The Cancer Cachexia Syndrome

THE SURGEON AND PALLIATIVE CARE

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THE CANCER CACHEXIA SYNDROME Kenneth C. H. Fearon, MD, FRCS, Matthew D. Barber, MBChB, FRCS, and Alastair G. W. Moses, BSc, MBChB, FRCS

CACHEXIA: A COMPLEX MULTILAYERED SYNDROME

Cancev cachexia, a term derived from the Greek words kakos and hexis meaning poor condition, covers a broad complex of symptoms and signs. Often the term is used to described the cancer patient with severe weight loss. Although weight loss is an essential component of cachexia, it is important to appreciate that patients with this syndrome experience many other symptoms and signs which reflect the multifactorial causes of the condition and contribute to the difficulties of instituting effective therapy. Cachexia is not exclusive to cancer but is seen in a variety of other conditions (e.g., acquired immunodeficiency syndrome and rheumatoid a r t h r i t i ~ ) This . ~ ~ ,points ~ ~ to its multifactorial cause. At the core of the syndrome lies the interaction between host cells and tumor cells, the sequelae of progressive tumor growth, and the sideeffects and toxicities of antineoplastic therapy. As a result of these key events (Fig. I), a variety of anorectic and catabolic mediators are released including activated cells of the inflammatory and immune system and soluble proinflammatory cytokines, tumor-derived cachectic factors, and counter-regulatory endocrine hormones. In turn, these cellular and humoral mediators can have direct effects or act indirectly through other metabolic pathways resulting in a reduction of food intake, an increase in energy expenditure, or a combination of the two. Consequently, a progressive negative energy and nitrogen balance is associated with changes in the function and mass of a variety of organs and tissues including skeletalmuscle, adipose tissue, the gut, liver, immune system,brain, and hematopoietic From the Department of Clinical and Surgical Sciences (Surgery), The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

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Figure 1. The syndrome of cancer cachexia is a complex multilayered phenomenon. As a result of progressive tumor growth, a complex mixture of mediators are released. In turn, alterations in food intake and body metabolism result in loss of tissue and organ mass function. These changes are experienced as a variety of symptoms and signs.

system. In general there is profound loss of tissue mass (e.g., skeletal muscle or adipose tissue).37Certain tissues, however, can become more active and undergo hypertrophy (e.g., the liver and spleen) such that there is a relative preservation of visceral protein mass (Fig. 2). This differentiates cachexia from simple starvation and emphasizes that not all changes in cachexia are dependent on a net negative energy and protein balance-a point that has important implications when considering therapeutic intervention. Finally, the previously mentioned changes in organ mass and function are translated into symptoms and signs, such as weight loss, weakness, anorexia, anemia, and edema. The overall effect is a decrease in functional ability and a reduction in the quality and perhaps quantity of life. The aim of this article is to review the importance of cachexia, explore some of the relevant metabolic mechanisms, and describe the potential mediators implicated in the cachectic process. In light of the many recent advances concerning the pathophysiology of cachexia, current therapy is surveyed and the potential for further progress is outlined. INCIDENCE AND IMPORTANCE QF CACHEXIA The majority of patients with advanced cancer lose weight and exhibit, to some extent, the features of cachexia. In terms of weight loss, this is more common in patients with lung and upper gastrointestinal cancer and is less common in patients with breast or lower gastrointestinal

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Changes in body composition associated with development of cancer cachexia in patients with advanced lung cancer. LBM = lean body mass; N S = not significant. (Adapted from Fearon KCH, Preston T: Body composition in cancer cachexia. lnfusionstherapie 17 [suppl 3]:63-66, 1990; with permission.) Figure 2.

cancer.26Although certain tumor types are more commonly associated with cachexia, it is remarkable how patients with the same tumor type can vary in the extent to which they become cachectic. Such observations point to variations in tumor phenotype or host genotype contributing to the development of cachexia and emphasize the importance of host-tumor interaction in the genesis of the syndrome.39 In many patients the onset of cachexia is associated with a reduction in functional ability. For example, in patients with advanced pancreatic cancer, there is a strong inverse relationship between severity of weight loss and performance score.6Although such findings have been observed in other groups of cancer patients,sOit is not clearly established whether such an association is causal or whether it is simply related to the presence of advanced cancer. Although a strong relationship between cachexia and reduced survival has been suggested by some a~thors,5~,lll cause and effect independent of tumor growth has not been proven because of the lack of clearly effective therapy for cancer cachexia. MECHANISMS OF CACHEXIA As mentioned previously, weight loss is a key feature of cachexia, and patients, in general, lose weight because of a reduction in food intake, an increase in energy expenditure, or a combination of the two.

