1. Introduction
The etymology of the word cachexia points to its association with poor prognosis: it is derived from the Greek kakos and hexia —“bad condition” and has long been recognised as a key sign in many cancers. It is a multifactorial condition which comprises skeletal muscle and adipose tissue loss which may be compounded by anorexia, a dysregulated metabolic state with increased basal energy expenditure and is resistant to conventional nutritional support. The pathophysiological mechanisms have begun to be elucidated and this has led to developments in therapeutic avenues [ 1 ].
Cachexia correlates with poor performance status, poor quality of life, and a high mortality rate in cancer patients [ 2 ]. In a meta-analysis of studies pertaining to patients with advanced cancer and survival of less than 90 days, symptoms including weight loss and anorexia correlated with poor prognosis [ 3 ]. Loss of greater than 5–10% of body weight is usually taken as a defining point for cachexia, although the physiological changes may be present long before this cutoff point is reached. Furthermore, the degree of weight loss which significantly impacts on prognosis or performance has not been defined. A longitudinal study has shown that 2.5 kg weight change over 6–8 weeks is sufficient to produce significant changes in performance status [ 4 ]. Death usually occurs when there is 30% weight loss [ 5 ].
The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance, and increased muscle protein breakdown are frequently associated with cachexia [ 6 ]. However, there is no clear consensus definition of this common problem in cancer patients leading to a poor understanding of the aetiology of the condition. Earlier definitions of cachexia described “a wasting syndrome involving loss of muscle and fat directly caused by tumour factors, or indirectly caused by an aberrant host response to tumour presence” [ 7 ], however more recent definitions have downplayed the importance of fat loss and describe cachexia as “a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass” [ 6 ], thus highlighting the unique consequences of muscle wasting—the hallmark of cachexia. Without an established definition, future studies in this area will be hampered. A recent consensus definition has been proposed to include further factors to diagnose the cachexia syndrome such as involuntary weight loss, decreased muscle mass, anorexia, and biochemical alterations ( C -Reactive Protein (CRP), albumin, haemoglobin [ 8 ]).
One such study looked at 170 pancreatic cancer patients with weight loss >5% and whether a triad of >10% weight loss, low food intake (<1500 kcal/day), and systemic inflammation (CRP > 10 mg/dL) could better predict adverse functional outcome as well as poor prognosis versus weight loss alone [ 8 ]. When two of three of these criteria were present, (representing 60% of the patients) a cohort of patients with adverse function and prognosis were identified [ 8 ].
The prevalence of cachexia is thought to be up to 80% of upper gastrointestinal cancer patients and 60% of lung cancer patients at the time of diagnosis [ 9 ]. There are no clear figures for the estimated prevalence within specific cancer cohorts. When the electronic medical records of over 8500 patients with a wide variety of malignancies were analysed for the prevalence of cachexia amongst the cohort, the proportion varied according to which standard definition was used: 2.4% using the World Health Organisation's International Classification of Diseases (ICD) cachexia diagnostic code; 5.5% for the ICD diagnosis of cachexia, anorexia, abnormal weight, and feeding difficulties; 6.4% were prescribed megestrol acetate, oxandrolone, somatropin, or dronabinol; 14.7% had >5% weight loss [ 10 ]. Despite methodological flaws, there was an interesting lack of overlap between the different criteria pointing to the underdiagnosis of cachexia in clinical practice.
Decreased muscle strength may help distinguish cachexia from other causes of anorexia and fatigue in cancer patients [ 11 ]. Decreased muscle strength could be used as a diagnostic criterion with greater sensitivity and specificity for cancer cachexia. Cancer patients who are losing weight and have a systemic inflammatory response have poorer performance status [ 4 ]. Until a clear definition with well-defined cut-offs emerges, identification and treatment of cachectic patients as well as research in the area will remain limited. A new consensus definition for diagnostic purposes has been suggested and is outlined in Table 1 [ 6 ].
2. Pathophysiology
Pathophysiological changes and clinical consequences of cachexia are summarised in Figure 1 .
2.1. Metabolic Changes
The metabolic changes found in cachexia resemble those of infection rather than starvation [ 12 ] and are multifactorial and complex. Weight loss of cancer cachexia is due to loss of both skeletal muscle and adipose tissue mass, whereas weight loss is mainly from adipose tissue stores in starvation [ 13 ]. In cachexia there is an increase in muscle protein catabolism leading to net loss of muscle mass. The ATP ubiquitin-dependent proteolytic pathway is the greatest contributor to proteolysis in cachexia [ 14 , 15 ]. Other proteolytic pathways such as lysosomal cathepsins B, H, D, and L [ 16 ] and activity of the calcium/calpain pathway have also been implicated [ 17 ]. Increased intracellular proteolytic activity usually manifests as loss of body weight. This proteolysis has been shown to occur even in the absence of weight loss in cancer patients. Activation of proteolysis is an early event during tumour growth and it may be present for a long time prior to its clinical manifestation. Protein synthesis may be increased or unchanged [ 18 ].
Loss of adipose tissue mass is due to lipolysis [ 5 ]. This process is driven by lipid mobilising factor (LMF) and tumour (and host) factor zinc-alpha-2 glycoprotein which has a direct lipolytic effect and sensitises adipocytes to lipolytic stimuli and shows increased expression in cachexia [ 19 ]. A further compounding factor is the increased resting energy expenditure due to the dysregulation of energy metabolism. Cancer patients have a higher resting energy expenditure than noncancer controls [ 20 ]. It has been speculated that this is due to altered gene expression of mitochondrial membrane uncoupling proteins which uncouple respiration from ATP production resulting in loss of energy as heat [ 5 ].
The metabolic changes seen in cachexia are a result of the interplay of tumour factors, host factors, and the interaction between the two.
2.2. Tumour Factors
Tumour cells produce both pro-inflammatory and procachectic factors, which stimulate a host inflammatory response [ 1 ]. Tumour produced procachectic factors include proteolysis-inducing [ 45 ] and Lipid-mobilising factors [ 46 ]. PIF has been identified in the urine of weight losing patients with pancreatic, colon, lung, ovarian, breast, and liver cancers [ 47 ]. In animals, PIF signals via NF κ B and STAT3 pathways [ 48 ]. Stimulation of these pathways, induces proteolysis in muscles via the ubiquitin-proteasome pathway [ 49 ] and in hepatocytes, results in production of IL-6, IL-8 and CRP [ 48 ]. Tumour xenografts expressing human PIF do not induce cachexia in mice [ 50 ]. Further attempts to correlate PIF levels and outcomes have not shown any correlation [ 51 ]. Therefore the proposed mechanisms of PIF have not yet been validated in humans. Parathyroid hormone-related peptide (PTHrP), another tumour-derived circulating factor, is associated with higher soluble tumour necrosis factor receptor levels and with lower albumin and transferrin levels [ 52 ].
Lipid mobilising factor has been found in cancer patients losing weight but not in those with stable weight [ 53 ]. It is thought that LMF sensitises adipocytes to lipolytic stimuli by increasing cyclic AMP production [ 54 ]. LMF may bind to beta adrenergic receptors and causes either increased receptor number or increased G protein expression [ 55 ].
2.3. Host-Tumour Interaction
Inflammatory cytokine production by the tumour microenvironment in response to tumour cells may drive the cachexia process. Rodent tumour models display increased systemic inflammatory cytokine production, which correlates with the amount of weight loss [ 56 , 57 ]. The murine model of cancer cachexia associated with systemic inflammation suggests that there is an interplay between IL-1 β and IL-6 within the tumour microenvironment, which leads to their amplification [ 58 ]. Reduction of IFN- γ by monoclonal antibody treatment reverses cachexia in the Lewis lung carcinoma in mice [ 59 ].
