Clinical Trials for the Treatment of Secondary

Wasting and Cachexia

Wasting in Cancer1
Michael J. Tisdale
Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, United Kingdom

ABSTRACT Progressive weight loss is a common feature of many types of cancer and is responsible not only for
a poor quality of life and poor response to chemotherapy, but also a shorter survival time than is found in patients
with comparable tumors without weight loss. Although anorexia is common, a decreased food intake alone is
unable to account for the changes in body composition seen in cancer patients, and increasing nutrient intake is

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unable to reverse the wasting syndrome. Although energy expenditure is increased in some patients, cachexia can
occur even with a normal energy expenditure. Various factors have been investigated as mediators of tissue
wasting in cachexia. These include cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6),
interferon-g (IFN-g) and leukemia inhibitory factor (LIF), as well as tumor-derived factors such as lipid mobilizing
factor (LMF) and protein mobilizing factor (PMF), which can directly mobilize fatty acids and amino acids from
adipose tissue and skeletal muscle respectively. Induction of lipolysis by the cytokines is thought to result from an
inhibition of lipoprotein lipase (LPL), although clinical studies provide no evidence for an inhibition of LPL in the
adipose tissue of cancer patients. Instead there is an increased expression of hormone sensitive lipase, the enzyme
activated by LMF. Protein degradation in cachexia is associated with an increased activity of the ATP-ubiquitin-
proteasome pathway. The biological activity of both the LMF and PMF was shown to be attenuated by eicosa-
pentaenoic acid (EPA). Clinical studies show that this polyunsaturated fatty acid is able to stabilize the rate of
weight loss and adipose tissue and muscle mass in cachectic patients with unresectable pancreatic cancer.
Knowledge of the mechanism of cancer cachexia should lead to the development of new therapeutic agents. J.
Nutr. 129: 243S–246S, 1999.

KEY WORDS: ● cachexia ● wasting ● cancer

About half of all cancer patients experience a wasting
syndrome called cachexia in which the tumor induces meta-
bolic changes in the host leading to loss of adipose tissue and
skeletal muscle mass. Patients with pancreatic and gastric
cancer have the highest frequency of weight loss (83– 87%)
(De Wys et al. 1980), and in patients with pancreatic cancer
weight loss (14%) is evident at the time of diagnosis, and is
progressive, increasing to a median of 24.5% just before death
(Wigmore et al. 1997). Patients with more than 15% weight
loss are likely to have significant impairment of respiratory
muscle function, which is probably the major contributor to
the shortened survival time of cancer patients with weight loss
(De Wys et al. 1980). Gender related differences in the rate of
weight loss in nonsmall cell lung cancer is responsible for the
significantly shorter survival time in men than women (40
versus 78 weeks after diagnosis) (Palomeres et al. 1996). Thus
a knowledge of the mechanism(s) of cancer cachexia could
lead to the development of agents which would increase the
survival time of cancer patients, without necessarily having an
antitumor effect.

1
ANOREXIA AND ENERGY EXPENDITURE
Presented at the workshop entitled: “Clinical Trials for the Treatment of
Secondary Wasting and Cachexia: Selection of Appropriate Endpoints,” May
22–23, 1997, Bethesda, MD. The workshop was sponsored by the Food and Drug
Cachexia is not a local effect of a tumor, but is thought to
Administration, Office of AIDS Research, National Cancer Institute, National In- arise from distant metabolic effects, i.e. it is a type of paraneo-
stitute of Mental Health, Bristol-Meyers Squibb, Abbott Laboratories, Serono plastic syndrome. Although some theories have suggested a
Laboratories, Inc., American Institute for Cancer Research, Roxane Laboratories,
National Institute of Drug Abuse, SmithKline Beecham, National Institute of Aging,
tumor/host competition for nutrients this seems unlikely, since
Eli Lilly Company and the American Society for Nutritional Sciences. Workshop some cancer patients with very large tumors show no signs of
proceedings are published as a supplement to The Journal of Nutrition. Guest cachexia, while in others cachexia can occur when the tumor
Editors for this supplement publication were D. J. Raiten and J. M. Talbot, Life mass represents less than 0.01% of the host weight (Morrison
Sciences Research Office, American Society for Nutritional Sciences, Bethesda,
MD. 1976).
2
Abbreviations used: LPL, lipoprotein lipase; TNF-a, tumor necrosis factor Weight loss can arise from a decreased energy intake, an
alpha; IL-6, interleukin 6; IFN-g, interferon gamma; LIF, leukemia inhibitory factor; increased energy expenditure or a combination of both. An-
EPA, eicosapentaenoic acid; PUFA, polyunsaturated fatty acid; LMF, lipid mobi-
lizing factor; PMF, protein mobilizing factor; TPN, total parenteral nutrition; REE, orexia is common in cancer patients with reports of incidences
resting energy expenditure. between 15 and 40% at presentation (De Wys 1972). How-

