REVIEWS

Understanding the mechanisms and treatment options in cancer cachexia

Kenneth Fearon, Jann Arends and Vickie Baracos
Abstract | Cancer cachexia is a metabolic syndrome that can be present even in the absence of weight loss (precachexia). Cachexia is often compounded by pre-existing muscle loss, and is exacerbated by cancer therapy. Furthermore, cachexia is frequently obscured by obesity, leading to under-diagnosis and excess mortality. Muscle wasting (the signal event in cachexia) is associated not only with reduced quality of life, but also markedly increased toxicity from chemotherapy. Many of the primary events driving cachexia are likely mediated via the central nervous system and include inflammation-related anorexia and hypoanabolism or hypercatabolism. Treatment of cachexia should be initiated early. In addition to active management of secondary causes of anorexia (such as pain and nausea), therapy should target reduced food intake (nutritional support), inflammation-related metabolic change (anti-inflammatory drugs or nutrients) and reduced physical activity (resistance exercise). Advances in the understanding of the molecular biology of the brain, immune system and skeletal muscle have provided novel targets for the treatment of cachexia. The combination of therapies into a standard multimodal package coupled with the development of novel therapeutics promises a new era in supportive oncology whereby quality of life and tolerance to cancer therapy could be improved considerably.
Fearon, K. etal. Nat. Rev. Clin. Oncol. 10, 9099 (2013); published online 4 December 2012; doi:10.1038/nrclinonc.2012.209

Introduction
Cachexia is clinically obvious in its advanced phase (with gross loss of fat and skeletal muscle), and as such has been recognized as an adverse effect of cancer since the time of Hippocrates. However, at this late stage, the window of opportunity for successful rehabilitation of the patients has long since passed. The recog nition that cachexia can move through different phases (precachexia, cachexia, refractory cachexia), and that the latter phases are less-amenable to reversal,1 brings the focus of therapy forwards to the time of cancer diagnosis. It is this fundamental shift of focus that underpins the approach to ongoing research and treatment outlined in this Review. Reduced food intake in patients with cancer is caused by primary anorexia and can be compounded by second ary nutrition impact symptoms. Concurrent hyper metabolism, hypercatabolism and hypoanabolism aggravate the associated weight loss and are provoked by systemic inflammation and catabolic factors that can act partially via the central nervous system. The combination of these dietary and metabolic factors result in the syndrome recognized clinically as cachexia. Healthy adults are notably resistant to attempts to lose weight; therefore, the appearance of involuntary weight loss is highly abnormal. With the exception of pre cachexia, the best available diagnostic feature of cancer cachexia is involuntary weight loss, making screening for weight loss and monitoring of body weight over time an important clinical assessment.2 Prior to reaching its refractory phase, cachexia is not completely irreversible. Often, the reversible component to reduced food intake (Figure1) can be treated through the active management of nutrition impact symptoms (for example, uncontrolled pain or constipation),3 or with appetite stimulants or artificial nutritional support.4,5 Equally, there might also be a degree of reversibility in the metabolic component of cachexia (for example, cancer-associated insulin resistance or diabetes mellitus). However, these potentially reversible components are often only minor contributors, and although improved nutritional intake can partly reverse fat loss, the metabolic changes resistant to current interventions largely preclude significant reversal of muscle wasting.4,5
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Clinical Surgery, School of Clinical Sciences and Community Health, University of Edinburgh, Royal Infirmary, 51Little France Crescent, Edinburgh EH16 4SA, UK (K.Fearon). Tumour Biology Center, University of Freiburg, Breisacher Strasse117, 79106Freiburg, Germany (J.Arends). Division of Palliative Care Medicine, Department of Oncology, University of Alberta, 11560University Avenue, Edmonton T6G1Z2, Canada (V.Baracos). Correspondence to: K. Fearon k.fearon@ed.ac.uk

What cachexia is and what it is not

Cancer cachexia is a multifactorial syndrome that is defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and that leads to progressive functional impairment.1 The pathophysio logy of cachexia is characterized by a negative protein and energy balance that is driven by a variable combi nation of reduced food intake and abnormal metabolism. 1
Competing interests
K. Fearon declares associations with the following companies: Abbott, Alder Biopharmaceuticals, Nutricia, Novartis. J. Arends declares associations with the following companies: Abbott, Baxter,B. Braun, Fresenius-Kabi, Nutricia. See the article online forfull details of the relationships. V. Baracos declares no competing interests.

