Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section A – Symptom Management and Palliative Care

Chapter 38 – Cachexia

Michael J. Tisdale




The cachectic syndrome is defined by body weight loss of ≥10%, reduced food intake (≤1500 kcal/day). and systemic inflammation (C-reactive protein ≥10 mg/L).



Patients with cachexia have a reduced quality of life, a lower activity level, and a reduced survival time.



Anorexia is often associated with cachexia, but there might not be a cause-and-effect relationship because of the following:



Body composition change in cachexia is different from that in anorexia, with equal loss of muscle and fat.



There is selective loss of skeletal muscle in cachexia.



It is not possible to reverse the loss of skeletal muscle by nutritional supplementation or drug-induced appetite stimulation.



Resting energy expenditure is not uniformly increased in all cancer patients.



Levels of uncoupling protein 3 increased in muscle of cachectic patients. This could convert lipid released from adipose into heat.



Factors involved in the loss of lipid from adipose tissue are the following:



Zinc α2-glycoprotein by the induction of lipolysis and increased expression of uncoupling proteins.



Cytokine (TNF-α, IL-6, IFN-γ) inhibition of lipoprotein lipase, although TNF-α can also induce lipolysis and induce uncoupling proteins.



Futile energy cycles such as the Cori cycle and the triacylgylcerol/fatty acid cycle.



There is loss of skeletal muscle due to a depression of protein synthesis and an increase in protein degradation.



Both calpain and the ubiquitin-proteasome proteolytic pathway are involved in the degradation of intact myofibrils.



Factors involved in the loss of skeletal muscle are proteolysis-inducing factor (PIF), angiotensin II, and tumor necrosis factor-α.



These factors stimulate increased expression of the ubiquitin-proteasome pathway by activation of the transcription factor NF-κB.



Although other cytokines such as interleukins-6 and -8 are elevated in cachectic patients, there is less evidence for a direct role in atrophy of skeletal muscle.



Pharmacologic management of cachexia may involve progestins, corticosteroids, eicosapentaenoic acid, β-hydroxy-β-methylbutyrate, or combination therapy.


The word cachexia comes from the Greek kakos hexis and literally means “bad condition.” In cancer patients, cachexia is a multifactorial syndrome characterized by a progressive loss of body weight with depletion of both adipose tissue and skeletal muscle mass. Cachexia is often, but not invariably, associated with anorexia as well as an elevated acute phase response. While patients are defined as cachectic when their body weight is 5% less than their preillness stable weight, weight loss alone does not identify the full effect of cachexia on physical function, and it is not a prognostic variable. However, by using weight loss (≥10%) together with reduced food intake (≤1500 kcal/day) and systemic inflammation (C-reactive protein ≥10 mg/L), it is possible to identify patients who have both adverse function and poor prognosis.[1]

The incidence of cachexia depends on tumor type, being highest in patients with pancreatic and gastric cancer and lowest in patients with breast cancer and non-Hodgkin's lymphoma. Overall weight loss occurs in 30% to 80% of cancer patients and is severe (>10% of initial body weight) in 15%.[2] Cancer therapies are also associated with the induction of anorexia and further weight loss. Patients with cachexia have a reduced quality of life, a lower activity level, and a reduced survival time.[2] Malnutrition also increases the risk of infections, treatment toxicity, and health care costs and decreases response to treatment.[3] A shorter survival time has been shown[4] to be independently associated with a weight loss of more than 8.1 kg in the previous 6 months and serum albumin levels less than 35 g/L. Weight loss often precedes tumor diagnosis and is often a presenting symptom.


