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
Author: Dr Van Rhijn
Weight Loss in Cancer
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.
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.
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.
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
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