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 muscle function, which is probably the major contributor to
syndrome called cachexia in which the tumor induces meta- the shortened survival time of cancer patients with weight loss
bolic changes in the host leading to loss of adipose tissue and (De Wys et al. 1980). Gender related differences in the rate of
skeletal muscle mass. Patients with pancreatic and gastric weight loss in nonsmall cell lung cancer is responsible for the
cancer have the highest frequency of weight loss (83– 87%) significantly shorter survival time in men than women (40
(De Wys et al. 1980), and in patients with pancreatic cancer versus 78 weeks after diagnosis) (Palomeres et al. 1996). Thus
weight loss (14%) is evident at the time of diagnosis, and is a knowledge of the mechanism(s) of cancer cachexia could
progressive, increasing to a median of 24.5% just before death lead to the development of agents which would increase the
(Wigmore et al. 1997). Patients with more than 15% weight survival time of cancer patients, without necessarily having an
loss are likely to have significant impairment of respiratory 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- the catabolic effects of LIF are less than that of TNF-a
creased food intake when expressed per kg of their usual (Marshall et al. 1994). Stimulation of lipolysis by TNF-a is not
weight, but not their current weight (Grosvenor et al. 1989). direct, since it became apparent only after a 6 h exposure at
In addition although food intake is reduced in advanced can- the earliest (Hauner et al. 1995). In contrast a number of
cer it is often normal in early disease, even though weight loss reports (Beck and Tisdale 1987, Kitada et al. 1980, Masuno et
may be apparent (Costa et al. 1981). These results suggest that al. 1981) have documented the production by cachexia-induc-
anorexia is not responsible for the weight loss in cancer ca- ing tumors of a lipid mobilizing factor (LMF) that causes
chexia. Clinical studies directed towards increasing energy immediate release of glycerol when incubated with murine
intake in cancer patients have failed to reverse the cachexia. epididymal adipocytes. Induction of lipolysis by LMF was
Such studies include dietary counseling (Oversen et al. 1993), associated with an increase in the intracellular level of cyclic
total parenteral nutrition (TPN) (Evans et al. 1985) and the AMP, possibly formed in response to activation of adenylate
appetite stimulant cyproheptadine (Kardinal et al. 1990). The cyclase (Tisdale and Beck 1991).
appetite stimulant megestrol acetate (Megace) has been re- Elevation of plasma levels of fatty acids and triglycerides in
ported (Loprinzi et al. 1993a) to induce a weight gain of cachectic cancer patients (Rofe et al. 1994) has often been
greater than 5% in 15% of the patients treated, although used as an argument for cytokine involvement in cancer ca-
significant changes in lean body mass were not generally chexia. However, patients with AIDS experience hypertriglyc-
observed (Loprinzi et al. 1993b). A general conclusion from eridemia, but still maintain their body weight for prolonged
these studies has been that cachectic patients who do gain periods of time (Grunfeld et al. 1989). In addition TNF-a