The association of anorexia with cachexia has led to the term cachexia-anorexia syndrome. Between 15% and 20% of patients are malnourished at the time of diagnosis, and for patients with advanced disease, this is up to 80% to 90%.[5] The tumor may cause reduced food intake, either directly, by interfering mechanically with the digestive tract, or indirectly, by producing inhibitory substances that act on peripheral receptors or in the hypothalamus. The principal biochemical mediators implicated in anorexia are (1) cytokines such as interleukin (IL)-1b, IL-6, IL-8, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and ciliary neurotrophic factor; (2) serotonin; (3) the hypothalamic neuropeptides neuropeptide Y (NPY) and corticotrophin-releasing factor; and (4) peptide hormones such as insulin, glucagon, and leptin. Although the exact mechanism that triggers cancer anorexia is not known, it has been suggested to result from an imbalance between NPY (orexigenic) and pro-opiomelanocortin (anorexigenic) signals in the hypothalamus.[6] In anorectic tumor-bearing rats, the paraventricular concentration of serotonin was increased.[7] However, in a mouse cachexia model showing mild anorexia, hypothalamic NPY mRNA was significantly raised, suggesting that suppression of hunger might be due to tumor products that inhibit NPY transport or release or that interfere with neuronal targets downstream of NPY.[8]

In humans, cancer anorexia is not due to a dysfunction of leptin production.[9] The levels of leptin are dependent only on the total amount of adipose tissue present in the patient and decrease as adipose mass decreases. Also mean plasma ghrelin levels, a neuropeptide released from the stomach in response to fasting and which stimulates food intake, were found to be higher among cachectic than noncachectic patients,[10] suggesting that this is not involved in the anorexia.

Of the cytokines, most studies show elevations of IL-6, IL-8, and IL-10 but not TNF-α, IL-1β, IFN-γ, or ciliary neurotrophic factor in the serum of cachectic cancer patients. [11] [12] [13] IL-6 levels are independently associated with levels of C-reactive protein, which in turn has been linked with survival.[11] Patients with IL-6 levels greater than 5.2pg/mL or IL-10 levels greater than 9.8pg/mL had significantly lower survival times than patients with lower levels.[12] Higher IL-6, IL-10, and IL-8 levels were also associated with poor performance status and/or weight loss. Some studies have shown that IL-6 levels increase gradually during the early stages of cachexia and then show a sudden steep rise just before death.[13] The systemic inflammatory response, as evidenced by increased serum C-reactive protein, has been shown to be an important factor in the progressive nutritional decline of patients with non-small-cell lung cancer and is a prognostic factor independent of stage, performance status, and treatment.[4]

Despite the association of anorexia with cachexia, no studies have been able to prove a cause-and-effect relationship. Rather, anorexia might be a separate phenomenon from the chronic wasting syndrome, although it might contribute to the loss of fat mass. Pair feeding experiments in animals have shown that this did not lead to either the same extent of weight loss or the metabolic abnormalities that are found in tumor-bearing animals. Thus, the changes in cachexia resemble those found in infection and injury rather than those found in starvation. Thus, in starvation, adipose tissue is lost preferentially to lean body mass, while in cachexia both are lost to a comparable extent. Also in starvation, when adipose stores are depleted, both skeletal muscle and visceral proteins are lost to an equal extent, while in cachexia, there is a selective loss of skeletal muscle mass. It is not possible to reverse this loss of skeletal muscle mass by nutritional supplementation or by drug-induced appetite stimulation, although such treatments do lead to some repletion of the adipose mass. This suggests that tumor factors or host factors induced by the tumor might lead to loss of adipose tissue and skeletal muscle mass in cachexia.