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Cancer cachexia is complex, and can often occur in the presence of malnutrition, age-related changes in anabolism, physical deconditioning and comorbidity.6 These factors can also form potentially reversible components of the overall cachexia burden. For example, in patients with lung cancer, there can be muscle wasting and deconditioning that is secondary to that caused by coexisting chronic obstructive pulmonary disease (COPD); such COPD-associated wasting can be managed actively via a pulmonary rehabilitation programme, therefore, partly relieving the patients overall cachexia burden.7 Separating cancer cachexia from the effects and compli c ations after cancer therapy is often diffi c ult. Muscle loss can be induced by surgery,8 cytotoxic chemo therapy,9 androgen-deprivation therapy 10 and targeted therapies that potentially interfere with pathways of muscle anabolism.11 Conversely, not all cancer treatment adversely affects the quality of life of a patient (particularly in the presence of a tumour response.).12 Nevertheless, the stepwise decline that occurs when patients with progressive disease receive different anticancer therapies is an aspect that can be neglected easily, especially when patients are handed on from one speci alty to another. Although not directly a component of cancer-associated cachexia, from a pragmatic viewpoint, treatment-associated wasting is best viewed as an integral part of the syndrome.
Key points
Cancer cachexia remains an important unmet medical need that affects patients quality of life and treatment outcomes Cachexia can be missed in an ever-increasingly obese population Therapy should start early and can run in parallel with antineoplastic therapy There is an urgent need to establish best supportive multimodal care for cachexia: beyond good clinical or oncological care, the treatable defects in dietary intake, physical activity and systemic inflammation should be addressed Patients with cachexia should be actively considered for entry into clinical trials

For example, a patient with small-cell lung cancer and severe B-type symptoms (such as pyrexia, sweating) and cachexia mainly due to hypermetabolism

Metabolic change

Reduced food intake

For example, a patient with pharyngeal cancer and cachexia mainly due to reduced food intake secondary to dysphagia

Figure 1 | Dual contribution of metabolic change and reduced food intake to cachexia. Cachexia is the outcome of a negative energy and protein balance driven by a variable combination of reduced food intake and abnormal metabolism. Careful attention to good medical management (for example, treatment of symptoms that affect appetite, such as uncontrolled pain) and basic physiological principles (for example, actively managing systemic inflammation) can help attenuate the effects of cachexia.

Hidden cachexia
Cachexia might be under-recognized in the context of epidemic obesity. When healthy individuals develop a chronic disease, the higher risk to health that is usually associated with obesity is reversed and obesity is associated with longer, rather than shorter survival, perhaps owing to increased fuel reserves. This reversal is known as the obesity paradox and supports the view in onco logy that overweight patients are at lower nutritional risk than normal-weight patients.13,14 However, even at the time of cancer diagnosis, overweight and obese patients can have substantial ongoing muscle depletion (sarcopenic obesity).15,16 The presence of sarcopenic obesity in patients with cancer can be assessed using image-based methods, such as CT, and is an independent risk factor for decreased survival.15,16 In addition to obesity, muscle and fat loss can be masked by weight gain in the form of ascites or peripheral oedema. Although ascites and oedema can lead to paradoxical weight gain, the patient is usually progressing towards refractory cachexia when these comorbidities are present.17

Detecting cachexia using imaging

Opportunistic use of oncology images obtained for routine staging or assessment of response (such as CT and MRI) has been proposed to reveal features of clinical importance, such as to quantify changes in body compo sition across the cancer trajectory.18 This approach can detect skeletal muscle wasting, altered distribution of body fat, accumulation of visceral adipose tissue and the pathological accumulation of lipids in tissues. In the
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past 5years, work assessing CT images from electronic clinical records11,15,16,19 has enabled the documentation of the natural history of cancer cachexia in hundreds of patients with solid tumours,11,15,16,19 including progressive alterations in skeletal muscle, adipose tissue, organs and tumour mass.19 Image analyses (Figure2) reveal muscle wasting in patients who clinically would not be suspected of any deficit in body mass or body constituent. 15,16 Defined, sex-specific reference values are essential to undertake the accurate assessment of skeletal muscle depletion. Although there is a paucity of reference values specific to patients with cancer, a generally accepted diagnostic criterion for muscle depletion that results in clinically significant impairment is an absolute muscularity below the fifth percentile.1 A low level of muscle is characterized by a statistically significant increase in health risk, such as mortality (Figure3). Muscle depletion can be detected by the following methods of assessment: mid-upper-arm muscle area by anthropometry (men <32cm2, women <18cm2), appendicular skeletal muscle index determined by dual-energy Xray absorptiometry (men <7.26kg/m2, women <5.45kg/m2), lumbar skeletal-muscle index determined from oncology CT imaging (men <55 cm2/m2, women <39cm 2/m 2), and whole-body fat-free mass index without bone determined by bioelectrical impedance (men <14.6kg/m2, women <11.4kg/m2).1 Although measurement of muscle mass is important, developing evidence shows that muscle function in cachexia can be reduced independent of mass and that this muscle function can vary between males and females.20 Thus, as in age-related sarcopenia, it is probably best to consider both muscle mass and function together when defining and treating cancer cachexia.
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a b c