Pro-inflammatory cytokines produced include TNF- α , IL-1 and IL-6 [ 1 ]. It is not certain whether the cytokine production is primarily from tumour or host inflammatory cells. It has been hypothesised that either tumour cell production of pro-inflammatory cytokines or the host inflammatory cell response to tumour cells is the source of the acute phase protein response seen in many malignancies and in cachexia. One study of oesophagogastric cancers showed cytokine protein concentrations of IL-1 β , IL-6 and TNF- α are significantly elevated in tumour tissue. Tumour tissue concentrations of IL-1 β protein correlated with serum CRP concentrations ( r = 0.31, P = .05; linear regression) and tumours with diffuse or patchy inflammatory cellular infiltrate were associated with elevated serum CRP [ 60 ]. Similarly the production of IL-6 by Peripheral Blood Mononuclear Cells (PBMCs) in pancreatic cancer patients induced an acute phase protein response in another study [ 61 ]. Martignoni et al. have suggested that IL-6-overexpression in cachectic pancreatic cancer patients is related to the ability of IL-6 producing tumours to sensitise PBMC and induce IL-6 expression in PBMCs [ 62 ].
TNF-alpha and the tumour factor proteolysis-inducing factor are the major contenders for skeletal muscle atrophy in cachectic patient. They both increase protein degradation through the ubiquitin-proteasome pathway and depress protein synthesis through phosphorylation of eukaryotic initiation factor 2 alpha [ 19 ]. Studies have shown that proteolysis-inducing factor levels correlate with the appearance of cachexia, but there is some disagreement regarding a correlation between serum levels of TNF-alpha and weight loss. Furthermore, only antagonists to proteolysis-inducing factor prevent muscle loss in cancer patients, suggesting that tumour factors are the most important.
2.4. Host Response Factors
2.4.1. Acute Phase Protein Response
Systemic changes in response to inflammation are denoted the acute phase response [ 63 ]. Up to 50% of patients with solid epithelial cancers may have an elevated acute phase protein response [ 64 ]. This acute phase protein response (APPR) has been associated with hypermetabolism: in pancreatic cancer patients APPR correlated with elevated resting energy expenditure and reduced energy intake [ 65 ]. Other longitudinal studies have found a poorer prognosis in patients displaying this response, independent of weight loss [ 66 ]. C -reactive protein (CRP) is the most prevalent method used to assess the magnitude of the systemic inflammatory response [ 63 ]. The modified Glasgow prognostic score (mGPS) ( Table 2 ) combines CRP and albumin concentrations to create a simple scoring system which is a prognostic factor independent of stage and treatment and predicts survival [ 21 , 67 ].
Raised CRP concentrations at the time of admission to hospital are indicative of an increased risk for all-cause mortality; there is a 22.8-fold increase in cancer mortality in patients with highly elevated CRP concentrations (>80 mg/L) [ 68 ]. This response appears to be prevalent amongst cancer patients with elevated CRP measured in almost 80% of 106 patients with inoperable nonsmall cell lung cancer (NSCLC), 40% of whom had >5% weight loss [ 69 ]. In patients without weight loss, those who displayed evidence of a systemic inflammatory response reported more fatigue ( P < .05) [ 69 ]. In patients with gastro-oesophageal cancer, the rate of weight loss correlates with serum concentrations of C -reactive protein [ 70 ]. Elevated CRP levels at the time of diagnosis has been found to be a predictor of poor prognosis in pancreatic, lung, melanoma, multiple myeloma, lymphoma, ovarian, renal, and gastrointestinal tumours [ 71 ].
The exact mechanisms linking cachexia, APPR, and poor outcomes is not known. It may be that this systemic alteration in protein metabolism drives the proteolysis of skeletal muscle to fuel the switch to acute phase reactant production. The APPR requires large amounts of essential amino acids: 2.6 g of muscle protein must be catabolised to produce 1 g of fibrinogen [ 72 ].
2.4.2. Neuroendocrine Factors
A number of neuroendocrine factors appear to be dysregulated in the cancer state resulting in insulin resistance, reduced anabolic activity, and elevated cortisol [ 47 ]. This dysregulation may be driven by the systemic inflammatory response associated with cancer. Inflammatory cytokines such as TNF- α and IL-6 have been implicated in insulin resistance [ 73 ]. The endogenous production of or response to anabolic growth factors in patients may be affected either by the tumour or the host response to the tumour and may contribute to cachexia. Testosterone or derivatives have been shown to increase protein synthesis and muscle mass [ 74 ]. Emerging evidence implicates reduction in insulin-like growth factor 1 in cachectic states [ 75 ].
2.5. Anorexia and Cachexia: An Interdependent Relationship?
Whilst loss of appetite and resultant decrease in energy intake undoubtedly contribute to weight loss associated with cancer cachexia, whether anorexia occurs by an independent process or is a result of the inflammatory process of cachexia is not fully understood. Anorexia itself may have a number of components—nausea, altered taste sensation, swallowing difficulties, or depression. The failure of aggressive supplementary nutritional regimes to reverse weight loss in many patients points to primacy of the cachexia disease process [ 5 ] and in fact, this disease process may act to establish anorexia. It is thought that lack of appetite is secondary to factors produced by the tumour or the immune response to the tumour. Specifically, cytokines may inhibit the neuropeptide Y pathway or mimic negative feedback action of leptin on the hypothalamus, leading to anorexia [ 76 , 77 ].
In a study of patients with gastro-oesophageal malignancy ( n = 220), 83% of whom had weight loss, multiple regression identified dietary intake (estimate of effect: 38%), serum CRP concentration (estimate of effect: 34%), and stage of disease (estimate of effect: 28%) as independent variables in weight loss in these patients [ 70 ]. If serum CRP is taken as a proxy measure of systemic inflammation due to cancer cachexia, this indicates that weight loss in cancer is not merely due to reduced calorie intake.
Recently, understanding of the physiological mechanisms of appetite regulation has been increasing. There are two sets of neurons within the arcuate nucleus of the hypothalamus identified to be involved: the melanocortin system and the neuropeptide Y system. Neuropeptide Y stimulates appetite on its own or via release of other orexigenic proteins [ 78 ]. Neurons which release α -melanocyte-stimulating hormone ( α -MSH) and signal via melanocortin-3 and 4 receptors (MC3R, MC4R) result in decrease in food-seeking behaviour, increased basal metabolic rate and decreased lean body mass [ 79 , 80 ]. These neurons are constitutively active as mutation in the MC4R results in childhood obesity [ 81 ]. Agouti-related protein (AgRP) is produced by neurons (which also produce neuropeptide Y) and counteracts the action of MC4R-stimulating proteins promoting appetite [ 82 ]. These “appetite neurons” also express receptors for circulating leptin [ 83 ] and interleukin-1 β (IL-1 β ) [ 84 ], both of which downregulate appetite and receptors for ghrelin (the orexigenic protein, which increases AgRP) [ 85 ].
3. Consequences
Cachexia results in a state of active inflammation whereby tumour-derived factors and the aberrant host response to these factors result in a catabolic state. Whether this catabolic state is the ultimate cause of death in some patients is unknown although a substantial proportion of cancer patients die with symptoms of advanced cachexia [ 9 ]. Cachexia directly impacts overall survival, quality of life, and physical activity.