Anorexia

Patients with cancer cachexia frequently have specific problems that lead to a reduction in nutritional intake. Such factors include physical obstruction of the gastrointestinal tract, nausea, constipation and debility, psychologic problems including depression, and pain and the side effects of treatment with opiates, radiotherapy, and chemotherapy. These clinical problems should all be treated actively in the anorexic cancer patient. Even if these factors are well controlled, however, those with cancer cachexia often describe poor appetite, early satiety, changes in taste, and classical anorexia.39These symptoms are similar to those seen in many groups of patients with inflammatory and infective illnesses and may constitute part of the host response to the cancer-bearing state. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight.57In particular, leptin, a molecule secreted by adipose tissue, has been shown to influence food intake and energy expenditure through neuropeptidergic effector molecules in the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the leptin loop and the potential role of these mediators in cancer-related anorexia is discussed later. Hypermetabolism

A heterogeneous picture of energy expenditure has been described in cancer patients with resting energy expenditure varying between less than 60% and more than 150% of predicted values.61Longitudinal studies in a rat model have suggested that animals initially may be hypermetabolic before passing through a relatively normometabolic period to a preterminal hypometabolic phase.lZ3Such longitudinal studies have not been performed in humans but this pattern would account for some of the observed variation. Patients with tumor types frequently associated with cachexia (such as the lung and pancreas) tend to exhibit an elevated resting ,~' appear, however, that the other compoenergy e ~ p e n d i t u r e . ~It~would nents of total energy expenditure (i.e.,the thermogenic response to feeding and physical activity) may be reduced resulting in an overall fall in total energy e ~ p e n d i t u r eIt. ~is~conceivable that the attempted maintenence of energy balance through such a reduced level of activity may impair quality of life. Substrate Metabolism

A variety of changes in nutrient metabolism have been described in patients with cancer cachexia. Patients frequently exhibit a relative glucose intolerance and insulin resistance with increased rates of glucose production and recycling through lactate (the Cori cycle).29These changes may become more pronounced with progress of the di~ease.9~ Most solid tumors seem to obtain their energy from the anaerobic metabolism of glucose54and

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there is debate as to what extent these changes develop in order to supply the tumor with nutrients. It has been suggested that increased glucose turnover may have an energy cost of up to 260 kcal per day or represent 10%to 15%of total energy e ~ p e n d i t u r e . ~ ~ Substantial loss of adipose tissue is observed in cancer cachexia37and this is associated with elevated fat oxidation rates. It contrast, lipolysis rates are not significantly increased but rather lipogenesis appears to be reduced.58This may be secondary to reduced levels of lipoprotein lipase.l1° Whether such changes in fat metabolism play a primary role in the wasting process or are generally adaptive in origin is not clearly established. Whole body protein turnover has been found to be increased in the majority of advanced cancer patients compared with starved normal individuals and weight-losing noncancer patients and appears to increase further with progression of disease.36The energy cost of this protein turnover has been estimated to be around 100 kcal/day. As with increased glucose turnover, however, in terms of the energy economy of the whole body it is not clear what impact changes of this magnitude have on net energy balance. The cancer-bearing state effects protein synthesis and breakdown in the different tissues of the body in a highly variable manner. Loss of skeletal muscle protein is a prominent feature of cachexia and a reduction in the rate of muscle protein synthesis has been described in humans.28Protein degradation is more difficult to measure in vivo. In a rat model of cancer cachexia, however, it has been suggested that muscle wasting is associated with an activation of the adenosine triphosphate (ATP)-dependent ubiquitinmediated proteolytic pathway with no effect on calcium-dependent or lysosomal proteolytic systems.64The relevance of this system to human cachexia remains to be explored. In terms of liver protein metabolism, hepatic export protein synthesis seems to be altered such that while albumin synthesis remains unchanged, fibrinogen synthesis rates are significantly i n c r e a ~ e d .These ~~,~~ changes occur on a background of a decrease in the circulating concentration of albumin and an increase in the concentration of fibrinogen. The influence of progressive tumor growth on albumin and fibrinogen degradation rates is not clearly established in humans. The Acute Phase Protein Response