0022-3166/99 $3.00 © 1999 American Society for Nutritional Sciences.

243S
244S SUPPLEMENT
ever, cancer patients with weight loss appear to have a de-
creased food intake when expressed per kg of their usual
weight, but not their current weight (Grosvenor et al. 1989).
In addition although food intake is reduced in advanced can-
cer it is often normal in early disease, even though weight loss
may be apparent (Costa et al. 1981). These results suggest that
anorexia is not responsible for the weight loss in cancer ca-
chexia. Clinical studies directed towards increasing energy
intake in cancer patients have failed to reverse the cachexia.
Such studies include dietary counseling (Oversen et al. 1993),
total parenteral nutrition (TPN) (Evans et al. 1985) and the
appetite stimulant cyproheptadine (Kardinal et al. 1990). The
appetite stimulant megestrol acetate (Megace) has been re-
ported (Loprinzi et al. 1993a) to induce a weight gain of
greater than 5% in 15% of the patients treated, although
significant changes in lean body mass were not generally
observed (Loprinzi et al. 1993b). A general conclusion from
these studies has been that cachectic patients who do gain
weight by provision of excess calories show an increase only in
body fat, without a significant change in total body nitrogen.
Patients with cancer have a highly variable change in
energy expenditure. Thus in comparison with control groups
patients with malignant disease have been reported to have a
reduced (Knox et al. 1983), normal (Nixon et al. 1988) or an
elevated (Fredrix et al. 1991) energy expenditure. Tumor type
appears to play an important role in determining energy ex-
penditure. Thus patients with lung (Fredrix et al. 1990) and
pancreatic (Falconer et al. 1994) cancer have an increased
resting energy expenditure (REE) compared with healthy con-
trol subjects. However, patients with gastric and colorectal
cancer (Fredrix et al. 1990) were reported to have no elevation
of REE. Thus weight loss can occur in some patients with what
appears to be a normal energy intake and a normal energy
expenditure. This suggests that tumor and/or host factors play
an important role in the depletion of body lipid and protein
during the process of cachexia.
FACTORS INFLUENCING FAT METABOLISM
IN CACHEXIA
Fat constitutes 90% of the adult fuel reserves and depletion
of fat is commonly seen in cancer cachexia. Fasting plasma
glycerol concentrations have been shown to be higher in
weight-losing cancer patients compared with weight-stable
individuals, providing evidence for an increased lipolyis (Drott
et al. 1989). Cancer patients with weight loss also have an
increased glycerol and fatty acid turnover when compared with
normal subjects or cancer patients without weight loss (Shaw
and Wolfe 1987).
Two mechanisms have been proposed to account for the
decrease in body lipids in cancer cachexia: (i) Inhibition of the
clearing enzyme lipoprotein lipase (LPL), which would pre-
vent adipocytes from extracting fatty acids from plasma li-
poproteins for storage, and would result in a net flux of lipid
into the circulation. (ii) Direct stimulation of triglyceride
hydrolysis in adipocytes by activation of triglyceride lipase, in
a manner similar to that observed with lipolytic hormones.
The cytokines tumor necrosis factor-alpha (TNF-a), interleu-
kin 6 (IL-6), interferon-g (IFN-g) and leukemia inhibitory
factor (LIF) are all thought to decrease carcass lipids through
inhibition of LPL (Strassman and Kambayashi 1995). The
potency of the various cytokines in inhibiting LPL is not the
same. Thus LIF is two- to ten-fold less potent than TNF-a and
IL-6 is 100-fold less potent than LIF. Also in 3T3-LI adipo-
cytes LIF caused a small increase in lipolysis, whereas TNF-a
increased lipolysis greater than two-fold, demonstrating that
the catabolic effects of LIF are less than that of TNF-a
(Marshall et al. 1994). Stimulation of lipolysis by TNF-a is not
direct, since it became apparent only after a 6 h exposure at
the earliest (Hauner et al. 1995). In contrast a number of
reports (Beck and Tisdale 1987, Kitada et al. 1980, Masuno et
al. 1981) have documented the production by cachexia-induc-
ing tumors of a lipid mobilizing factor (LMF) that causes
immediate release of glycerol when incubated with murine
epididymal adipocytes. Induction of lipolysis by LMF was