Adipose Tissue

Adipose tissue is the main source of energy for the body, and its loss could reflect an increase in resting energy expenditure. However, resting energy expenditure can be unchanged, increased, or decreased in relation to the predicted energy expenditure.[2] In patients with pancreatic cancer, when resting energy expenditure was increased in comparison with the predicted values for healthy individuals, both total energy expenditure and physical activity level were reduced,[14] as might be expected in malnourished subjects. Levels of mRNA for the uncoupling protein 3 (UCP-3) have been shown to be significantly higher in muscle of cancer patients compared with controls and with cancer patients who had not lost weight; this increased level could increase energy expenditure and thus contribute to weight loss.[15] Studies in both animals and humans support a role for UCP-3 in energy balance and lipid metabolism. Transgenic mice that overexpress UCP-3 in skeletal muscle are hyperphagic but weigh less than wild-type littermates, and there is a large reduction in adipose tissue mass.[16] Although UCP-1, found only in brown adipose tissue (BAT), is considered to be the principal UCP involved in decreasing the level of coupling of respiration to ADP phosphorylation, the low level of BAT in adult humans could mean that UCP-3 in muscle is of major importance.

Factors Involved in Loss of Adipose Tissue in Cachexia

Zinc α2-Gylcoprotein

One of the principal mechanisms by which lipid is lost from adipose tissue in cachexia is through an increased lipolysis, and the UCPs might serve to utilize the excess lipid that is mobilized. Zinc α2-glycoprotein (ZAG), a 43-kd glycoprotein, is overexpressed in cachexia-inducing tumors and acts as a lipid-mobilizing factor that stimulates lipolysis in adipocytes.[17] ZAG binds to the β3-adenoreceptor and stimulates lipolysis through a cyclic AMP–dependent mechanism.[18] Administration of ZAG to mice caused a time-dependent decrease of body mass that was attributed entirely to a loss of body fat without an effect on food and water intake.[18] There was an increased expression of UCP-1 in BAT, which probably contributed to the loss of adipose tissue. Both the glucose utilization rate and the rate of lipid oxidation were increased by ZAG lipid-mobilizing factor, suggesting that it increased energy utilization.[19] Although ZAG was originally thought to be produced by the tumor, further studies[17]showed that it was expressed in both white adipose tissue (WAT) and BAT, suggesting that it was produced locally by adipocytes. Tumor-bearing mice with a 19% loss of body weight and a 61% loss of fat mass showed a tenfold increase in ZAG mRNA and protein in WAT and a threefold increase in ZAG mRNA and a 20-fold increase in protein in BAT. In contrast to ZAG, leptin mRNA was suppressed 33-fold, while the adiponectin mRNA level was unchanged. ZAG expression in both WAT and BAT has been shown to be induced by glucocorticoids,[20] suggesting a relationship between the elevated cortisol levels in cachectic cancer patients and induction of ZAG.


Cytokines such as TNF-α, IL-6, and IFN-γ are also capable of reducing adipose tissue mass. The primary mechanism is thought to be suppression of the clearing enzyme lipoprotein lipase (LPL), although there is evidence that TNF-α can directly induce lipolysis.[21] LPL is a rate-limiting enzyme that is responsible for the hydrolysis of circulating triglyceride-rich lipoproteins, such as chylomicrons and very low-density lipoproteins. It is bound to the luminal surface of capillary endothelium in adipose tissue and muscle, and the fatty acids that are generated are utilized by adipose tissue for the synthesis of triglycerides. Thus, inhibition of LPL would deplete adipose tissue of the basic building blocks for lipid synthesis required to maintain levels in the presence of lipolysis. In addition to the cytokines, there are still unidentified factors that can inhibit LPL, since a study of five human cancer cell lines that induced cachexia in nude mice showed that they exhibited LPL-inhibitory activity, which was not due to any of the known cytokines.[22] An unknown lipid mobilizing factor of molecular weight less than 1 kd and stable to heat was also identified. The induction of lipolysis by TNF-α requires prolonged incubation (12 to 24 hours), and although the mechanism involves cyclic AMP, as with ZAG,[18] this is through stimulation of mitogen-activated protein kinase and extracellular signal-regulated kinase rather than through stimulation of adenylate cyclase.[21] As with ZAG, TNF-α induces increased expression of UCPs, which can metabolize released fatty acids.