Total skeletal muscle (parapinal, psoas, transverse/oblique abdominus, rectus abdominus) Visceral adipose tissue Subcutaneal adipose tissue Intermuscular adipose tissue

Figure 2 | Extensive muscle wasting can be obscured by large fat mass. CT images at the third lumbar vertebra comparing three male patients with oesophageal cancer. a | Frankly cachexic patient with a BMI of 17kg/m2, little adipose tissue and severe muscle depletion. b | An overweight patient with a BMI of 25kg/m2 and c|an obese patient with a BMI of 38kg/m2 have no obvious deficit of body weight; however, both have severe muscle wasting, with a total muscle amount similar to that of the patient who is overtly cachexic.

The effect on patients and families

Cachexia in patients with cancer is associated with significantly impaired survival,21 most probably because of decreased tolerance to anticancer treatments 22 and increased susceptibility to infections and other complications.23 Cachexia can have tremendous adverse effects on the well being of the patient, with severe secondary strains on all members of the surrounding support network. As cancer cachexia advances, physical activity is impaired by the loss of muscle tissue, concentration and alertness are diminished by fatigue,24 and mood is dominated by lethargy and increasing indifference.25 Patients can become isolated owing to reduced physical, mental and emotional activity. Some families exhaust themselves trying to fight the patients visible loss of weight and powerurging him or her to eat despite the absence of appetiteand, finally, experiencing f r ustration, h elplessness and fear.26

and severe muscle depletion experienced more severe toxic effects when treated with systemic cytotoxic therapy (5-fluorouracil, capecitabine, sorafenib or combi nation chemotherapy [adjuvant 5fluorouracil, epirubicin, cyclophosphamide]) than patients with no apparent muscle depletion.29 One explanation for such findings is that drug exposure is increased in muscle-depleted patients. In support of this concept, the plasma AUC (area under curve) of sorafenib in patients with hepatocellular carci noma with severe muscle depletion has been shown to be double that of patients without muscle wasting. 30 However, the precise mechanisms linking increased drug toxicity with cachexia (altered volume of distribution, transport or metabolism) remain to be resolved. Evaluation of the fitness of patients to tolerate specific antineoplastic therapies is a key part of clinical decision making in oncology and this is exemplified by the choice between cisplatin-based and carboplatin-based chemotherapy in non-small-cell lung cancer. Cisplatin-based chemotherapy is slightly superior to carboplatinbased chemotherapy in terms of response rate, but is also associated with more-severe nausea, vomiting and nephrotoxicity 31 and is, therefore, targeted to patients with better performance status. Although manifestations of cachexia have been shown to predict excess toxi city,2729 no objective criteria are available for planning the treatment of a patient with weight loss or muscle wasting that ensures they remain within a clinically acceptable range of treatment toxicity. Further pharmaco kinetic studies as well as dose-response studies for efficacy and toxicity are urgently needed to define treatment plans for patients with overt or covert cachexia.

Mechanisms of cachexia
Inflammation One proposed mechanism of cancer cachexia is that of an integrated physiological response of substrate mobili zation driven by inflammation.32 Energy homeostasis is established in the body by a system of highly regulated controls (Figure4).32 Body weight and metabolism are controlled in the brain, whereby specific hypothalamic nuclei integrate cognitive, visual and sensory inputs, and peripheral signals indicate body energy reserves, the activity of the gastrointestinal tract and nutrient intake.32 These controls help the organism store food energy optimally, or conversely, to mobilize reserves under appropri ate circumstances. Cancer cachexia could initially be considered to be an adaptive response to access body stores of energy and protein.32 Mobilization of skeletal muscle and adipose tissue is an organized and (evolutionarily) conserved response.32 Inflammation is a unifying mechanism for the entire cluster of sickness behaviours (asthenia, increased slow-wave sleep, mood alteration, lethargy, depression, anorexia, fever, anhedonia, cognitive impairment, hyperalgesia and decreased social interaction), including lipolysis and muscle proteo lysis.33,34 Inflammation is generated in the brain, by the tumour, by tissues in the locale of the tumour and by a diversity of host cells including skeletal muscle, adipose tissue and cells of the immune system and liver.32 The specific
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How cachexia limits treatment