associated with an increase in the intracellular level of cyclic
AMP, possibly formed in response to activation of adenylate
cyclase (Tisdale and Beck 1991).
Elevation of plasma levels of fatty acids and triglycerides in
cachectic cancer patients (Rofe et al. 1994) has often been
used as an argument for cytokine involvement in cancer ca-
chexia. However, patients with AIDS experience hypertriglyc-
eridemia, but still maintain their body weight for prolonged
periods of time (Grunfeld et al. 1989). In addition TNF-a
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induced hypertriglyceridemia persists in animals despite the
development of tachyphylaxis to its anorectic/cachectic effect.
Further studies showed the hypertriglyceridemia to be the
result of stimulation of hepatic lipogenesis rather than inhibi-
tion of LPL (Grunfeld and Feingold 1991). Thompson et al.
(1993) were not only unable to detect elevated TNF-a levels
in cachectic cancer patients, but in addition the total LPL
enzyme activity and the relative levels of the mRNA’s for LPL
and fatty acid synthase were not significantly different between
cancer patients and controls. There was, however, a two-fold
elevation in the relative level of the mRNA for hormone-
sensitive lipase in the adipose tissue of the cachectic cancer
patients, providing evidence for lipid breakdown through the
cyclic AMP pathway. Disruption of lipid metabolism through
inhibition of LPL alone is unlikely to induce the large deple-
tion of body fat seen in cancer cachexia. Patients with type 1
hyperlipidemia have an inherited deficiency of LPL, but are
not cachectic and have normal fat stores.
The serum and urine of cachectic cancer patients contains
a LMF the activity of which has been shown to correlate with
the extent of weight loss (Groundwater et al. 1990). Such
activity is not detectable in normal subjects or in patients with
weight loss due to Alzheimer’s disease. The LMF appears to
correlate with tumor burden, since activity was found to be
reduced in patients responding to chemotherapy (Beck et al.
1990). Further evidence for the importance of LMF in cancer
cachexia has been provided by clinical studies on the polyun-
saturated fatty acid (PUFA), eicosapentaenoic acid (EPA)
(Wigmore et al. 1996). In vitro studies using a LMF isolated
from a cachexia-inducing murine tumor (MAC16) showed
that out of a range of PUFA only EPA was an effective
inhibitor of biological activity and only EPA was effective in
vivo against the cachexia induced by the MAC16 tumor.
Patients with unresectable pancreatic cancer receiving EPA
showed a stabilization in the rate of weight loss, adipose tissue
and muscle mass as well as the REE (Wigmore et al. 1996).
This study is the first to show that pharmacological interfer-
ence with a tumor factor is capable of counteracting the
wasting of cachexia.
FACTORS INFLUENCING MUSCLE METABOLISM
IN CACHEXIA
Lean body mass and visceral protein depletion is character-
istic of patients with cancer cachexia and the degree of deple-
tion may be associated with reduced survival (Nixon et al.
1980). The major site of this protein loss is the skeletal
musculature (McMillan et al. 1994). A reduced rate of protein
 WASTING IN CANCER
synthesis and an increased rate of degradation has been ob-
served in muscle biopsies from cancer patients with weight loss
(Lundholm et al. 1976). Elevated whole body protein turnover
may be apparent in patients with a small tumor burden (Fe-
aron et al. 1988), and in one study increased total body protein
turnover was observed in patients with pre-cachectic lung
cancer (Heber et al. 1982), which was found to be inversely
proportional to the small degree of weight loss that had oc-
curred.
TNF-a appears to be involved with an enhanced protein
degradation, although this does not appear to be related to
weight loss. Thus treatment with TNF-a has been shown to
enhance protein degradation in rat skeletal muscle in vivo, and
although body weight loss was not apparent there was a re-
duced protein accumulation (Llovera et al. 1993). Treatment
of rats bearing the Yoshida AH-130 ascites hepatoma with
goat anti m TNF-a IgG decreased protein degradation rates in
heart, liver and gastrocnemius muscle, but did not affect
weight loss (Costelli et al. 1993). In both skeletal muscle from