Futile Energy Cycles

Futile energy cycles also contribute to energy loss in cancer patients. One of the most important of these is the Cori cycle, which might account for an additional loss of energy of 300 kcal/day.[23] The Cori cycle involves utilization of the carbon skeleton of lactate to form glucose in the liver. Tumors consume large amounts of glucose and convert it to lactate, not because of mitochondrial dysfunction but because the oxygen tension is too low for the Krebs cycle and mitochondrial oxidative phosphorylation to operate. Thus, in effect, the liver consumes energy to convert lactate into glucose, which is converted back to lactate again by the tumor. In addition, in mice bearing a cachexia-inducing tumor, the triacylglycerol fatty acid substrate cycle is increased.[24] In this process, a high proportion of nonesterified fatty acids released from adipose tissue are immediately reesterified into triacylglycerol. The reason for the increased operation of this cycle is not known but could be related to a high rate of release of fatty acids combined with a low utilization rate. The interrelationship between tumor and host factors in WAT and BAT and energy-utilizing cycles such as the Cori cycle is shown in Figure 38-1 .


Figure 38-1  Breakdown of adipose tissue and energy utilization in cachectic cancer patients. BAT, brown adipose tissue; FA, fatty acid; TG, triglyceride; WAT, white adipose tissue.



Skeletal Muscle

Loss of muscle mass in cachexia leads to muscle weakness (asthenia), reduced respiratory function, and reduced immunity and is probably the most important factor contributing to the shortened survival time. Muscle atrophy is characterized by a decrease in protein content, fiber diameter, force production, and fatigue resistance. About half of the total muscle protein is myofibrillar protein, which is lost at a faster rate than other proteins during atrophy. Not all myofibrillar proteins are lost at the same rate. Thus, of the core myofibrillar proteins, there is selective loss of myosin heavy chain during muscle atrophy, while losses of actin, troponin, and tropomyosin remain constant.[25] Depending on the initiating signal, loss of myosin heavy chain can occur through an RNA-dependent or a proteasome-dependent process. A change in muscle myosin isoform expression has also been reported,[26] with a decrease in type I and an increase in type II (fast) isoform expression.

Muscle atrophy in cachexia is due to a depression in protein synthesis together with an increased rate of protein degradation. The depression of protein synthesis is due to a reduction in both RNA content and RNA activity, that is, the amount of protein synthesized per unit weight of RNA per hour. It has also been suggested that the balance of amino acids might not be correct for muscle protein synthesis because of the synthesis of acute phase proteins, which contain relatively high levels of sulfur amino acids. However, the situation must be more complicated than this, since nutritional supplementation alone is unable to reverse the muscle atrophy. This has been attributed to the high rate of protein degradation through an increased expression and activity of the ubiquitin-proteasome proteolytic pathway.[27] [28] Protein substrates are marked for degradation by the attachment of a polyubiquitin chain by a series of enzymes: E1′s ubiquitin-activating enzyme, E2′s ubiquitin-conjugating enzymes, and E3′s ubiquitin-protein ligases. Two muscle-specific E3s, MuRF1 and atrogin-1/MAFbx, have been identified [29] [30] and are thought to act as critical components in muscle atrophy in cachexia. Protein degradation occurs in the 26S proteasome, a multisubunit proteolytic complex consisting of a central catalytic core (20S proteasome) and two terminal regulatory complexes (19S and 11S). The 19S regulatory complex plays a central role in the recognition and degradation of proteins by recruiting proteasomal substrates utilizing polyubiquitin chains and chaperone-like binding activities and by opening the access to the core of the 20S proteasome to promote degradation. The expression of mRNA for USP19, a 50-kd deubiquiting enzyme, was shown to be increased in skeletal muscle in a number of catabolic conditions, including cancer cachexia.[31] This suggests that it might play a role in the regeneration of free ubiquitin and might also be involved in post-translational processing of polyubiquitin.