That weight loss is prognostic for both the severity of treatment-related toxic effects and reduced survival has been known for some time.27 In a large series of Eastern Cooperative Oncology Group clinical trials, weight loss as little as 5% was a significant predictor of chemotherapyrelated toxic effects.27 The increased preva lence of toxic adverse effects associated with this weight loss are of sufficient severity to require dose reductions, treatment delays or definitive termination of treatment, such that weight-losing patients do not achieve the full potential benefit of their cancer therapy.22,28 As indicated above, for a subset of patients with cancer the simultaneous tendencies to gain adipose tissue and lose skeletal muscle culminates in severe muscle wasting in individuals with apparently normal or high body weight.15,16 Patients with such altered body composition are highly prone to treatment-related toxic effects, even when drugs are administered in relation to body mass or surface area.29 For example, patients with solid tumours
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identity of the inflammation mediators participating in cancer cachexia is emerging.35,36 In the brain, injection of IL1 elicits a rapid induction of muscle catabolism and atrophy gene expression.36 Inflammation in muscle might induce expression of molecules involved in leukocyte trafficking, such as Pselectin glycoprotein ligand 1, as an early event in the catabolic response.36 Indeed, patients with cancer who have a single nucleotide polymorphism associated with a low expression of the gene that codes for Pselectin glycoprotein ligand 1 (SELPLG) have a reduced likelihood of developing cancer cachexia than those with the more-common genotype.37 The physiology of different organs and tissues are carefully integrated, and, in the past year, evidence from a murine knockout model has suggested that fatmuscle crosstalk might be a critical regulator in the development of cachexia.38 A goal of anorexiacachexia therapy is to interfere with these responses to inflammation: to restore positive energy balance and to promote the gain of skeletal muscle mass. Understanding the specific management of the initiating inflammatory pathways is crucial to that end.
4.5 Threshold for increased health risk

3.5 Hazard ratio for death

2.5

1.5

0.5 0 0 Least 25 50 Muscularity (rank) 75 100 Most

Catabolism In patients with cancer, a number of factors increase the catabolic response, leading to unsustainable levels of fat and muscle mobilization and levels of muscle depletion that cause significant morbidity and mortality. These factors include tumour progression, comorbid conditions, old age, physical deconditioning, nutritional deficiency, drugs and medical interventions.6 Tumours alter energy regulation by eliciting an excessive inflammatory response, which will augment both central and peri pherally mediated catabolic events.32 There is also direct macronutrient consumption by the tumour. In late-stage disease, when the overall tumour mass reaches >0.75kg, the energy consumption of the tumour is quanti tatively important. It has been estimated in metastatic colorectal cancer that increases in visceral organ mass and tumour mass represented a cumulative incremental resting energy expenditure of ~17,700kcal over a time period of 3months, and as such might contribute substantially to cachexia-associated weight loss.19 Owing to their age and overall health status, patients with cancer are prone to physical deconditioning and to nutritional deficits.6 Inactivity causes muscle wasting perse, potentiates catabolic signals and desensitizes muscle to anabolic signals; for example, 10days of bed rest in otherwise healthy adults over 65years of age results in a 6% loss of muscle in the lower limb, 30% reduction in muscle protein synthesis and 16% loss of isokinetic strength.39 Bed rest also increases the catabolic response of skeletal muscle to low doses of cortisol by threefold in humans.40 This finding might be an especi ally important problem because the muscle protein catabolic response initiated in the brain by inflammation is mediated by cortisol.36 The role of malnutrition in promoting and exacer bating cancer cachexia is not fully understood. One theme in the clinical literature is the importance of treatable causes of reduced food intake. Some data suggest a
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Figure 3 | Threshold definition for sarcopenia: a low level of muscle, characterized by a statistically significant increase in health risk. Muscularity (that is, muscle mass adjusted for stature) has a sex-specific range in any given population. When studied as a continuous variable, high muscularity has the lowest risk of death, with progressively increasing risk of death with decreasing muscularity. Astatistical test for a threshold value (that is, optimal stratification) can be used to define a cut-off point for the definition of sarcopenia. Health risks associated with decreased muscularity include mortality, treatment toxicity, infection and physical disability.

gross deficiency of essential nutrients in patients with cancer; one good example is a deficiency of long chain n3 polyunsaturated fatty acids.41 Specific supplementation with these fatty acids limited catabolic losses of skeletal muscle in patients with lung cancer undergoing chemotherapy.42,43 Further work is required with respect to other classes of essential nutrients that might be defici ent in patients with cancer, includingbut not limited tovitamin D and choline.44,45 Several drugs used to treat patients with cancer add to the risk of muscle wasting (Figure5). The best-known culprits are high-dose corticosteroids (which induce a Cushings-like muscle wasting and insulin resistance).46 No treatment is generally provided to offset the catabolic effects of corticosteroids, even though agents such as oxandrolone have demonstrated clinical efficacy in this regard.47,48 Cancer therapy is increasingly targeted against molecular pathways that are responsible for tumour cell proliferation, such as the PI3K, AKT, and mTOR pathways that are associated with cancer initiation and are also involved in activating muscle protein anabolism.4951 It would be reasonable to anticipate that muscle wasting would be a significant toxicity of drugs that target thesepathways.