The changes in hepatic protein synthesis mentioned previously are known to reflect aspects of the acute phase protein response, a reprioritization of liver protein synthesis often seen in trauma, inflammation, and infection.12 An acute phase protein response may be seen in a significant proportion of patients with cancer of the pancreas, lung, kidney, and esophagus,17,33, 98, and the proportion of pancreatic cancer patients exhibiting an acute phase response tends to increase with disease progre~sion.~~ The presence of an acute phase response has been related to accelerated weight-loss in lung and pancreatic cancer and melanoma.51,91,98,117

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Moreover, the presence of such a response in cancer patients is associated strongly with a shortened survival in renal, pancreatic, and colorectal cancer.17,35, 78 The acute phase protein response is known to aid tissue repair, blood clotting, the prevention of ongoing tissue damage, and the destruction of infective organisms.12 The value of the acute phase protein response in patients with cancer is not clear, and it may be that it occurs as part of a stereotyped response to inflammation. It is stimulated at least in part by proinflammatory cytokines, notably interleukin IL-6.21Some tumor cell lines produce proinflammatory ~ytokines,"~ and it is conceivable that the tumor may benefit from changes associated with the acute phase response, such as altered energy substrate metabolism, which may aid nutrition of the tumor. Alternatively, the strong association between an acute phase protein response and survival being shortened in some malignan~ies~~ may be caused by a link between proinflammatory cytokine production and the phenotype of the tumor. For example, anIL-1receptor blockade reduces the metastatic votential of melanoma cells in vivo.lo9Finallv, it is possible that an acute phase response contributes to shortened survival by accelerating the development of muscle wasting as a result of the greater demand for amino acids to support increased hepatic export protein synthesis. . I

MEDIATORS OF CACHEXIA It has been suggested that a tumor constitutes a new metabolically active organ that requires its own sustenance and increases demand for nutrients, which causes weight loss if these are not forthcoming.The presence and severity of cachexia, however, often correlates poorly with the size of the tumor. Cachexia often is seen early in the course of the disease and manifestations such as alterations in appetite and nutrient metabolism cannot be explained easily by this hypothesis.lo7Parabiotic studies in rats where the tumor-bearing animal induces cachexia in the non-tumor-bearing partner suggest circulatingmediators are responsible for this p h e n ~ m e n o nIt. ~ ~ appears likely that the metabolic changes seen are the result of mediators produced by the tumor or by the body in response to the tumor. Neurotransmitters

Serotinergic activity in the hypothalamus suppresses appetite. Increased levels of free tryptophan, the precursor of serotonin, are found in cancer patients and correlate with reduced food intake.19In cancer-bearing rats, it is thought that the compensatoryresponse to weight loss is inhibited because of dysregulation of the hypothalamic neuropeptidergic pathways as demonstrated by decreased appetite stimulatory (neuropeptide Y) or increased appetite suppressive (corticotrophin releasing factor) activity.57 Tumor-bearing rats are refractory to the effects of neuropeptide-Y when it is injected into the h y p ~ t h a l a m uthereby s ~ ~ suggesting that altered receptor sensitivity might explain the lack of a compensatory rise in food intake in

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response to weight loss in the cancer host. The role of such neurotransmitters in weight-loss in humans is just beginning to be explored. Current understanding of the control mechanisms of appetite, however, is limited and the presence of the blood-brain barrier makes the design of pharmacologic agents to act centrally on appetite a difficult but challenging long-term prospect. Cytokines