3.1. Survival
Weight loss has been indicated as an important prognostic factor for cancer patients. A classic study by DeWys and colleagues underscores the impact and outcome of weight loss in cancer patients [ 2 ]. Using retrospective evaluation in a multicentre study of more than 3000 patients with different tumour types, these researchers reported moderate to severe weight loss in 30% to 70% of patients, depending on the tumor type. The amount of weight loss depends upon tumor site, size, type, and stage. Age and treatment type also play a role. The greatest incidence of weight loss was seen among patients with solid tumours, for example, gastric, pancreatic, lung, colorectal, and head and neck. Patients with solid tumours are often likely to lose 10% or more of their usual body weight. There is a lower risk of weight loss in patients with breast and hematological cancers. Within each tumour type, survival times were shorter for patients who had experienced weight loss than in those who did not. Not only did weight loss predict overall survival, but it also indicated a trend towards lower chemotherapy response rates.
In more recent studies, similar findings of reduced survival have been reported. Buccheri and Ferrigno (2001) [ 86 ] reported in 388 NSCLC cases that total weight loss was the best indicator of prognosis. In ovarian cancer Hess et al. (2007) [ 87 ] found a significant relationship between weight change and survival—on multivariate analysis the risk of death increased by 7% for each 5% drop of body weight. In Gastro-oesophageal cancer Deans and Wigmore (2009) [ 71 ] reported that patients with the lowest rate of weight loss had a median survival of 30.2 months versus 7.5 months in those with the highest rate of weight loss. Similar findings have also been reported in pancreatic cancer [ 88 ].
One proposed mechanism to explain why patients with weight loss have a poorer survival is the increased incidence of complications from surgical, radiotherapeutic, and chemotherapeutic treatments. In a study by Andreyev et al. [ 89 ], 1555 patients with a number of different gastrointestinal tumour types were analysed to examine whether weight loss affected prognosis. In patients with weight loss: chemotherapy doses were lower; they developed more frequent and more severe dose limiting toxicity and received, on average, one month less chemotherapy ( P < .001 in all). Weight loss correlated with shorter failure-free survival, overall survival, decreased response, quality of life, and performance status ( P < .001 in all) [ 89 ]. Whether reduced survival is due to a more aggressive tumour profile in patients with weight loss or due to suboptimal treatment related to weight loss, remains unknown.
3.2. Quality of Life
Cachexia contributes substantially to morbidity in cancer patients. It is associated with symptoms such as fatigue, weakness, poor physical performance, and thus leads to a lower self-rated quality of life. Indeed, when the impact of various factors is related to self-rated quality of life scores, the proportion determined by weight loss is 30% and by nutritional intake 20%, compared to cancer location (30%), disease duration (3%), and stage (1%) [ 90 ]. Patients who continue to lose weight while receiving palliative chemotherapy have reduced global quality of life and performance scores when compared to those whose weight loss stabilises [ 91 ].
3.3. Physical Activity
Physical activity has been described as a novel, objective, and robust functional outcome measure that is frequently impaired in cachectic states [ 92 ]. Activity levels are influenced by several conventional quality of life domains. Measurement of physical activity has long represented a challenge for researchers using time-consuming and expensive tools such as doubly labelled water and indirect calorimetry. However research using these methods has revealed that although resting energy expenditure may be elevated in cachectic patients, total energy expenditure is reduced because weight-losing cancer patients reduce the magnitude of their energy deficit through reductions in physical activity. This reduction in physical activity can be significant—in one study the measured mean physical activity rate was equivalent to that of spinal cord injury patients living at home and greatly reduced versus normal controls [ 93 ]. In a more recent study by Dahele et al. (2007) [ 94 ] using advanced ambulatory pedometer technology, cancer patients receiving palliative chemotherapy were shown to spend significantly more time lying and sitting, and significantly less time in quiet standing or stepping compared with controls, taking on average 43% less steps than healthy controls. It is known that bed rest leads to a decrease in skeletal muscle mass in healthy patients, due to reduced protein synthesis [ 95 ]. Thus, loss of physical function results in decreases in performance status, ability to perform activities of daily living, decreased social interactions, and alterations in body image, all of which manifest as reduced quality of life [ 96 ]. Interventions which increase physical activity would be anticipated to be highly beneficial.
Antineoplastic therapies such as surgery, radiotherapy and chemotherapy, may also impact on the development of systemic inflammation and particularly may impact on swallowing difficulties and anorexia due to nausea [ 97 ].
4. Therapeutic Approaches
4.1. Goals of Therapy
Clearly since cancer cachexia is associated with a poor prognosis, the aim of management is often to improve symptoms and quality of life. It is noted that a response to chemotherapeutic treatment by shrinkage of the tumour burden often leads to improvement in the cachectic state. The primary endpoints of optimal treatment of cancer cachexia are improvements in lean body mass, resting energy expenditure, fatigue, anorexia, quality of life, performance status, and a reduction in pro-inflammatory cytokines.
A greater understanding of the process of inflammation and its fundamental role in the development of cachexia has led to new avenues opening up in the approach to management of the condition. The hypothesis is that effective treatment of cancer cachexia will improve performance status and quality of life and by inhibiting the process driving cachexia, survival may be improved. In patients who stop losing weight while receiving chemotherapy for gastrointestinal cancers, median survival is improved (15.7 months versus 8.1 months, P = .0004) [ 89 ]. Animal models are generally unsatisfactory models for assessing the efficacy of intervention due to the larger proportional size and the aggressive doubling rate of tumours: thus the biological behaviour is different to that seen in the clinical setting [ 98 ].
There has been recent progress in producing trials of high clinical quality for licensing purposes but these trials may be beset by difficulties in adequate endpoint analysis due to the numbers lost to followup or patients being unable to comply with therapy due to their poor overall condition, thus limiting their duration, power, or generalisability [ 99 , 100 ]. In addition there is a degree of heterogeneity in defining relevant end points for analysis of intervention in cancer cachexia. Table 3 summarises the range of endpoints which may be used. One study of 388 nonsmall cell lung cancer patients found that total weight loss was the best predictor of prognosis rather than speed of weight loss [ 101 ]. However, weight loss alone does not identify the full effect of cachexia on physical function [ 8 ]. It is the loss of fat-free mass (FFM) that is responsible for the reduced functional status, increased mortality, and other negative outcomes associated with malnutrition [ 102 ]. Body fat is easier to gain than FFM, so studies that show improved body weight may not translate into reductions in morbidity or improvements in functional status. To improve functional ability and hence quality of life patients need not only to become weight stable but regain the lean tissue lost in the cachectic process. Thus, interventions which lead to improvements in functional status would be expected to cause increases in lean body mass rather than fat mass, however, this distinction is often not reported in interventions.
The strong impact that cancer cachexia has on cancer patients' outcome and quality of life suggests that nutritional issues should be taken into consideration from the beginning of the natural history of cancer, a concept termed the parallel pathway [ 103 ]. Indeed studies of nutritional intervention that have reported a better weight maintenance in patients are in those who are treated in the “precachexia” phase, that is, prior to loss of >10% of body weight and prior to elevations of CRP. Dietary counselling with or without oral nutritional supplements has proven efficacy in stabilising nutritional status in pre-cachectic patients [ 104 , 105 ]. A nutritional assessment to seek reversible causes of weight loss is the first step in management in cachectic patients. Approximately 40% of cancer patients eat less than the 34 kcal/kg/day required to maintain weight [ 106 ]. The European Society of Parenteral and Enteral Nutrition (ESPEN) report in a consensus statement that there is Grade A evidence for intensive dietary counselling with food plus or minus oral nutritional supplements in preventing therapy-associated weight loss, preventing treatment interruptions and increasing dietary intake in gastrointestinal or head and neck cancer patients undergoing radio- or chemotherapy [ 107 ].