Outcomes of cachexia therapy

Unfortunately, cachexia is rarely managed actively, in part owing to a lack of knowledge about clinical nutrition in the oncology field,52 but also because of a lack of
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of improvement in tolerance to therapy or survival would imply intervention at the earliest possible indication that cachexia has started to develop, or even preventative intervention in patients who can reasonably be expected to develop it (precachexia). Very few of the clinical trials to date have been conducted with such a pre-emptive strategy in mind; indeed, most were done in the context of end-stage disease. Thus, the utility of cachexia therapy to substantially alter treatment toxicity, tumour response or survival remains unproven. The other side of the outcome equation regards what payers are willing to fund. In terms of drug or manpower costs, this value is likely to be determined by criteria set by bodies, such as the National Institute for Health and Clinical Excellence in the UK, and will be assessed in terms of duration and quality of life. The fact that, in many European countries, pulmonary rehabilitation is now standard of care for patients with COPD55 bodes well for the future and suggests that if an evidence base can be established, then multimodal management of cancer cachexia could also be made available. The role of patient groups in establishing the demand for this service could be critical.

CRH TRH GHRH TSH

ACTH POMC

Sensory input SNS output

Thyroid

Adrenal gland Adrenalin Cortisol

Energy substrate storage and interconversion

Energy appeal signals Cytokines Eicosanoids

Tumour

Energy fuels Glucose Fatty acids Amino acids

T3 T4

Activated immune system

Figure 4 | Integration of fuel metabolism in the tumour-bearing state. The CNS integrates the regulation of food intake and of energy expenditure. CNS outputs include neural (SNS) outputs, as well as neuroendocrine outputs (pituitary, adrenal, thyroid). The sites of energy storage (adipose tissue and skeletal muscle) and the site of integration and transformation of energy fuels (liver) provide an energy fuel mixture for systemic use during starvation. An elevated level of mobilization of energy stores is required to fuel immune responses during activation of the immune system, and an energy appeal reaction for this purpose is mediated directly by proinflammatory cytokines acting both in the CNS and periphery. Enhanced inflammation in the tumour-bearing state creates an additional load of inflammatory signals, promoting intense loss of muscle and adipose tissue.24 Abbreviations: ACTH, adrenocorticotropic hormone; CNS, central nervous system; CRH, corticotropin-releasing hormone; GHRH, growth-hormonereleasing hormone; POMC, pro-opiomelanocortin; SNS, sympathetic nervous system; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone.