rats treated with TNF-a (Llovera et al. 1993) and from rats
bearing the Yoshida AH-130 hepatoma (Llovera et al. 1994)
an increase in polyubiquitin gene expression was observed.
Atrophy of muscles was also observed in IL-6 transgenic mice
which was associated with increased mRNA levels of ubiquit-
ins (poly and mono). The pathway responsible for the accel-
erated proteolysis in starvation, acidosis and after transplanta-
tion of certain tumors is thought to be the ubiquitin-
proteasome system. Although early studies failed to find a
direct action of TNF-a on protein degradation, when either
tyrosine or 3-methylhistidine were used as a measure of the
proteolytic rate (Goldberg et al. 1988), a recent report (Ll-
overa et al. 1997) has shown an increase in ubiquitin gene
expression in rat soleus muscle after incubation with TNF-a
for 180min in vitro, with no change in the expression of the C8
proteasome subunit. Also using C2C12 myotubes in vitro Ebisui
et al. (1995) found that recombinant human IL-6 (rh IL-6)
shortened the half-life of long lived proteins and increased the
activity of the 26S proteasome and cathepsins B and B1L.
Interestingly recombinant human TNF-a (rh TNF-a) was
shown to prolong the half-lives of long-lived proteins while
reducing the protease activities of the 26S proteasome and
cathepsins B and B1L. The variability of the response of
cytokines in different systems and the lack of correlation with
the wasting process may be due to the fact that they do not act
directly, but instead cause induction of further factor(s), which
themselves may be responsible for the wasting.
One such mediator could be a protein mobilizing factor
(PMF), which has been recently isolated from a cachexia-
inducing murine tumor (MAC16) and from the urine of pa-
tients with cancer cachexia (Todorov et al. 1996a). This
material was shown to be a sulfated glycoprotein or proteogly-
can of molecular weight 24 kDa, the structure of which was
distinct from the recognized cytokines. Administration of the
PMF to non tumor-bearing mice induced a state of cachexia
with loss of 2.7 g body weight over a 24 h period without an
effect on food and water intake. Blood glucose levels were
significantly decreased, but there was no alteration in plasma
triglyceride levels, unlike the effect observed with cytokines.
Body composition analysis showed a reduction in lean body
mass without a change in water composition. The PMF was
capable of inducing tyrosine release from isolated gastrocne-
mius muscle and the effect could be blocked by a monoclonal
antibody specific to the PMF (Todorov et al. 1996b). Western
blotting of urine using the monoclonal antibody showed the
24 kDa glycoprotein to be present in all cancer patients with
weight loss, but absent from cancer patients with little or no
245S
weight loss, confirming the specificity to the cachectic state. In
addition it was absent from the urine of normal subjects or
those with weight loss due to major burns, multiple injuries or
surgery-associated catabolism and sepsis (Todorov et al.
1996a). Thus this material appears to be specific for muscle
wasting in cancer. In addition the PMF was shown to be
attenuated by EPA (Smith and Tisdale 1993) which has been
shown to preserve muscle mass in cachectic cancer patients
(Wigmore et al. 1996).
SUMMARY AND CONCLUSION
Unlike simple starvation, where body fat is lost preferen-
tially, cancer cachexia is associated with depletion of both fat
and skeletal muscle mass. Although anorexia is frequently
associated with cachexia a reduction of nutrient intake alone
could not explain the progressive wasting. Instead the process
appears to be mediated by circulatory tumor-produced cata-
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bolic factors acting either alone or in concert with certain
cytokines. A knowledge of the mechanisms involved should
lead to the development of effective pharmacological inter-
vention. Effective therapy should not only improve the quality
of life of the cancer patient, but should lead to an increase in
survival. Since cachexia is so common in cancer host products
may be required for tumor homeostasis. Thus further knowl-
edge in this area may lead to the development of new agents
for the treatment of cancer.
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