The proteasome does not degrade intact myofibrils. Degradation of Z-band associated proteins, in particular titin and alpha-actinin, and release of myosin and actin from the myofibrils is mediated by the calcium-dependent enzyme calpain, which has been shown to be elevated in both skeletal muscle and heart during cancer cachexia in mice.[32] A diagram illustrating the factors involved in the degradation of myofibrillar proteins is shown in Figure 38-2 .


Figure 38-2  Steps in the breakdown of myofibrillar proteins.



The end-product of the ubiquitin-proteasome proteolytic pathway is oligopeptides, and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II, together with various aminopeptidases, to form tripeptides and amino acids. In mice bearing a cachexia-inducing tumor, both proteasome proteolytic activity and tripeptidyl-peptidase II activity were found to increase in parallel with increasing weight loss, suggesting that both activities are regulated in a parallel manner.[33]

Factors Involved in Loss of Skeletal Muscle in Cachexia

Proteolysis-Inducing Factor

Proteolysis-inducing factor (PIF) is a 24-kd sulfated glycoprotein produced by both primary and metastatic cachexia-inducing tumors, which induces muscle atrophy through a depression of protein synthesis and an increase in protein degradation. PIF acts both in vitro and in vivo to upregulate expression of both the mRNA and protein of the principal components of the ubiquitin-proteasome pathway including ubiquitin, E2, and proteasome subunits.[34] PIF also induces an increase in activity of tripeptidyl-peptidase II in parallel with the increase in proteasome activity.[33] The mechanism for induction of the ubiquitin-proteasome pathway by PIF involves activation of the transcription factor nuclear factor-κB (NF-κB), and inhibitors of this process, such as resveratrol, attenuated protein degradation induced by PIF in vitro, and muscle protein loss in mice bearing a cachexia-inducing tumor.[35] PIF also induces an increase in apoptosis in muscle cells in vitro,[36] although the importance of this in human cancer has been questioned for patients with a weight loss of less than 10%.[37] However, muscle loss is very small in patients with this degree of weight loss. In rabbits bearing the cachexia-inducing VX-2 tumor, the apoptotic index in skeletal muscle reached 54% to 56% when the loss of lean body mass reached 18%.[38] This suggests that further studies are required in humans at higher levels of weight loss.

Angiotensin II

The vasoconstrictor angiotensin II (Ang II) has also been shown to influence muscle mass by decreasing protein synthesis[39] and increasing protein degradation.[40] The latter effect occurs through the Ang II type 2 (AT2) receptor by inducing an increased activity and expression of the ubiquitin-proteasome pathway. Like PIF, Ang II is capable of acting directly in vitro as well as in vivo, and as with PIF, induction of the ubiquitin-proteasome pathway occurs through the transcription factor NF-κB.[40]



TNF-α also inhibits protein synthesis and increases protein degradation in muscle, although most studies report that it is inactive when used alone in vitro but that its activity is enhanced when it is used with another cytokine, such as IFN-γ.[25] The induction of protein degradation by TNF-α is due to an increased expression of the ubiquitin-proteasome pathway. In rats bearing the Yoshida AH-130 ascites hepatoma, in which TNF-α plays a pivotal role in the pathogenesis of muscle wasting, treatment with pentoxyfilline, an inhibitor of TNF-α synthesis, prevented the depletion of muscle mass and significantly reduced the activity of both ATP-ubiquitin and the calpain-dependent proteolytic pathways.[41] As with PIF and Ang II, activation of NF-κB is important in the degradation of muscle proteins by TNF-α.[42] Activation of NF-κB by TNF-α in differentiating mouse myocytes has also been shown to inhibit their differentiation, by suppressing production of MyoD mRNA at the post-transcriptional level.[43] MyoD is a transcription factor that is essential for differentiation of skeletal muscle, as well as for repair of damaged tissue, and it may be important for replenishing atro-phied muscle. These results suggest that TNF-α has the potential to induce muscle atrophy, although, as was previously discussed, most studies [11] [12] [13] have been unable to show elevations in the level of TNF-α in the serum of cachectic cancer patients. While the short half-life of biologically active TNF-α and formation of complexes with its soluble receptor contribute to the lack of detection, this does not explain why it can be detected in other wasting syndromes, such as cardiac cachexia.[44]