Treatment options
Clinical trials At present, altering major clinical outcomes is not possi ble in terms of cancer cachexia. However, by developing rational, practical and standardized baseline cachexia management, successful randomized trials of novel agents or combination treatments could be facilitated using a process that could be compared with the development of modern combination chemotherapy. Combination chemo therapy was developed by assessing initial low- efficacy regimens in the context of symptom management in the palliative setting until effective regimens were discovered and were then developed further to alter survi val in the adjuvant setting.56 The potential difference in cachexia therapy is that early intervention during active adjuvant or palliative cancer therapy (suppor tive onco logy) is a better setting to develop treatment rather than when the patient has become likely refractory to anti cachexia treatment (end-of-life care). However, competi tion with chemotherapy trials makes for a challenging environment to fund and undertake such upfront large randomized cachexia interventional trials. Basic multimodal cachexia therapy Cancer cachexia is a multidimensional syndrome whereby the interdependence of its components means that a unimodal approach is unlikely to work. Owing to this interdependence, there are now several specialized multidisciplinary clinics and trials that are in the process of adding treatment elements together to try and establish a basic programme or regimen for multimodal intervention.57 Such baseline management usually addresses reversible clinical contributory factors (good medical management) and residual reversible physio l ogical problems (baseline management of nutrition, exercise and systemic inflammation; Figure6).
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an adequate evidence base for therapy. Current progress in cachexia therapy promises to improve the therapeutic armamentarium and might soon reverse the nihilism that drives the systematic under-recognition of cachexia. Prolonged survival remains the prime aim during both the potentially curative and palliative phases of cancer therapy, and the management of cachexia has sometimes aimed to complement this objective.22 However, for reasons related to the complex and resistant nature of cachexia, some of the optimism for the development of cachexia therapy has been ill founded.53 If treatment of cachexia has been successful, there must be a tangi ble benefit sensed by the patient; thus, in assessing the success of cachexia therapy focusing, in general, on quality of life is reasonablespecifically, on those components of a patients quality of life that are likely to be sensitive to a change in muscle mass.54 In proof-ofconcept studies that aim to reverse or stabilize muscle wasting, determining muscle mass (for example, by imaging approaches) and function (for example, using strength tests) would be logical; and would be followed by measurement of patient-centred outcomes, such as physical activity or health-related quality of life. Once improvements in these outcomes have been achieved, it would then be relevant to look at broader clinical outcomes, such as tolerance of therapy or survival. The aim
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Nutrition and exercise Total energy expenditure is a combination of resting energy expenditure (basal metabolism) and the energy expenditure associated with physical activity.58 As such, patients energy expenditure can vary considerably. Within such limitations, the average caloric deficit of a weight-losing patient with advanced-stage cancer has been estimated to be approximately 200kcal per day.59 Moreover, the average protein intake of these patients is about 0.71.0g/kg per day.60 If such a patient is to start some minimal daily exercise and reach a protein intake that might combat anabolic resistance (recommended intake 1.01.5g/kg per day), it is evident that food energyintake needs to increase by 300400kcal per day and protein intake increase by up to 50%. If the predisease protein and calorie intake of the patient was low, then this increase may require patients not only to eat their normal diet but to exceed such an intake. These are difficult goals to achieve particularly in frail, anorectic, elderly, comorbid patients who are also receiving anti cancer therapy. The as treated analysis of a randomized trial that in addition to oral nutritional support, used parenteral nutrition to circumvent this limitation, suggested a short (68weeks), but significant (P<0.001), p r olongation of survival when nutritional goals wereachieved.61 Clearly, the best way to maintain or increase energy and protein intake is with normal food. However, often this is difficult and in addition to dietary counselling, oral nutritional supplements are required. A meta- analysis published last year of oral nutritional interventions in malnourished patients with cancer identified 13 studies and included 1,414 patients.62 There was consi derable variation in the quality of the studies and statistical heterogeneity; nevertheless, nutritional intervention was associated with a significant increase in energy intake (430kcal per day) and a weight gain of 1.9kg. There was a beneficial effect on some aspects of quality of life (i ncluding appetite and global quality of life).62 The average daily energy expenditure of a patient with advanced-stage cancer is 1,6001,800kcal.63 Patients take about 4,000 steps a day (compared with a healthy indivi dual who takes about 9,000 steps per day) and spend less than 3h a day standing or walking.63 Muscle anabolism is induced by exercise training and, thus, resistance exercise might antagonize muscle atrophy in cachexia and endurance training might improve fatigue.64 A random ized trial reported in 2010 showed that, in patients with advanced-stage cancer, exercise is feasible and that although fatigue is not reduced, physical performance is improved significantly.65 A combination of resistance and aerobic muscle training has been suggested to be incorporated into cachexia treatment programmes; unfortunately, experience with such programmes is still limited,66 and definitive regimens have yet to be established. Drugs No widely approved drug for the treatment of cancer cachexia is available. However, steroid hormones have been shown to be effective in stimulating appetite, with
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2013 Macmillan Publishers Limited. All rights reserved Insulin and growth factor receptors

Leucine

Sorafenib

Ras

PI3K

Raf TSC1 MEK TSC2

AKT

mTOR

Everolimus 4E-BP1

ERK

P70S6K

Proliferation

Initiation of translation Protein synthesis

Figure 5 | Muscle-cell proliferation and protein synthesis in response to growth factors and amino acids can be impaired by targeted cancer therapies. The mTOR kinase integrates signals from nutrients (amino acids and energy), insulin and growth factors to regulate cell growth, cell-cycle progression and protein synthesis in skeletal muscle. In addition, pathways involving Ras, Raf, MEK and ERK regulate muscle cell proliferation. These anabolic and proliferative pathways are targets of antineoplastic agents, such as everolimus and sorafenib. Sorafenib has been demonstrated to directly cause skeletal muscle wasting, independent of disease response.11 Abbreviations: 4E-BP1, eukaryotic initiation factor 4E binding protein; TSC, tuberous sclerosis complex.