Several proinflammatory cytokines, including tumor necrosis factor (TNF),interleukin-1 (IL-I),interleukin-6 (IL-6),interferon gamma (IFN-y), and ciliary neurotrophic factor (CNTF), have been implicated in cachexia (Table 1).In animals, administration of many of these cytokines leads to anorexia, weight loss, an acute phase protein response, protein and fat breakdown, an increase in levels of cortisol and glucagon, and a decrease in insulin levels, insulin resistance, anemia, fever, and elevated energy e~penditure.~, ', 52r 76, 77, 92, 99 Some tumor cell lines produce cytokines in culture.l14It is rare, however, to detect elevated circulating concentrations of proinflammatory cytokines in cancer patients, even those losing although elevated circulating concentrations of IL-6 have been found to be associated with weight loss and the acute phase protein response in lymphoma, lung, and colorectal cancer patients.38,63, 91 Antibodies to TNF and IL-6 have produced a limited effect on the cachectic p r o c e ~ s ~ ~ , ~ ~ and different models of cachexia seem to rely on different cytokines. Production of TNF and IL-6 by isolated peripheral blood mononuclear cells has been shown to be elevated in weight-losing pancreatic cancer patients with an acute phase protein response suggesting that local rather than systemic production of this cytokine may be important.33Production of proinflammatory cytokines also induces the production of corresponding anti-inflammatory cytokines, such as IL-15 and IL-1 receptor antagonist (Table 2). Clearly the balance between such proinflammatory and antiinflammatory mediators may be crucial in determining the net clinical effect. Specific inhibitors of prostaglandin synthesis abolish the experimental cachectic effects of TNF62and IL-l.52They also block many of the proinflammatory actions of TNF in animal models.59Other studies, however, have failed to find any effect on TNF-induced weight loss.69It has been Table 1. PROINFLAMMATORY CYTOKINES AND ANTI-INFLAMMATORY CYTOKINES ANTAGONISTS THAT MAY CONTRIBUTE TO THE NETWORK OF MEDIATORS IMPLICATED IN CACHEXIA Proinflammatory

Anti-inflammatory

Interleukin-1 Interleukin-6 Tumor necrosis factor Interferon-y Ciliary neurotrophic factor

Interleukin-1 receptor antagonist Interleukin-4 Soluble tumor necrosis factor receptors Interleukin-12 Interleukin-15

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Table 2. BENEFITS AND LIMITATIONS OF PHARMACEUTICALS USED IN CACHEXIA

Steroids Nonsteroidal anti-inflammatory drugs Progestationalagents Fish oil

Side effects preclude long-term use Improve mood and appetite Caution required because of potentiaI for gastrointestinal bleeding effects May slow weight loss and improve survival Causes fluid retention Improves appetite Generally nontoxic Appears to stabilize weight and may prolong survival

suggested that prostaglandins form part of the network of mediators of cachexia. A variety of proinflammatory cytokines appear to play a major role in aspects of cachexia. It is apparent, however, that individual cytokines do not work alone in the in vivo situation and that a complex network of cytokines in combination with other factors are involved. This limited understanding of the role of inflammatory mediators in cachexia has opened up a new opportunity for intervention to manipulate the inflammatory response and influence the development of cachexia. Hormones

Infusion of hydrocortisone or cortisol, glucagon, and adrenaline in humans produces features of cachexia, such as protein loss, an acute phase protein response, increased energy expenditure, and glucose i n t ~ l e r a n c e . ' Changes ~ , ~ ~ ~ in hormone levels and target-organ sensitivity have been described in animals and humans with cachexia. Profound changes are seen in hormone levels in experimentaltumor-bearing animals although the patterns of change vary with the tumor cell line implanted.15 In humans with cancer, elevated levels of cortisol and glucagon have been 0bserved,8~,~~ and these may amplify the acute phase protein response.12 A blunted insulin secretory response to a glucose load has been described in patients with colorectal cancer.55In addition, insulin resistance in terms of glucose metabolism has been noted, particularly in pancreatic cancer, although this appears to be unrelated to the loss of pancreatic tissue and seems to be caused by the production of islet amyloid polypeptide (amylin)by the surrounding normal pancreatic tissue.81,90 The production of amylin appears to be stimulated by the presence of pancreatic cancer cells although the signal involved has not been identified.27Amylin induces anorexia and weight loss when administered to rats.2 Frank diabetes in cancer patients undoubtedly contributes to catabolism and should be treated appropriately. It is possible that the increase in circulating cortisol and the reduction in insulin documented in cachectic cancer patients results in a significant increase in the cortisol:insulin ratio and that this may contribute to the catabolism of peripheral tissues.40

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Therapeutic manipulation of these subtle changes in neuroendocrine activity is, however, both difficult to achieve and may interfere with what might primarily be an adaptive response. It has been suggested that leptin, the hormone produced by fat that suppresses appetite and increases energy expenditure to maintain weight stability,121may be involved in cancer cachexia as elevated leptin levels are seen in some models of inflamrnati~n.~~ The administration of TNF also increases leptin concentration^.'^^ Initial studies have found that levels of leptin are appropriately low in weight-losing cancer patients.95It remains possible, however, that cytokines may play a pivotal role in the long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from l e ~ t i n . ~ ~ Tumor-Specific Products