Of the cytokines, IL-6 is the most closely correlated with the development of cachexia in cancer patients, [11] [12] [13] and has been shown to be independently associated with levels of C-reactive protein as a measure of the acute phase response.[11] IL-6 is thought to be the prime regulator of acute phase protein production in human hepatocytes, which has been correlated with a shorter survival time of cancer patients.[45] This possibly explains why IL-6 levels rise sharply before death.[13] In addition to induction by cytokines, IL-6 production in human hepatocytes is induced by PIF, through activation of the transcription factors NF-κB and STAT3.[46] Some human pancreatic tumors also produce IL-6.[47]

Despite the correlation of serum IL-6 levels with the development of cachexia there are doubts about whether it plays a direct regulatory role in muscle protein degradation.[48] Thus, IL-6 did not affect the rate of protein degradation in vitro in rat muscle preparations, and although it induced an acute phase response in mice, it did not induce cachexia and had no effect on the expression of ubiquitin transcripts in muscle. This suggests either that IL-6 is a marker of the cachexia process or that it acts in concert with known or unknown factors to induce muscle atrophy.


While serum levels of IL-1β were not significantly elevated in patients with pancreatic carcinoma, levels of IL-8 were significantly elevated and were correlated with weight loss.[12] Several studies have failed to demonstrate an effect on IL-1β on muscle protein breakdown in vitro, while the IL-1 receptor antagonist had no effect on protein hypercatabolism in rats bearing a cachexia-inducing tumor.[48]There are no reports on the ability of IL-8 to induce protein degradation in muscle. However, IL-8 is a potent angiogenic factor and might play a role in tumor proliferation.

Dystrophin Glycoprotein Complex Dysfunction

Skeletal muscle wasting has been linked to a dysfunctional dystrophin glycoprotein complex, a membrane structure that is associated with muscular dystrophy.[49] Muscles from tumor-bearing mice with cachexia showed reduced levels of dystrophin and increased glycosylation on dystrophin glycoprotein complex proteins. Dystrophin glycoprotein complex dysfunction was shown to mediate the induction of the E3 ubiquitin ligase MuRF1. Carcinoma patients with marked weight loss had large reductions in dystrophin compared to weight-stable healthy controls. These results suggest a similarity between cachexia and muscle dystrophy.


Established Agents


Megestrol acetate (MA) and medroxyprogesterone acetate (MPA) are two synthetic progestins derived from 17α-hydroxyprogesterone that have received an extensive evaluation for the treatment of cachexia.[50] These agents are used in the treatment of hormone-dependent tumors, and it was during the evaluation of their antitumor activity that an increase of body weight and appetite was observed, independently of objective response. The mechanism of action of these agents may be related to their glucocorticoid activity. They might stimulate appetite via NPY in the ventromedial hypothalamus,[51]or they might act in part by downregulating the synthesis and release of proinflammatory cytokines.

Maltoni and colleagues[50] reviewed 15 randomized clinical trials of progestin therapy. Dosages ranged from 160 to 1600 mg/day for MA and from 300 to 1000 mg/day for MPA. The pooled odds ratio for weight gain was 2.66, indicating that patients who were treated with progestins had more than twice the probability of gaining weight than did patients who were treated with placebo. However, the pooled odds ratio for appetite was somewhat larger. [4] [23] Body composition studies of patients who gain weight with both MA and MPA have shown that the vast majority of the gained weight was adipose tissue and water and that there was no significant effect on fat free mass. This probably explains why the studies showed no improvement in the quality of life.[50] The duration of treatment in the studies was very short, lasting from 1 to 12 weeks, which probably overcame some of the side effects of therapy, which were significantly greater than were observed in the control arm. The side effects of long-term treatment (>12 weeks) are principally hypertension and edema resulting from water retention, as well as thromboembolic events. In a study of elderly men treated with MA (800 mg/day), there was an antianabolic effect on muscle with a significant reduction in thigh muscle cross-sectional area despite a significant increase in body weight.[52] Thus, administration of MA might actually accentuate the loss of lean body mass in cachectic cancer patients. It is surprising, therefore, that MA and MPA are the only agents that are routinely used for the treatment of weight loss in cancer anorexia and cachexia.