corticosteroids and progestins being more effective than androgens; however, corticosteroids are associated with additional unwanted effects.67 Gained weight is mostly fat and water in patients receiving progestins, but is more likely to be lean body tissue in those receiving androgens. The positive effects of corticosteroids are shortlasting and progestins are associated with an increased risk of thromboembolism.67 Thus, the benefitrisk ratio for s teroids is low. Cannabinoids increase appetite in patients with AIDS, but not in those with cancer.68 In terms of targeting the inflammatory response, cyclooxygenase inhibitors, such as indomethacin and ibupro fen, reduce the level of acute-phase reactants and resting energy expenditure; in a randomized study in 135patients with solid tumours and malnutrition, indomethacin (250mg per day) prolonged mean survival compared with placebo from 250 to 510days.69 Similar findings by the same group have been reported in subsequent studies.70 Amongst their widespread biological activities, n3 fatty acids are known to be competitive antagonists of arachidonic acid (the major proinflammatory eicosanoid precursor).71 A Cochrane meta-analysis in 2007 concluded that evidence from a very few randomized controlled studies was insufficient to give a recommendation on the use of n3 fatty acids in the treatment of cancer cachexia.72 More-recent studies within the past
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Tumour-associated and treatment-associated factors

Energy intake

Activity

Cachexia

In ammation

Tumour stroma and infections

Target for cachexia therapy

Figure 6 | Main targets for anticachexia treatments are those factors with an immediate effect on the development and aggravation of cachexia. Body weight depends on energy and nutrient intake and muscle mass on physical activity, and systemic inflammation compromises the body cell mass of major tissues. Thus, anticatabolic therapy should target systemic inflammation (anti-inflammatory); normalize intake of energy and substrates (nutrition support) and increase physical activity (exercise training). In addition, antineoplastic treatment can reduce the proinflammatory strain of the tumour stroma, whereas rapid and efficient antimicrobial therapy minimizes the inflammatory burden of repeated infections. Every effort should be undertaken to remove or alleviate all factors disturbing food intake and physical activity (supportive care).

2years, however, suggest a positive effect in patients with advanced-stage lung cancer on muscle loss, antineoplastic treatment effect and potentially on overall survival.42,43,73 Thalidomide inhibits the production of the inflammation-related cytokine TNF by human macro phages.74 Treatment with thalidomide might improve anorexia and nausea,75 as well as weight loss in patients with inoperable oesophageal cancer 76 and advancedstage pancreatic cancer.77 However, thalidomide is teratogenic and associated with frequent and potentially severe adverse effects, including peripheral neuropathy, fatigue, constipation, thromboembolism, pulmonary oedema, atelectasis, aspiration pneumonia, hypotension and renal insufficiency.78 Another possible target of anticachexia drug therapy is patient meta bolism. Administration of insulin to patients with cancer can decrease the wholebody protein breakdown rate79 and increase muscle protein synthesis.80 In a randomized study in 338 patients with cancer cachexia, daily insulin treatment (0.11IU/kg) compared with no insulin treatment increased wholebody fat (but not lean body mass), improved metabolic efficiency during exercise (but not maximum exercise capacity or spontaneous physical activity) and signifi cantly improved median overall survival by some 50% from 128 to 181days.81 There is current interest in the use of m etformin both from an anticancer and anticachexia viewpoint.