Additional potential mediators for cachexia have been described recently. A 24-kd glycoprotein proteolysis-inducing factor (PIF) has been isolated from the urine of weight-losing cancer patients but not those losing weight because of other causes.'08This produces protein breakdown in experimental animals and appears distinct from known ~ytokines.~" A mouse tumor derived from lipid mobilizing factor (LMF) has also been de~cribed:~and this has been identified recently in the urine of weightlosing cancer patients and appears to be associated with zinc a-2 gly~oprotein.~' The failure of proinflammatory cytokines, such as IL-6, to reliably induce cachexia in animal models has led to the suggestion that tumor-derived factors such as PIF may act as cofactors with host- or tumorderived cytokines to produce a cachectic state.42 MANAGEMENT OF CANCER CACHEXIA: NUTRITIONAL APPROACHES

The best way to treat cancer cachexia is to cure the cancer. Unfortunately, this remains an infrequent achievement among adults with advanced solid tumors. For the majority with incurable disease, basic aspects of the overall care of the patient must be considered first as these may impair food intake or mobility (see Table 4). The next obvious option is to increase nutritional intake by enteral or parenteral means. Two substantial randomized trials have examined the effect of oral nutritional supplements in patients with advanced cancer undergoing c h e m ~ t h e r a p y .Both ~ ~ , ~studies ~ included patients with a variety of diagnoses who were randomized to receive nutritional counseling to raise their energy and protein intake or to remain on ad lib intake. Both trials were able to demonstrate a significant increase in nutritional intake in the intervention group for over 3 months. This produced no benefit in terms of weight, anthropometric measures, response rate, survival, or quality of life, however, between the two groups.

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Parenteral nutrition is difficult to supply over long periods and has its own complications. A number of trials of parenteral nutrition were performed in cancer patients in the 1980s and showed, in general, no benefit in terms of nutritional indices. Moreover, infective complications were increased. This led the American College of Physicians to conclude that in cancer patients "parenteral nutritional support was associated with net harm, and no conditions could be defined in which such treatment appeared to be of benefit." Since then a number of large trials of parenteral nutrition in cancer patients, particularly in the perioperative setting, have been performed. These studies showed a significant improvement in energy intake in patients administered parenteral nutrition but no improvement in nutritional measures or functional outcome. Once again there were increased complications and trends to decreased survival.18,88,104 It has been suggested that severely malnourished patients may derive some benefit. These conclusions, however, were based on small numbers of patients within much larger studies.lo4

MANAGEMENT OF CANCER CACHEXIA: PHARMACOLOGIC APPROACHES Reversing, or even stemming, the malnutrition of cachexia by conventional nutritional intervention has proved difficult for a number of reasons. The protein-energy deficit and associated wasting are chronic processes that short-term, invasive, nutritional therapy cannot adequately r e d r e ~ s The . ~ anorexia and early satiety often encountered in these patients make it difficult to achieve additional oral intake. Finallv, the altered metabolism exhibited in this condition appears to act as a bio&ic brake to the accretion of lean tissue, even when additional calories and protein can be provided.43This last feature has led to attempts to use drugs or specific nutrients (in pharmacologic doses) to try and modulate the underlying metabolic problems and thereby allow conventional nutritional support to be more effective. Among the most widely used pharmacologic agents in patients with cancer cachexia are steroids. Prednisolone at a dose of 5 mg three times dailylZ0and dexamethasone 3 to 6 mg daily75have been shown to produce significantly greater improvement in appetite when tested against placebo. Methylprednisolone (125 mg daily) given intravenously improves quality of life.32,85 Steroids, however, have not been shown to affect weight loss and symptomatic benefits are often short lived. Steroids have a number of adverse effects including water retention, protein breakdown, and insulin resistance. Steroids tend to be used in the preterminal phases of a patient's illness and are not suitable for early intervention. The nonsteroidal anti-inflammatorydrug (NSAID)ibuprofen at a dose of 400 mg three times daily has been shown to reduce levels of acute phase proteins, interleukin-6, and cortisol and to normalize whole-body protein kinetics in cachectic colorectal cancer patient^.^^,^^ Ibuprofen also reduces levels of acute phase proteins and resting energy expenditure in