These include dexamethasone, prednisolone, and methylprednisolone. They induce a temporary effect on symptoms such as appetite, food intake, sensation of well-being, and performance status but show no beneficial effect on body weight. They tend to be used in patients in the end stages of cancer in an attempt to improve the quality of life.

Agents Undergoing Clinical Evaluation

Omega-3 Fatty Acids

Cold water fish such as mackerel, sardines, and salmon contain an oil under their skin containing omega-3 polyunsaturated fatty acids, the major components being eicosapentaenoic acid (EPA:20:5:) and docosahexaenoic acid (DHA; 22:6, ω3). Of the two fatty acids, only EPA has been shown to be effective in attenuating weight loss in a murine cachexia model.[53] Muscle mass is preserved and protein degradation suppressed through inhibition of the ubiquitin-proteasome pathway. EPA has been shown to attenuate the induction of the ubiquitin-proteasome pathway by PIF in murine myotubes by preventing activation of NF-κB.[54]

While most of the clinical studies have been carried out with fish oil, two studies have been carried out with EPA either as free acid[55] or as the propane diol diester.[56] Patients with pancreatic cancer and a median rate of weight loss of 2 kg/month who were administered EPA (6 g/day) showed weight stabilization over the 12-week study period.[55] However, in a placebo-controlled randomized study with EPA ester (2 or 4 g daily), patients with advanced gastrointestinal or lung cancer and with a mean weight loss of 18% showed no statistically significant improvement in survival, weight, or other nutritional variables.[56] A further uncontrolled study of fish oil capsules (supplying 4.7 g EPA/day) in patients with advanced malignancy and weight loss showed weight stabilization over a 1.2-month period.[57]When fish oil was combined with an energy- and protein-dense nutritional supplement, initial studies showed that patients gained 2 kg over a 7-week period and that this represented lean body mass.[58]However, in a randomized double-blind trial, intention to treat group comparisons indicated that omega-3 fatty acids did not provide a therapeutic advantage, mainly because of problems with compliance.[59] Post hoc analysis, however, showed a net gain of weight and lean tissue and improved quality of life in patients with measured increases in plasma EPA. In addition, total energy expenditure and physical activity level increased.[14] The increased physical activity level might reflect an improved quality of life. Interestingly, in a further randomized study, although fewer patients taking the EPA supplement gained 10% or more of baseline weight over a 3-month period than did patients taking MA, the percentage of patients with appetite improvement was similar in the two groups.[60] This suggests that EPA could also be used as an appetite stimulant. Further studies are required to confirm the anticachectic activity of EPA.


Thalidomide is being evaluated for the treatment of cancer cachexia owing to its ability to promote weight gain in HIV-infected patients. Thalidomide has been shown to block NF-κB regulated genes through suppression of IκB kinase activity.[61] A small study with 10 patients with nonobstructing and inoperable esophageal cancer showed thalidomide (200 mg daily) to increase both body weight (1.29 kg) and lean body mass (1.75 kg), while an isocaloric diet caused a loss of both body weight and lean body mass.[62] A further study in 50 patients with advanced pancreatic cancer who had lost at least 10% of their body weight substantiated these results.[63] Thus, after 4 weeks, patients receiving thalidomide (200 mg daily) had gained an average of 0.37 kg in body weight and 1cm3 in arm muscle mass compared with a weight loss of 2.2 kg and arm mass of 4.46cm3 in the placebo group. After 8 weeks, patients on thalidomide had lost 0.06 kg in weight and 0.5cm3 in arm mass, while the placebo group had lost 3.62 kg and 8.4cm3, respectively. These results suggest that thalidomide has the potential to attenuate muscle wasting in cachexia.