Investigational new treatments In line with the rapidly expanding understanding of the clinical basis of cancer cachexia, newly initiated trials are assessing the potential clinical benefit of new agents.
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Unfortunately, owing to the fact that best supportive care (basic multimodal management) has not yet been clearly defined, many of these trials do not incorporate such elements and, therefore, might under-perform and fail to show an improvement in the patients taking part. Compared with saline infusion, infusion of the gastric 28-amino-acid hunger-stimulating peptide ghrelin in seven anorexic patients with cancer increased food intake signifi cantly by 31%.82 The orally active ghrelin receptor agonist anamorelin hydrochloride showed similar activity in patients with cancer cachexia, inclu ding a significant increase in appetite and body weight with few associated adverse effects. 83 A phaseIII, randomized, placebo- controlled clinical trial assessing anamorelin hydro chloride in patients with nonsmall-cell lung c ancerassociate d cachexia is currently recruitingpatients.84 Selective androgen receptor modulators have been developed for treatment of muscle wasting and osteoporosis. Enobosarm was shown to significantly increase lean body mass and muscle function in a double-blind placebo-controlled phaseIIb trial in 120 healthy elderly men and women. 85 At present, enobosarm is being assessed in a randomized, placebo-controlled, phaseIII clinical trial in patients with non-small-cell lung cancer receiving first-line chemotherapy treatment.86 IL6 is a putative mediator of muscle wasting. 87 A humanized anti-IL6 antibody has been shown to be safe and well tolerated; in early clinical studies in patients with non-small-cell lung cancer, treatment with BMS945429 improved lung symptoms, reversed fatigue, and a trend towards a decrease in the loss of lean body mass was noted.88 These findings resonate with the results of a phaseII trial that assessed selumetinib (an inhibitor of MAPK1 and of IL6 secretion) in 20patientswith cholangio carcinoma.89 Overall, 84% of patients gainedmuscle after initiating therapy with s elumetinib; mean muscle gain was 2.3kg.89 Growth/differentiation factor 8 (also called myostatin) is a member of the TGF family; its normal action is to limit muscle mass.90 Inhibitors of myostatin signalling or mutations in the gene encoding myostatin (MSTN) result in dramatic increases in muscle mass, whereas over expression results in cachexia-like wasting.90 Some evidence shows that blocking myostatin improves survi val in rodent models of cancer cachexia.91,92 Extensive efforts have been directed at developing agents capable of modulating myostatin signalling for applications in clinical settings. One of these agents is LY2495655, an antimyostatin monoclonal antibody. A phaseII multicentre, randomized, double-blind, placebo-controlled trial in participants with locally advanced or metastatic pancreatic cancer will investigate two different doses of LY2495655 in combi nation with gemcitabine.93 Overall survival is the primary outcome of this study, with second ary end points including muscle mass and physical performance. BYM338 is another antimyostatin antibody undergoing phaseII evaluation in patients with stage IV non-small-cell lung cancer or stage III or IV pancreatic cancer.94
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Personalized care or one fit for all?
A diverse spectrum of deficits contributes to cachexia in patients with cancer (Figure6). As not all deficits will be present in every patient, multimodal management might need to be individualized to offer optimal care. However, a standardized basic approach to treatment is more pragmatic. Thus, it should be considered: first, to target the tumour (antineoplastic therapy); second, to target systemic inflammation (anti-inflammatory drugs or nutrients); third, to target all apparent or hidden factors disturbing food intake and physical activity should be sought and treated adequately; fourth, intake of energyand substrates should be normalized (nutrition support); and, finally, physical activity should be r ecommended and adequate support given. other countries, sophisticated certification systems have been established to ensure the diagnostic and therapeutic quality of cancer centres; nutritional expertise, however, is barely mentioned in some of these programmes and is ill-defined.101,102 Similarly, the very-detailed accreditation and designation user manual of the Organisation of European Cancer Institutes does not mention the term nutrition.103 In 2003, the European Council, after analysis of the incidence and impact of malnutrition in European hospitals demanded more and better programme s to improve hospital structures and expertise.104

Conclusions
To implement optimal routine basic multimodal manage ment of cachexia in patients with cancer the following items are required: first, knowledge about the impact of nutritional and metabolic deficits; second, expertise to recognize and monitor relevant nutritional and metabolic defects; third, knowledge about the relevant treatment options; and, finally, an ability to implement adequate treatment options. To establish these essential items within high-quality cancer care, the eventual goal has to be to offer adequate nutritional and metabolic support to all patients with cancer. The demonstration of beneficial nutritional or clinical outcomes by specialized cachexia or cancer rehabilitation clinics and multimodal intervention trials would be a strong stimulus to such action. Training programmes could then be developed and installed, expert teams integrated into cancer centres and structures implemented to ensure screening, diagnosis and treatmen t of nutritional and metabolicderangements.
Review criteria
A formal literature search for this Review was not performed. This Review includes a summary of the authors work and knowledge based on reading the oncology and palliative care literature. Literature searches in PubMed (1980 onwards) included the terms cancer cachexia, metabolism, and treatment. Knowledge gained from regular attendance at conferences, workshops, and other national and international meetings was also included.

Self-help programmes
Nutritional intake is one of the few areas that patients with cancer feel remains under their control and yet little clear advice is given to patients about what or what not to eat. Patients might easily be confused with the abundant literature accessible to lay persons that indicates that saturated fats or red meat might be a factor in carcinogenesis, consequently dropping these vital elements that would otherwise provide a balanced, energy-dense and high-protein diet to combat cachexia. Similarly, guidance is required to alert patients to remain physically active. The provision of easily accessible and simple information via national cancer websites is one method to approach this problem.

Implementation of guidelines
The best available evidence to guide treatment of cancer cachexia has been presented in guidelines published by different international bodies.2,9598 Currently, fewpatients receive optimal nutrition management and few academicphysician scientists are interested in cachexia therapy.99 Thus, many oncology units function without integrated nutritional and metabolic expertise. In the US, the Commission on Cancer has recently issued an update of its standards for patient-centred care, highlighting and specifying the required nutrition services.100 In

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