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weight by provision of excess calories show an increase only in induced hypertriglyceridemia persists in animals despite the
body fat, without a significant change in total body nitrogen. development of tachyphylaxis to its anorectic/cachectic effect.
Patients with cancer have a highly variable change in Further studies showed the hypertriglyceridemia to be the
energy expenditure. Thus in comparison with control groups result of stimulation of hepatic lipogenesis rather than inhibi-
patients with malignant disease have been reported to have a tion of LPL (Grunfeld and Feingold 1991). Thompson et al.
reduced (Knox et al. 1983), normal (Nixon et al. 1988) or an (1993) were not only unable to detect elevated TNF-a levels
elevated (Fredrix et al. 1991) energy expenditure. Tumor type in cachectic cancer patients, but in addition the total LPL
appears to play an important role in determining energy ex- enzyme activity and the relative levels of the mRNA’s for LPL
penditure. Thus patients with lung (Fredrix et al. 1990) and and fatty acid synthase were not significantly different between
pancreatic (Falconer et al. 1994) cancer have an increased cancer patients and controls. There was, however, a two-fold
resting energy expenditure (REE) compared with healthy con- elevation in the relative level of the mRNA for hormone-
trol subjects. However, patients with gastric and colorectal sensitive lipase in the adipose tissue of the cachectic cancer
cancer (Fredrix et al. 1990) were reported to have no elevation patients, providing evidence for lipid breakdown through the
of REE. Thus weight loss can occur in some patients with what cyclic AMP pathway. Disruption of lipid metabolism through
appears to be a normal energy intake and a normal energy inhibition of LPL alone is unlikely to induce the large deple-
expenditure. This suggests that tumor and/or host factors play tion of body fat seen in cancer cachexia. Patients with type 1
an important role in the depletion of body lipid and protein hyperlipidemia have an inherited deficiency of LPL, but are
during the process of cachexia. not cachectic and have normal fat stores.
The serum and urine of cachectic cancer patients contains
FACTORS INFLUENCING FAT METABOLISM a LMF the activity of which has been shown to correlate with
IN CACHEXIA the extent of weight loss (Groundwater et al. 1990). Such
activity is not detectable in normal subjects or in patients with
Fat constitutes 90% of the adult fuel reserves and depletion weight loss due to Alzheimer’s disease. The LMF appears to
of fat is commonly seen in cancer cachexia. Fasting plasma correlate with tumor burden, since activity was found to be
glycerol concentrations have been shown to be higher in reduced in patients responding to chemotherapy (Beck et al.
weight-losing cancer patients compared with weight-stable 1990). Further evidence for the importance of LMF in cancer
individuals, providing evidence for an increased lipolyis (Drott cachexia has been provided by clinical studies on the polyun-
et al. 1989). Cancer patients with weight loss also have an saturated fatty acid (PUFA), eicosapentaenoic acid (EPA)
increased glycerol and fatty acid turnover when compared with (Wigmore et al. 1996). In vitro studies using a LMF isolated
normal subjects or cancer patients without weight loss (Shaw from a cachexia-inducing murine tumor (MAC16) showed
and Wolfe 1987). that out of a range of PUFA only EPA was an effective
Two mechanisms have been proposed to account for the inhibitor of biological activity and only EPA was effective in
decrease in body lipids in cancer cachexia: (i) Inhibition of the vivo against the cachexia induced by the MAC16 tumor.
clearing enzyme lipoprotein lipase (LPL), which would pre- Patients with unresectable pancreatic cancer receiving EPA
vent adipocytes from extracting fatty acids from plasma li- showed a stabilization in the rate of weight loss, adipose tissue
poproteins for storage, and would result in a net flux of lipid and muscle mass as well as the REE (Wigmore et al. 1996).
into the circulation. (ii) Direct stimulation of triglyceride This study is the first to show that pharmacological interfer-
hydrolysis in adipocytes by activation of triglyceride lipase, in ence with a tumor factor is capable of counteracting the
a manner similar to that observed with lipolytic hormones. wasting of cachexia.
The cytokines tumor necrosis factor-alpha (TNF-a), interleu-
kin 6 (IL-6), interferon-g (IFN-g) and leukemia inhibitory FACTORS INFLUENCING MUSCLE METABOLISM
factor (LIF) are all thought to decrease carcass lipids through IN CACHEXIA
inhibition of LPL (Strassman and Kambayashi 1995). The
potency of the various cytokines in inhibiting LPL is not the Lean body mass and visceral protein depletion is character-
same. Thus LIF is two- to ten-fold less potent than TNF-a and istic of patients with cancer cachexia and the degree of deple-
IL-6 is 100-fold less potent than LIF. Also in 3T3-LI adipo- tion may be associated with reduced survival (Nixon et al.
cytes LIF caused a small increase in lipolysis, whereas TNF-a 1980). The major site of this protein loss is the skeletal
increased lipolysis greater than two-fold, demonstrating that musculature (McMillan et al. 1994). A reduced rate of protein
 WASTING IN CANCER 245S

synthesis and an increased rate of degradation has been ob- weight loss, confirming the specificity to the cachectic state. In
served in muscle biopsies from cancer patients with weight loss addition it was absent from the urine of normal subjects or
(Lundholm et al. 1976). Elevated whole body protein turnover those with weight loss due to major burns, multiple injuries or
may be apparent in patients with a small tumor burden (Fe- surgery-associated catabolism and sepsis (Todorov et al.
aron et al. 1988), and in one study increased total body protein 1996a). Thus this material appears to be specific for muscle
turnover was observed in patients with pre-cachectic lung wasting in cancer. In addition the PMF was shown to be
cancer (Heber et al. 1982), which was found to be inversely attenuated by EPA (Smith and Tisdale 1993) which has been
proportional to the small degree of weight loss that had oc- shown to preserve muscle mass in cachectic cancer patients
curred. (Wigmore et al. 1996).
TNF-a appears to be involved with an enhanced protein
degradation, although this does not appear to be related to SUMMARY AND CONCLUSION
weight loss. Thus treatment with TNF-a has been shown to
enhance protein degradation in rat skeletal muscle in vivo, and Unlike simple starvation, where body fat is lost preferen-
although body weight loss was not apparent there was a re- tially, cancer cachexia is associated with depletion of both fat
duced protein accumulation (Llovera et al. 1993). Treatment and skeletal muscle mass. Although anorexia is frequently
of rats bearing the Yoshida AH-130 ascites hepatoma with associated with cachexia a reduction of nutrient intake alone
goat anti m TNF-a IgG decreased protein degradation rates in could not explain the progressive wasting. Instead the process
heart, liver and gastrocnemius muscle, but did not affect appears to be mediated by circulatory tumor-produced cata-

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weight loss (Costelli et al. 1993). In both skeletal muscle from bolic factors acting either alone or in concert with certain
rats treated with TNF-a (Llovera et al. 1993) and from rats cytokines. A knowledge of the mechanisms involved should
bearing the Yoshida AH-130 hepatoma (Llovera et al. 1994) lead to the development of effective pharmacological inter-
an increase in polyubiquitin gene expression was observed. vention. Effective therapy should not only improve the quality
Atrophy of muscles was also observed in IL-6 transgenic mice of life of the cancer patient, but should lead to an increase in
which was associated with increased mRNA levels of ubiquit- survival. Since cachexia is so common in cancer host products
ins (poly and mono). The pathway responsible for the accel- may be required for tumor homeostasis. Thus further knowl-
erated proteolysis in starvation, acidosis and after transplanta- edge in this area may lead to the development of new agents
tion of certain tumors is thought to be the ubiquitin- for the treatment of cancer.
proteasome system. Although early studies failed to find a
direct action of TNF-a on protein degradation, when either LITERATURE CITED
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