For patients with advanced cachexia (>10% weight loss, systemic inflammation and poor appetite) studies seeking to assess the effect of targeted nutritional advice and supplements have generally reported no significant improvement in nutritional status. Standard enteral or parenteral supplements do not appear to result in lean mass weight gain for the typical cancer patient [ 5 , 98 , 108 ]. The largest evaluation of the literature regarding nutritional supplementation (NS) (oral or tube) in cancer patients was the systematic review by Elia et al. (2006) showing no difference in mortality in patients undergoing chemotherapy/radiotherapy (4 RCTs) or surgery (4 RCTs) [ 109 ]. A systematic review of parenteral nutrition in cancer patients showed no difference in mortality (19 RCTs), increase in total complication rates in those given parenteral nutrition (8 RCTs), and significantly lower tumour response rate in patients receiving parenteral nutrition (15 RCTs) [ 110 ].
This is likely because the inflammatory response of cachexia prevents anabolism. In many cases an attempt is being made to reverse or halt a rapidly advancing catabolic process and it is unrealistic to expect a reversal with calories and protein alone.
The poor results observed with conventional nutrition support in cachectic patients led to the emergence of so-called nutraceuticals or immunonutrition supplements, in an attempt to nutritionally modify the metabolic milieu by providing anti-inflammatory substances, such as eicosapentaenoic acid (EPA), at levels much higher than that typically found in the diet.
4.2. Eicosapentaenoic Acid
Eicosapentaenoic acid (EPA), a long-chain polyunsaturated fatty acid (PUFA) of the omega-3 (n-3) family, has been studies in relation to cancer cachexia for over 15 years. It is of interest in the context of cancer cachexia as it has potential to impact on both the underlying metabolic abnormalities of tumour-induced weight loss, as well as modulation of immune function. When EPA is consumed at levels above that normally found in the diet, it replaces arachidonic acid (AA), an n-6 PUFA, in cell membrane phospholipids. It then acts as a substrate for the production of the 3 series prostaglandins and the 5 series leukotrienes. Eicosanoids synthesized from the n-3 PUFAs (i.e., EPA) rather than the n-6 PUFAs (i.e., AA) have lower potential for promoting inflammation. Modulation of dietary fatty acids can therefore have an impact on many immune processes such as proliferation, phagocytosis, cytotoxicity, and cytokine production [ 111 ].
Despite initial studies showing anabolic effects, principally gains of lean body mass, improvements in grip strength, quality of life, and reductions in IL-6 and PIF could be achieved in a variety of cancers [ 99 ], including pancreatic cancer [ 112 , 113 ], lung cancer [ 114 ], and colorectal cancer [ 115 ], analysis of RCTs only, using the Cochrane approach, did not show any differences between EPA supplementation and placebo [ 39 ]. Whether this is a true representation or a reflection of the advanced cachexia of participants or inherent differences in EPA metabolism between individuals (with only a proportion of patients able to respond to EPA) needs further examination. On subgroup analysis, patients who comply with EPA supplementation seem to have improved lean body mass [ 116 ].
EPA-enriched oral nutritional supplements (ONSs) have been compared to megestrol acetate in the North Central Cancer Treatment Group trial of 421 patients with weight loss, poor intake, and anorexia [ 117 ]. In a 3-month intervention period, patients were randomized to either EPA-enriched ONS plus placebo liquid suspension, standard ONS plus megestrol acetate suspension, or EPA-enriched ONS plus megestrol acetate suspension. Weight gain was highest in the megestrol acetate group but unfortunately body composition was not assessed and so changes in water weight cannot be controlled for. There was no difference in survival, appetite, or quality of life scores between the groups, however patients on megestrol acetate reported higher rates of impotence. The fact that an EPA enriched ONS scored as well as drug therapy on certain clinical endpoints (e.g., survival and global quality of life) underscores the limitations of each treatment.
β -hydroxyl β -methyl butyrate (HMB), glutamine, and arginine supplementation have been combined in the hope of a synergistic effect of HMB (a modulator of protein turnover) and the amino acids (immunomodulatory) would increase weight. A phase III RCT of this combination did not show any difference in lean body mass between control and intervention groups [ 100 ].
4.3. Pharmacological Agents
Pharmacological options are summarised in Table 4 . Among orexigenic agents, megestrol acetate is by far the most widely prescribed and at least 15 randomised controlled clinical trials have demonstrated that this drug, at doses ranging from 160–1600 mg/d significantly improves appetite with respect to placebo [ 118 ]. A recent Cochrane meta-analysis reported that it improves weight gain and appetite in cancer patients [ 29 ]. Although this increase in appetite is very desirable for both patients and their carers, in most of these trials no definitive improvement in global quality of life was observed [ 29 ].
Anti-inflammatory agents (COX inhibitors) can reduce weight loss and aid maintenance of performance status in advanced cancer [ 119 ]. The COX-2 inhibitor, meloxicam showed activity against PIF-induced proteolysis, prior to its withdrawal from the market [ 120 ]. Beta-adrenoreceptor blockade can reduce resting energy expenditure in patients with cancer ( n = 10) but have not been trialled in larger-scale studies [ 121 ]. They are thought to inhibit proteolysis and lipolysis [ 122 ] and have been shown to downregulate catecholamine-induced catabolism in burns patients [ 123 ]. Agents which reduced cytokine levels such as thalidomide and pentoxifylline have only shown modest or minimal activity. At RCT, thalidomide has been shown to attenuate weight loss and lead to improved physical function [ 35 ]. Pentoxifylline did not have any clinical benefit. Specific antitumour necrosis factor- (TNF-) α agents, etanercept and infliximab, did not show any positive effect on appetite or body weight in RCTs [ 124 , 125 ]. Corticosteroids, although widely used, have significant side effects including protein breakdown, insulin resistance, water retention, and adrenal suppression and tend to be used during the preterminal phase of patient illness [ 23 , 126 ]. Anabolic steroid derivatives such as nandrolone and oxandrolone have not been studied in clinical trials in a cancer cohort. Insulin [ 27 ], ATP infusions [ 28 ], and melatonin [ 41 ] have produced modest positive effects in small clinical trials and require further substantiation.
4.4. Combination Therapy
In unresectable cancer cases, there is currently no goal standard treatment that can attenuate catabolism and inflammation, stimulate appetite and intake and consequently promote anabolism (specifically of lean body mass). A multimodal approach has therefore been advocated in the treatment of cancer cachexia. Mantovani (2010) randomised 332 patients with cancer-related anorexia/cachexia syndrome to one of five arms of treatment: (1) medroxyprogesterone 500 mg/d or megestrol acetate 320 mg/d; (2) oral supplementation with eicosapentaenoic acid (EPA); (3) L-carnitine 4 g/d; (4) thalidomide 200 mg/d; (5) a combination of the above for a total of 4 months [ 127 ]. Results showed the superiority of arm 5 over the others for all primary endpoints. Significant improvements were observed in arm 5 in LBM, fatigue scores, appetite, and total energy and active energy expenditure with REE decreasing significantly. Toxicity was negligible and comparable between treatment arms.