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those with pancreatic cancer.l15The administration of indomethacin (50mg twice daily) to a heterogeneous group of advanced cancer patients in a randomized controlled trial has been shown to be associated with a significant prolongation in survival.68NSAIDs, therefore, may have a role in the management of cachetic patients. Concerns about gastrointestinal toxicity remain, however. The use of NSAIDs in combination with conventional nutritional support has not as yet been tested in a prospective randomized trial. The effects of the progestational agents megestrol acetate and medroxyprogesterone acetate on weight loss in cancer patients have been studied extensively following observations of unwanted weight gain in patients with breast cancer using these agents. Several randomized trials in mixed groups of weight-losing cancer patients have suggested that megestrol acetate improves appetite and stabilizes weight to an extent greater than p l a ~ e b o . ~Doses ~ , ~ "have ~ varied from 240 to 1600mg per day. Medroxyprogesterone acetate has also been shown to increase appetite and food intake with resulting stabilization of weight at a dose of 500 mg twice daily.94 These agents have a number of side effects including venous thrombosis and peripheral edema. The frequency of edema and the fact that weight gained by patients taking megestrol acetate tends to consist of fat and wateF6 means that it may not be a useful drug for arresting the loss of lean tissue. Of more concern is a recent trial of megestrol acetate in patients receiving chemotherapy that found an inferior response to therapy and a trend to poorer survival.87The mechanisms of action of progestational agents in cachexia are unknown but steroid-like effects including suppression of proinflammatory mediators have been suggested. Pentoxifylline has been shown to inhibit production of TNFlo0and suppress protein breakdown in a tumor-bearing rat models of cachexia.24 A controlled trial of pentoxifylline in patients with cancer cachexia failed to demonstrate any benefit in terms of appetite or nutritional measures compared with placebo, however.46This probably reflects that TNF suppression alone is not sufficient to reverse the activation of the various mediator pathways involved in cachexia. Hydrazine sulfate inhibits phosphoenolpyruvate kinase, an enzyme that drives gluconeogenesis from lactate. It was hoped that interrupting this process would normalize some aspects of carbohydrate metabolism in cachexic cancer patients and improve nutritional status. Given orally at a dose of 60 mg three times daily, hydrazine sulfate has been shown to have marginal benefits over placebo in terms of appetite and maintenence of weight in a mixed group of cancer patient^.'^ A randomized trial in lung cancer patients67has shown no effect on weight loss with a trend to worse survival and quality of life in hydrazine-treated patients, however. Manipulation of the hormonal environment has also been used in an attempt to promote skeletal muscle anabolism. The administration of insulin in patients with cancer may reduce protein breakdown in cachectic cancer patients; however, this requires careful control of blood glucose.53In addition, effects are limited by a resulting increase in glucagon secretion9 and concerns over the promotion of tumor growth by insulin.13 Subsequent animal studies have suggested that the combination of insulin with