β-Hydroxy-β-methylbutyrate (HMB) is a metabolite of leucine formed by transamination to α-ketoisocaproate in muscle, followed by oxidation of the α-ketoisocaproate in the cytosol of the liver and possibly other tissues. HMB has been shown to attenuate the loss of body weight and skeletal muscle mass in mice bearing a cachexia-inducing tumor by attenuating the increased expression of the ubiquitin-proteasome pathway.[64] HMB acts like EPA to attenuate PIF-induced signaling pathways in muscle, leading to an increased proteasome expression by preventing activation of NF-κB.[65] Only a single clinical study has been reported on the effect of HMB in cancer cachexia.[66] This showed that HMB (3 g/day) in combination with L-arginine (14 g/day) and L-glutamine (14 g/day) produced a 0.95 kg gain in body weight in 4 weeks, whereas control subjects lost 0.26 kg. This gain was the result of a significant increase in fat free mass, and this was maintained over a 24-week study period. Further studies are required to confirm the clinical efficacy of HMB.

Combination Treatment

Evidence has been presented to indicate that oxidative stress plays an important role in age-dependent skeletal muscle atrophy.[67] Since an increase in oxidative stress has been observed in cancer patients, Mantovani and colleagues[68] administered vitamins A, E, and C (antioxidants), polyphenols, omega-3 fatty acids, α-lipoic acid, carboxycysteine, MPA, and a selective COX-2 inhibitor, with or without anti-TNF-α antibodies, to 25 cachectic cancer patients. Over a 4-month period, body weight was significantly increased from 51.3 to 58.1 kg together with lean body mass, appetite, grip strength, and quality of life. It is not certain which components of the treatment were responsible for the beneficial effect, since some have not been tested individually, but combination of agents attacking various components of the cachexia syndrome might be the way forward for improved clinical treatment of cachectic cancer patients.

In addition to these treatments there are a number of experimental agents that require clinical investigation:



Adenosine 5′-triphosphate[69]



Cyclooxygenase inhibitors (COX-1 and COX-2)[70]















Antibodies to parathyroid hormone–related protein[74]



Melanocortin-4-receptor antagonists[75]



Lipoxygenase inhibitors[76]






β2-adrenergic receptor agonists (e.g., formoterol)[78]


Progress in basic science has improved our understanding of the cellular mechanisms underlying tissue wasting in cachexia and has provided new molecular targets for therapeutic drug development. Further studies on tumor and host factors involved in the cachectic process, together with their cellular receptors, will aid in drug design and provide rational drug combinations for therapy. Attention in clinical trials is moving away from appetite and total body weight to measurements of lean body mass and physical functioning, which are important factors in maintaining the quality of life. This is not to say that anorexia is not an important factor that needs attention. Feeding is an important social interaction and something in which the family can help in the treatment of severely malnourished patients. Advances in our understanding of neuropeptides and their relationship to cancer anorexia will lead to new developments in this field, although few have received rigorous clinical evaluation.

Nutritional therapy could prove to be synergistic with other types of agents. Thus, inhibitors of the activation of NF-κB, such as EPA, HMB, and thalidomide, might be expected to attenuate muscle protein degradation but not improve protein synthesis. This is borne out by clinical trials, which show attenuation of the loss of muscle mass but no marked increase in size. Certain amino acids, principally the branched-chain amino acids, are known to stimulate protein synthesis at the translational level and might be expected to be synergistic with agents targeting muscle protein degradation.

Cure of the cancer would of course abolish the need to treat cachexia. However, until this happens, there will be a need for palliative therapy to improve the quality of life of the cancer patient.


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