4.5. Potential Therapeutic Targets
Due to the lack of clinical efficacy of agents which seemed promising in the laboratory setting, ongoing research has continued to explore new therapeutic targets and to develop new agents. Much of this has focussed on manipulation of the melanocortin system of appetite regulation [ 128 ]. Activation of the Melanocortin-4-receptor (MC4R) in murine models decreases food-seeking behaviour, increases basal metabolic rate, and decreases lean body mass [ 80 ]. Treatment with a MC4R antagonist attenuated these responses [ 79 ]. Ghrelin induces the release of growth hormone, regulates appetite, and has anti-inflammatory properties [ 129 , 130 ]. Initial human studies in Phase I open trials have confirmed safety and show some increase in appetite and body weight [ 131 ]. Myostatin is a growth factor involved in the normal regulation of muscle mass [ 132 ]. Myostatin inhibitors and IL-6 antagonists are currently at Phase I RCT stage in development [ 131 ].
5. Conclusions
A consensus definition incorporating clinical, functional, and biochemical parameters is necessary in order to adequately identify and treat patients with cancer cachexia. A greater understanding of the pathophysiology, particularly in terms of the processes which drive cachexia will lead to new therapeutic target development. A number of issues remain to be resolved including whether inflammation drives the process or is a byproduct of the process. Does reversal of weight loss alone result in improved survival? By improving cachexia (i.e., leading to improved physical and physiological function) in cachexia, can patients become better able to tolerate anticancer therapies such as chemotherapy?
Composite endpoints which measure clinically relevant outcomes such as physical activity and quality of life are required in order to best assess the impact of interventions on cancer cachexia patients. Objective measures of function (as represented by physical activity) using advance ambulatory technology and integrated subjective quality of life parameters are likely to become standard practice in the clinical trial setting.
Acknowledgment
This paper is funded through an Irish Cancer Society Research Scholarship.
1 Tisdale MJ Mechanisms of cancer cachexia Physiological Reviews 2009 89 2 381 410 19342610 10.1152/physrev.00016.2008
2 Dewys WD Begg C Lavin PT Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group American Journal of Medicine 1980 69 491 497 7424938 10.1016/s0149-2918(05)80001-3
3 Maltoni M Caraceni A Brunelli C Prognostic factors in advanced cancer patients: evidence-based clinical recommendations—a study by the steering committee of the european association for palliative care Journal of Clinical Oncology 2005 23 25 6240 6248 16135490 10.1200/JCO.2005.06.866
4 O’Gorman P McMillan DC McArdle CS Longitudinal study of weight, appetite, performance status, and inflammation in advanced gastrointestinal cancer Nutrition and Cancer 1999 35 2 127 129 10693165 10.1207/S15327914NC352_5
5 Tisdale MJ Cachexia in cancer patients Nature Reviews Cancer 2002 2 11 862 871 12415256 10.1038/nrc927
6 Evans WJ Morley JE Argilés J Cachexia: a new definition Clinical Nutrition 2008 27 6 793 799 18718696 10.1016/j.clnu.2008.06.013
7 MacDonald N Easson AM Mazurak VC Dunn GP Baracos VE Understanding and managing cancer cachexia Journal of the American College of Surgeons 2003 197 1 143 161 12831935 10.1016/S1072-7515(03)00382-X
8 Fearon KC Voss AC Hustead DS Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis American Journal of Clinical Nutrition 2006 83 6 1345 1350 16762946 10.1093/ajcn/83.6.1345
9 Bruera E ABC of palliative care: anorexia, cachexia, and nutrition British Medical Journal 1997 315 7117 1219 1222 9393230 10.1136/bmj.315.7117.1219 PMC2127742
10 Fox KM Brooks JM Gandra SR Markus R Chiou CF Estimation of cachexia among cancer patients based on four definitions Journal of Oncology 2009 2009 Article ID 693458. 10.1155/2009/693458 PMC2705834 19587829
11 Strasser F Diagnostic criteria of cachexia and their assessment: decreased muscle strength and fatigue Current Opinion in Clinical Nutrition and Metabolic Care 2008 11 4 417 421 18542001 10.1097/MCO.0b013e3283025e27
12 Argilés JM Moore-Carrasco R Fuster G Busquets S López-Soriano FJ Cancer cachexia: the molecular mechanisms International Journal of Biochemistry and Cell Biology 2003 35 4 405 409 12565701 10.1016/s1357-2725(02)00251-0
13 Moley JF Aamodt R Rumble W Body cell mass in cancer-bearing and anorexic patients Journal of Parenteral and Enteral Nutrition 1987 11 3 219 222 3474427 10.1177/0148607187011003219
14 Khal J Hine AV Fearon KCH Dejong CHC Tisdale MJ Increased expression of proteasome subunits in skeletal muscle of cancer patients with weight loss International Journal of Biochemistry and Cell Biology 2005 37 10 2196 2206 16125116 10.1016/j.biocel.2004.10.017
15 DeJong CH Busquets S Moses AG Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia Oncology Reports 2005 14 1 257 263 15944798
16 Bosutti A Toigo G Ciocchi B Situlin R Guarnieri G Biolo G Regulation of muscle cathepsin B proteolytic activity in protein-depleted patients with chronic diseases Clinical Nutrition 2002 21 5 373 378 12381333 10.1054/clnu.2002.0557
17 Busquets S García-Martínez C Alvarez B Carbó N López-Soriano FJ Argilés JM Calpain-3 gene expression is decreased during experimental cancer cachexia Biochimica et Biophysica Acta 2000 1475 1 5 9 10806331 10.1016/s0304-4165(00)00050-7
18 McMillan DC Preston T Fearon KCH Burns HJG Slater C Shenkin A Protein synthesis in cancer patients with inflammatory response: Investigations with [N]glycine Nutrition 1994 10 3 232 240 7919675
19 Tisdale MJ Cancer cachexia Current Opinion in Gastroenterology 2010 26 2 146 151 19918173 10.1097/MOG.0b013e3283347e77
20 Hyltander A Drott C Korner U Sandstrom R Lundholm K Elevated energy expenditure in cancer patients with solid tumours European Journal of Cancer 1991 27 1 9 15 1826450 10.1016/0277-5379(91)90050-n
21 McMillan DC Systemic inflammation, nutritional status and survival in patients with cancer Current Opinion in Clinical Nutrition and Metabolic Care 2009 12 3 223 226 19318937 10.1097/MCO.0b013e32832a7902
22 Mantovani G Macciò A Madeddu C Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results Nutrition 2008 24 4 305 313 18262758 10.1016/j.nut.2007.12.010
23 Willox JC Corr J Shaw J Prednisolone as an appetite stimulant in patients with cancer British Medical Journal 1984 288 6410 p. 27 10.1136/bmj.288.6410.27 PMC1444189 6418303
24 Moertel CG Schutt AJ Reitemeier RJ Hahn RG Corticosteroid therapy of preterminal gastrointestinal cancer Cancer 1974 33 6 1607 1609 4135151 10.1002/1097-0142(197406)33:6<1607::aid-cncr2820330620>3.0.co;2-v
25 Bruera E Roca E Cedaro L Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study Cancer Treatment Reports 1985 69 7-8 751 754 2410117
26 Chlebowski RT Herrold J Ali I Influence on nandrolone decanoate on weight loss in advanced non-small cell lung cancer Cancer 1986 58 1 183 186 3518910 10.1002/1097-0142(19860701)58:1<183::aid-cncr2820580131>3.0.co;2-3