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somatostatin, sometimes with the addition of growth hormone, attenuates weight loss with an apparent gain in muscle mass without an obvious increase in tumor growth rate.g,10 It has also been shown that the combination of insulin-like growth factor-1 and its binding protein3 (IGF-l/IGFBP-3) stimulates muscle protein synthesis in undernourished rats. This combination has been shown to reduce the rate of weight loss in tumor-bearing mice.lol Growth hormone improves carcass weight in cachectic tumorbearing rats.'' Small clinical studies of growth hormone administration suggest it may improve nitrogen balance although this effect may not be seen in more malnourished patients.lo2Concerns also remain about the effects of growth hormone on tumor growth.' Eicosapentaenoic acid is an essentialpolyunsaturated fatty acid of the n-3 class found in relatively large quantities in fish oil. In doses of 2 to 6 g daily it has been shown to have anti-inflammatory effects in lowering production of proinflammatory cytokines in healthy volunteers31,74 and in patients with pancreatic cancer.l18 Eicosapentaenoic acid and fish oil also downregulate the acute phase protein r e ~ p o n s e . ~ 'I9, It ~~ appears ~, to impair the end-organ effects of proteolysis inducing factor and lipid mobilizing factor probably by an effect on cell signaling.106Several studies have also suggested that eicosapentaenoic acid and fish oil impair the growth of tumor cell lines in vitro and slow the growth of experimental tumors in animal models.25, 34, lo5An'imal work has also demonstated that eicosapentaenoic acid has a weight stabilizingeffect in cachectic tumor-bearing mice apparently independent of any antitumor effect.14Uncontrolled studies of fish oil or eicosapentaenoic acid in weight-losingpancreatic cancer patients have suggested that it may stabilize eight.^^^'^ (Table 2). MANAGEMENT OF CANCER CACHEXIA: COMBINED NUTRITIONAL AND PHARMACOLOGIC APPROACHES With the relative success of anti-inflammatory agents in normalizing aspects of the metabolic response in cancer, attempts have been made to combine these agents with an improvement in nutritional intake. The combination of ibuprofen (to downregulate the inflammatory response) with megestrol acetate (to increase food intake) has been studied and shown to stabilize quality of life and weight in advanced gastrointestinal cancer patients while control subjects continue to d e t e r i ~ r a t e . ~Further ' , ~ ~ investigation of this combination is required. A recent uncontrolled study of a combination of fish oil with oral nutritional supplementation (providing 2 g eicosapentaenoic acid and 600 kcal and 30 g protein/day) in weight-losing cancer patients produced reversal of weight loss in association with improvements in appetite and performance s t a t ~ sMost . ~ significantly, the lean body mass of the patients increased, thereby suggesting a fundamental reversal of the cachectic state. A recent prospectiverandomized trial in patients with advanced cancer has suggested that fish oil capsules supplemented with vitamin E can prolong survival.45These results provide substantial hope that significant progress

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in the treatment of cachexia may be achieved in the near future. The results of further prospective randomized studies are awaited. SUMMARY Cancer cachexia can often seem a hopeless condition to treat. If one is to be successful in palliating patients with advanced cancer, however, cachexia must be addressed as control of cachexia has the potential to produce substantial benefits in terms of the patient's quality of life. Although immense progress has been made in understanding the physiologic changes that give rise to weight loss in cancer patients and the mediators involved, it remains a significant cause of morbidity and mortality in malignant disease. The metabolic alterations that occur in these patients appear to prevent the effective use of conventional nutritional support. A number of pharmacologic agents have shown promise in normalizing some of these proinflammatory metabolic changes and it may be that a combination of one of these agents, with an increase in nutritional intake and optimal clinical care, offers the best hope for future progress. The clinical management of cachexia includes the following. Correct factors that may contribute to reduced food intake (e.g., pain). Correct factors contributing to debility (e.g.,anemia). Optimize food intake with appetizing food, dietetic support, and nutritional s u ~ ~ l e m e n t s . Encourage mG6ility as an endogenous anabolic stimulus. Correct underlying metabolic abnormalitieswith anti-inflammatory agents.' such as NSAIDs or fish oil. Use steroids and progestational agents to improve mood and appetite. Caution is required because of potential side effects. V

References 1. Akaza H, Matsuki K, Matsushima H, et al: Stimulatory effects of growth hormone on rat bladder carcinogenesis. Cancer 68:2418-2421,1991 2. Amelo U, Permert J, Adrian TE, et al: Chronic infusion of islet amyloid polypeptide causes anorexia in rats. Am J Physiol271:R1654-R1659,1996 3. Ballmer PE, McNurlan MA, Southorn BG, et al: Effects of human recombinant interleukin-lb on protein synthesis in rat tissues compared with a classical acute-phase reaction induced by turpentine. Biochem J 279:683-688,1991 4. Barber MD, Wigmore SJ, Ross JA, et al: Eicosapentaenoicacid attenuates cachexia associated with advanced pancreatic cancer. Prostaglandins Leukotrienes and Essential Fatty Acids 57:204,1997 5. Barber MD, Fearon KCH: Should cancer patients with incurable disease receive parenteral or enteral nutritional support? Eur J Cancer 34:279-285,1998 6. Barber MD, Ross JA, Fearon KCH: Changes in nutritional, functional, and inflammatory markers in advanced pancreatic cancer. Nutrition and Cancer 35:106-110,1999 7. Barber MD, Ross JA, Preston T, et al: Fish oil-enriched nutritional supplement attenuates progression of the acute-phase response in weight-losing patients with advanced pancreatic cancer. J Nutr 129:1120-1125,1999

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