. Numerous factors are activated, such as increased acute-phase protein10, 11 and cytokine production12, 13, elevation of cortisol14, glucagons and catecholamines levels, increased fatty acid & amino acid mobilisation and hepatic uptake with enhanced gluconeogenesis15.

Weight loss and muscle wasting, the major determinant of BCM wasting, is associated with high circulating levels of tumor necrosis factor receptor (sTNF-Rs), lipopolysaccharide-binding protein (LBP), the release of cytokine inflammatory mediators (IL-116, IL-617, 18, 19 & TNF20, 21, 22), interferon (IFN)-gamma and leukemia inhibitory factor (LIF)23, which have direct proteolytic effects on muscle tissue. The cytokine-triggered (acute-phase response) reprioritization of body protein metabolism may contribute to proteolysis in pancreatic cancer24, but the balance between two cytokine types (procachectic: anticachectic) may have a key role in cancer cachexia25. The TNF-induced decrease in muscle protein synthesis & albumin 26 and the decreased production of two anabolic hormones, testosterone27 & insulin-like growth factor-I (IGF-I)28, also contribute to BCM wasting. Cytokines may also play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signalling from leptin (via stimulation of anorexigenic neuropeptides)29. Cytokines (TNF & IL-1) may also induce a decrease in food intake30. The tumor-derived cytokines that induce cancer cachexia syndrome may be referred to as toxohormones31.

Activity Markers?

Alterations in fat metabolism associated with suppression of tissue lipoprotein lipase (LPL) activity in patients with advanced gastrointestinal or breast cancer may reflect changes in nutritional status32. It is suggested that sTNF-RI33 or soluble interleukin-2 receptor (sIL-2R)34 could be important prognostic factors, to be able to predict the advance of gastric and colorectal cancers and deterioration of the patient's nutritional and immune activity. Serum levels of IL-6 also correlate with the clinical development of cachexia in pancreatic cancer35.

Conclusion

It appears that cancer-related anorexia/cachexia syndrome (CACS) is associated with the presence of increased serum inflammatory mediators, suggesting a systemic low-grade inflammatory state and decreased IGF-I level. Anti-inflammatory nutrients36, 37 and IGF-I39 may combat a rapid decline in BCM and therefore increase survival rates in cancer patients.

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