27 Lundholm K Körner U Gunnebo L Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning Clinical Cancer Research 2007 13 9 2699 2706 17473202 10.1158/1078-0432.CCR-06-2720
28 Agteresch HJ Beneficial effects of adenosine triphosphate on nutritional status in advanced lung cancer patients: a randomized clinical trial Nutrition in Clinical Practice 2004 19 4 p. 413 10.1200/JCO.2002.20.2.371 11786563
29 Berenstein EG Ortiz Z Megestrol acetate for the treatment of anorexia-cachexia syndrome Cochrane Database of Systematic Reviews 2005 2 Article ID CD004310. 10.1002/14651858.CD004310.pub2 15846706
30 Mantovani G Macciò A Esu S Medroxyprogesterone acetate reduces the In vitro production of cytokines and serotonin involved in anorexia/cachexia and emesis by peripheral blood mononuclear cells of cancer patients European Journal of Cancer Part A 1997 33 4 602 607 9274442 10.1016/s0959-8049(96)00486-8
31 Jatoi A Windschitl HE Loprinzi CL Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study Journal of Clinical Oncology 2002 20 2 567 573 11786587 10.1200/JCO.2002.20.2.567
32 Strasser F Luftner D Possinger K Comparison of orally administered cannabis extract and delta-9- tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group Journal of Clinical Oncology 2006 24 21 3394 3400 16849753 10.1200/JCO.2005.05.1847
33 Argils JM Meijsing H Pallars-Trujillo J Guirao X Lpez-Soriano FJ Cancer cachexia: a therapeutic approach Medicinal Research Reviews 2001 21 1 83 101 11135301 10.1002/1098-1128(200101)21:1<83::aid-med4>3.0.co;2-1
34 Kardinal CG Loprinzi CL Schaid DJ A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia Cancer 1990 65 12 2657 2662 2187585 10.1002/1097-0142(19900615)65:12<2657::aid-cncr2820651210>3.0.co;2-s
35 Gordon JN Trebble TM Ellis RD Duncan HD Johns T Goggin PM Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial Gut 2005 54 4 540 545 15753541 10.1136/gut.2004.047563 PMC1774430
36 Moreira AL Sampaio EP Zmuidzinas A Frindt P Smith KA Kaplan G Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation The Journal of Experimental Medicine 1993 177 6 1675 1680 8496685 10.1084/jem.177.6.1675 PMC2191046
37 Gordon JN Goggin PM Thalidomide and its derivatives: emerging from the wilderness Postgraduate Medical Journal 2003 79 929 127 132 12697909 10.1136/pmj.79.929.127 PMC1742651
38 Goldberg RM Loprinzi CL Mailliard JA Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial Journal of Clinical Oncology 1995 13 11 2856 2859 7595749 10.1200/JCO.1995.13.11.2856
39 Dewey A Baughan C Dean T Higgins B Johnson I Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia Cochrane Database of Systematic Reviews 2007 1 Article ID CD004597. 10.1002/14651858.CD004597.pub2 PMC6464930 17253515
40 Price SA Tisdale MJ Mechanism of inhibition of a tumor lipid-mobilizing factor by eicosapentaenoic acid Cancer Research 1998 58 21 4827 4831 9809986
41 Lissoni P Paolorossi F Ardizzoia A A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state Journal of Pineal Research 1997 23 1 15 19 9379341 10.1111/j.1600-079x.1997.tb00329.x
42 Lissoni P Is there a role for melatonin in supportive care? Supportive Care in Cancer 2002 10 2 110 116 11862501 10.1007/s005200100281
43 Kotler DP Cachexia Annals of Internal Medicine 2000 133 8 622 634 11033592 10.7326/0003-4819-133-8-200010170-00015
44 Lundholm K Daneryd P Körner U Hyltander A Bosaeus I Evidence that long-term COX-treatment improves energy homeostasis and body composition in cancer patients with progressive cachexia International Journal of Oncology 2004 24 3 505 512 14767534
45 Todorov P Cariuk P McDevitt T Coles B Fearon K Tisdale M Characterization of a cancer cachectic factor Nature 1996 379 6567 739 742 8602222 10.1038/379739a0
46 Hirai K Hussey HJ Barber MD Price SA Tisdale MJ Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients Cancer Research 1998 58 11 2359 2365 9622075
47 Skipworth RJE Stewart GD Dejong CHC Preston T Fearon KCH Pathophysiology of cancer cachexia: much more than host-tumour interaction? Clinical Nutrition 2007 26 6 667 676 17507116 10.1016/j.clnu.2007.03.011
48 Watchorn TM Waddell I Dowidar N Ross JA Proteolysis-inducing factor regulates hepatic gene expression via the transcription factors NF-(kappa)B and STAT3 The FASEB Journal 2001 15 3 562 564 11259367 10.1096/fj.00-0534fje
49 Whitehouse AS Tisdale MJ Increased expression of the ubiquitin—proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF- κ B British Journal of Cancer 2003 89 6 1116 1122 12966435 10.1038/sj.bjc.6601132 PMC2376944
50 Monitto CL Dong SM Jen J Sidransky D Characterization of a human homologue of proteolysis-inducing factor and its role in cancer cachexia Clinical Cancer Research 2004 10 17 5862 5869 15355918 10.1158/1078-0432.CCR-04-0435
51 Wieland BM Stewart GD Skipworth RJE Is there a human homologue to the murine proteolysis-inducing factor? Clinical Cancer Research 2007 13 17 4984 4992 17785548 10.1158/1078-0432.CCR-07-0946
52 Deans C Wigmore S Paterson-Brown S Black J Ross J Fearon KCH Serum parathyroid hormone-related peptide is associated with systemic inflammation and adverse prognosis in gastroesophageal carcinoma Cancer 2005 103 9 1810 1818 15800880 10.1002/cncr.20972
53 Todorov PT McDevitt TM Meyer DJ Ueyama H Ohkubo I Tisdale MJ Purification and characterization of a tumor lipid-mobilizing factor Cancer Research 1998 58 11 2353 2358 9622074
54 Khan S Tisdale MJ Catabolism of adipose tissue by a tumour-produced lipid-mobilising factor International Journal of Cancer 1999 80 3 444 447 9935188 10.1002/(sici)1097-0215(19990129)80:3<444::aid-ijc18>3.0.co;2-u
55 Islam-Ali B Khan S Price SA Tisdale MJ Modulation of adipocyte G-protein expression in cancer cachexia by a lipid-mobilizing factor (LMF) British Journal of Cancer 2001 85 5 758 763 11531264 10.1054/bjoc.2001.1992 PMC2364135
56 Gelin J Moldawer LL Lonnroth C Sherry B Chizzonite R Lundholm K Role of endogenous tumor necrosis factor α and interleukin 1 for experimental tumor growth and the development of cancer cachexia Cancer Research 1991 51 1 415 421 1703040
57 Strassmann G Fong M Kenney JS Jacob CO Evidence for the involvement of interleukin 6 in experimental cancer cachexia Journal of Clinical Investigation 1992 89 5 1681 1684 1569207 10.1172/JCI115767 PMC443047
58 Yasumoto K Mukaida N Harada A Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice Cancer Research 1995 55 4 921 927 7850809
59 Matthys P Heremans H Opdenakker G Billiau A Anti-interferon- γ antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia European Journal of Cancer 1991 27 2 182 187 1827286 10.1016/0277-5379(91)90483-t
60 Deans DAC Wigmore SJ Gilmour H Paterson-Brown S Ross JA Fearon KCH Elevated tumour interleukin-1beta is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer British Journal of Cancer 2006 95 11 1568 1575 17088911 10.1038/sj.bjc.6603446 PMC2360731
61 O’Riordain MG Falconer JS Maingay J Fearon KC Ross JA Peripheral blood cells from weight-losing cancer patients control the hepatic acute phase response by a primarily interleukin-6 dependent mechanism International Journal of Oncology 1999 15 4 823 827 10493968 10.3892/ijo.15.4.823
62 Martignoni ME Kunze P Hildebrandt W Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia Clinical Cancer Research 2005 11 16 5802 5808 16115919 10.1158/1078-0432.CCR-05-0185
63 Gabay C Kushner I Acute-phase proteins and other systemic responses to inflammation The New England Journal of Medicine 1999 340 6 448 454 9971870 10.1056/NEJM199902113400607
64 Falconer JS Fearon KCH Ross JA Acute-phase protein response and survival duration of patients with pancreatic cancer Cancer 1995 75 8 2077 2082 7535184 10.1002/1097-0142(19950415)75:8<2077::aid-cncr2820750808>3.0.co;2-9
65 Falconer JS Fearon KCH Plester CE Ross JA Carter DC Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer Annals of Surgery 1994 219 4 325 331 7512810 10.1097/00000658-199404000-00001 PMC1243147
66 O’Gorman P McMillan DC McArdle CS Prognostic factors in advanced gastrointestinal cancer patients with weight loss Nutrition and Cancer 2000 37 1 36 40 10965517 10.1207/S15327914NC3701_4
67 McMillan DC An inflammation-based prognostic score and its role in the nutrition-based management of patients with cancer Proceedings of the Nutrition Society 2008 67 3 257 262 18452641 10.1017/S0029665108007131
68 Marsik C Kazemi-Shirazi L Schickbauer T C-reactive protein and all-cause mortality in a large hospital-based cohort Clinical Chemistry 2008 54 2 343 349 18156283 10.1373/clinchem.2007.091959
69 Scott HR McMillan DC Brown DJF Forrest LM McArdle CS Milroy R A prospective study of the impact of weight loss and the systemic inflammatory response on quality of life in patients with inoperable non-small cell lung cancer Lung Cancer 2003 40 3 295 299 12781428 10.1016/s0169-5002(03)00077-1
70 Deans DAC Tan BH Wigmore SJ The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal cancer British Journal of Cancer 2009 100 1 63 69 19127266 10.1038/sj.bjc.6604828 PMC2634686
71 Deans C Wigmore SJ Systemic inflammation, cachexia and prognosis in patients with cancer Current Opinion in Clinical Nutrition and Metabolic Care 2005 8 3 265 269 15809528 10.1097/01.mco.0000165004.93707.88
72 Reeds PJ Fjeld CR Jahoor F Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states? Journal of Nutrition 1994 124 6 906 910 7515956 10.1093/jn/124.6.906
73 Feinstein R Kanety H Papa MZ Lunenfeld B Karasik A Tumor necrosis factor- α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates Journal of Biological Chemistry 1993 268 35 26055 26058 8253716
74 Orr R Fiatarone Singh M The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety Drugs 2004 64 7 725 750 15025546 10.2165/00003495-200464070-00004
75 Costelli P Muscaritoli M Bossola M IGF-1 is downregulated in experimental cancer cachexia American Journal of Physiology 2006 291 3 R674 R683 16614058 10.1152/ajpregu.00104.2006
76 Ramos EJB Suzuki S Marks D Inui A Asakawa A Meguid MM Cancer anorexia-cachexia syndrome: cytokines and neuropeptides Current Opinion in Clinical Nutrition and Metabolic Care 2004 7 4 427 434 15192446 10.1097/01.mco.0000134363.53782.cb
77 Inui A Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Research 1999 59 18 4493 4501 10493494
78 Chance WT Balasubramaniam A Thompson H Mohapatra B Ramo J Fischer JE Assessment of feeding response of tumor-bearing rats to hypothalamic injection and infusion of neuropeptide Y Peptides 1996 17 5 797 801 8844769 10.1016/0196-9781(96)00108-8
79 Markison S Foster AC Chen C The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist Endocrinology 2005 146 6 2766 2773 15774557 10.1210/en.2005-0142
80 Marks DL Ling N Cone RD Role of the central melanocortin system in cachexia Cancer Research 2001 61 4 1432 1438 11245447
81 Farooqi IS Keogh JM Yeo GSH Lank EJ Cheetham T O’Rahilly S Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene The New England Journal of Medicine 2003 348 12 1085 1095 12646665 10.1056/NEJMoa022050
82 Ollmann MM Wilson BD Yang YK Antagonism of Central Melanocortin receptors in vitro and in vivo by agouti-related protein Science 1997 278 5335 135 138 9311920 10.1126/science.278.5335.135
83 Seeley RJ Yagaloff KA Fisher SL Melanocortin receptors in leptin effects Nature 1997 390 6658 p. 349 10.1038/37016 9389472
84 Whitaker KW Reyes TM Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1 β administration Neuropharmacology 2008 54 3 509 520 18082228 10.1016/j.neuropharm.2007.10.014 PMC2323450
85 Kamegai J Tamura H Shimizu T Ish S II Sugihara H Wakabayashi I Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and agouti-related protein mRNA levels and body weight in rats Diabetes 2001 50 7–12 2438 2443 11679419 10.2337/diabetes.50.11.2438
86 Buccheri G Ferrigno D Importance of weight loss definition in the prognostic evaluation of non-small-cell lung cancer Lung Cancer 2001 34 3 433 440 11714541 10.1016/s0169-5002(01)00273-2
87 Hess LM Barakat R Tian C Ozols RF Alberts DS Weight change during chemotherapy as a potential prognostic factor for stage III epithelial ovarian carcinoma: a Gynecologic Oncology Group study Gynecologic Oncology 2007 107 2 260 265 17675142 10.1016/j.ygyno.2007.06.010 PMC2517223
88 Bachmann J Heiligensetzer M Krakowski-Roosen H Friess H Martignoni ME Cachexia worsens prognosis in patients with resectable pancreatic cancer Journal of Gastrointestinal Surgery 2008 12 7 1193 1201 18347879 10.1007/s11605-008-0505-z
89 Andreyev HJN Norman AR Oates J Cunningham D Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? European Journal of Cancer 1998 34 4 503 509 9713300 10.1016/s0959-8049(97)10090-9
90 Ravasco P Monteiro-Grillo I Marques Vidal P Camilo ME Cancer: disease and nutrition are key determinants of patients’ quality of life Supportive Care in Cancer 2004 12 4 246 252 14997369 10.1007/s00520-003-0568-z
91 Persson C Glimelius B The relevance of weight loss for survival and quality of life in patients with advanced gastrointestinal cancer treated with palliative chemotherapy Anticancer Research 2002 22 6 3661 3668 12552973
92 Dahele M Fearon KCH Research methodology: cancer cachexia syndrome Palliative Medicine 2004 18 5 409 417 15332419 10.1191/0269216304pm906ra
93 Moses AWG Slater C Preston T Barber MD Fearon KCH Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids British Journal of Cancer 2004 90 5 996 1002 14997196 10.1038/sj.bjc.6601620 PMC2409623
94 Dahele M Skipworth RJE Wall L Voss A Preston T Fearon KCH Objective physical activity and self-reported quality of life in patients receiving palliative chemotherapy Journal of Pain and Symptom Management 2007 33 6 676 685 17360150 10.1016/j.jpainsymman.2006.09.024
95 Biolo G Ciocchi B Stulle M Metabolic consequences of physical inactivity Journal of Renal Nutrition 2005 15 1 49 53 15648007 10.1053/j.jrn.2004.09.009
96 Fouladiun M Körner U Gunnebo L Sixt-Ammilon P Bosaeus I Lundholm K Daily physical-rest activities in relation to nutritional state, metabolism, and quality of life in cancer patients with progressive cachexia Clinical Cancer Research 2007 13 21 6379 6385 17975150 10.1158/1078-0432.CCR-07-1147
97 Bozzetti F Basics in clinical nutrition: nutritional support in cancer e-SPEN 2010 5 3 e148 e152
98 Bozzetti F Gavazzi C Mariani L Crippa F Artificial nutrition in cancer patients: which route, what composition? World Journal of Surgery 1999 23 6 577 583 10227927 10.1007/pl00012350
99 Bruera E Strasser F Palmer JL Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study Journal of Clinical Oncology 2003 21 1 129 134 12506181 10.1200/JCO.2003.01.101
100 Berk L James J Schwartz A A randomized, double-blind, placebo-controlled trial of a β -hydroxyl β -methyl butyrate, glutamine, and arginine mixture for the treatment of cancer cachexia (RTOG 0122) Supportive Care in Cancer 2008 16 10 1179 1188 18293016 10.1007/s00520-008-0403-7
101 Buccheri G Ferrigno D Importance of weight loss definition in the prognostic evaluation of non-small-cell lung cancer Lung Cancer 2001 34 3 433 440 11714541 10.1016/s0169-5002(01)00273-2
102 Tchekmedyian NS Zahyna D Halpert C Heber D Clinical aspects of nutrition in advanced cancer Oncology 1992 49 supplement 2 3 7 1461624 10.1159/000227118
103 Muscaritoli M Costelli P Aversa Z Bonetto A Baccino FM Fanelli FR New strategies to overcome cancer cachexia: from molecular mechanisms to the ’Parallel Pathway’ Asia Pacific Journal of Clinical Nutrition 2008 17 supplement 1 387 390 18296386
104 Ravasco P Monteiro-Grillo I Vidal PM Camilo ME Dietary counseling improves patient outcomes: a prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy Journal of Clinical Oncology 2005 23 7 1431 1438 15684319 10.1200/JCO.2005.02.054
105 Ravasco P Monteiro-Grillo I Vidal PM Camilo ME Impact of nutrition on outcome: a prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy Head and Neck 2005 27 8 659 668 15920748 10.1002/hed.20221
106 Hutton JL Martin L Field CJ Dietary patterns in patients with advanced cancer: implications for anorexia-cachexia therapy American Journal of Clinical Nutrition 2006 84 5 1163 1170 17093170 10.1093/ajcn/84.5.1163
107 Arends J Bodoky G Bozzetti F ESPEN guidelines on enteral nutrition: non-surgical oncology Clinical Nutrition 2006 25 2 245 259 16697500 10.1016/j.clnu.2006.01.020
108 Evans WK Makuch R Clamon GH Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer Cancer Research 1985 45 7 3347 3353 2988769
109 Elia M Van Bokhorst-de van der Schueren MA Garvey J Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: a systematic review International Journal of Oncology 2006 28 1 5 23 16327975 10.3892/ijo.28.1.5
110 Koretz RL Lipman TO Klein S AGA technical review on parenteral nutrition Gastroenterology 2001 121 4 970 1001 11606512 10.1053/gast.2001.28031
111 Fritsche K Fatty acids as modulators of the immune response Annual Review of Nutrition 2006 26 1 45 73 10.1146/annurev.nutr.25.050304.092610 16848700
112 Barber MD Ross JA Voss AC Tisdale MJ Fearon KCH The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer British Journal of Cancer 1999 81 1 80 86 10487616 10.1038/sj.bjc.6690654 PMC2374349
113 Wigmore SJ Barber MD Ross JA Tisdale MJ Fearon KCH Effect of oral Eicosapentaenoic acid on weight loss in patients with pancreatic cancer Nutrition and Cancer 2000 36 2 177 184 10890028 10.1207/S15327914NC3602_6
114 Guarcello M Riso S Buosi R D’Andrea F EPA-enriched oral nutritional support in patients with lung cancer: effects on nutritional status and quality of life Nutritional Therapy and Metabolism 2007 24 168 175
115 Read JA Beale PJ Volker DH Smith N Childs A Clarke SJ Nutrition intervention using an eicosapentaenoic acid (EPA)-containing supplement in patients with advanced colorectal cancer. Effects on nutritional and inflammatory status: a phase II trial Supportive Care in Cancer 2007 15 3 301 307 17021855 10.1007/s00520-006-0153-3
116 Fearon KCH Von Meyenfeldt MF Moses AGW Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial Gut 2003 52 10 1479 1486 12970142 10.1136/gut.52.10.1479 PMC1773823
117 Jatoi A Rowland K Loprinzi CL An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort Journal of Clinical Oncology 2004 22 12 2469 2476 15197210 10.1200/JCO.2004.06.024
118 López AP Roqué I Figuls M Cuchi GU Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome Journal of Pain and Symptom Management 2004 27 4 360 369 15050664 10.1016/j.jpainsymman.2003.09.007
119 Gridelli C Gallo C Ceribelli A Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study Lancet Oncology 2007 8 6 500 512 17513173 10.1016/S1470-2045(07)70146-8
120 Hussey HJ Tisdale MJ Effect of the specific cyclooxygenase-2 inhibitor meloxicam on tumour growth and cachexia in a murine model International Journal of Cancer 2000 87 1 95 100 10861458 10.1002/1097-0215(20000701)87:1<95::aid-ijc14>3.0.co;2-d
121 Hyltander A Daneryd P Sandström R Körner U Lundholm K β -adrenoceptor activity and resting energy metabolism in weight losing cancer patients European Journal of Cancer 2000 36 3 330 334 10708933 10.1016/s0959-8049(99)00273-7
122 Ryall JG Lynch GS The potential and the pitfalls of β -adrenoceptor agonists for the management of skeletal muscle wasting Pharmacology and Therapeutics 2008 120 3 219 232 18834902 10.1016/j.pharmthera.2008.06.003
123 Herndon DN Hart DW Wolf SE Chinkes DL Wolfe RR Reversal of catabolism by beta-blockade after severe burns The New England Journal of Medicine 2001 345 17 1223 1229 11680441 10.1056/NEJMoa010342
124 Jatoi A Dakhil SR Nguyen PL A placebo-controlled double blind trial of etanercept for the cancer anorexia/weight loss syndrome: results from NOOC1 from the North Central Cancer Treatment Group Cancer 2007 110 6 1396 1403 17674351 10.1002/cncr.22944
125 Jatoi A Ritter HL Dueck A A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9) Lung Cancer 2010 68 2 234 239 19665818 10.1016/j.lungcan.2009.06.020 PMC5951722
126 Loprinzi CL Kugler JW Sloan JA Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia Journal of Clinical Oncology 1999 17 10 3299 3306 10506633 10.1200/JCO.1999.17.10.3299
127 Mantovani G Maccio A Madeddu C Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia Oncologist 2010 15 2 200 211 20156909 10.1634/theoncologist.2009-0153 PMC3227938
128 DeBoer MD Update on melanocortin interventions for cachexia: progress toward clinical application Nutrition 2010 26 2 146 151 20004082 10.1016/j.nut.2009.07.003 PMC2818056
129 Nakazato M Murakami N Date Y A role for ghrelin in the central regulation of feeding Nature 2001 409 6817 194 198 11196643 10.1038/35051587
130 DeBoer MD Xin XZ Levasseur P Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia Endocrinology 2007 148 6 3004 3012 17347304 10.1210/en.2007-0016
131 Kung T Springer J Doehner W Anker SD Von Haehling S Novel treatment approaches to cachexia and sarcopenia: highlights from the 5th Cachexia Conference Expert Opinion on Investigational Drugs 2010 19 4 579 585 20367196 10.1517/13543781003724690
132 Zimmers TA Davies MV Koniaris LG Induction of cachexia in mice by systemically administered myostatin Science 2002 296 5572 1486 1488 12029139 10.1126/science.1069525