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Pathogenesis, clinical features, and assessment of cancer cachexia

Pathogenesis, clinical features, and assessment of cancer cachexia
Authors:
Aminah Jatoi, MD
Charles L Loprinzi, MD
Section Editor:
Paul J Hesketh, MD
Deputy Editor:
Diane MF Savarese, MD
Literature review current through: Dec 2022. | This topic last updated: Apr 18, 2022.

INTRODUCTION — Hippocrates described a syndrome of wasting and progressive inanition among patients who were ill and dying. The Greek words kakos, meaning "bad things," and hexus, meaning "state of being," have led to the term "cachexia" to describe this syndrome. Cachexia, a hypercatabolic state defined as accelerated loss of skeletal muscle in the context of a chronic inflammatory response, can occur in the setting of advanced cancer as well as in chronic infection, AIDS, heart failure, rheumatoid arthritis, and chronic obstructive pulmonary disease [1]. Although the body composition changes are not identical in all of these disease states, the term cachexia is used in all of these settings. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Prevalence and clinical significance' and "Assessment and management of anorexia and cachexia in palliative care", section on 'Etiology and pathogenesis'.)

Across malignancies, cachexia is highly prevalent, impacting approximately one-half of patients with advanced cancer [2,3]. While loss of appetite with weight loss is common among cancer patients [4-6], the profound weight loss suffered by patients with cachexia cannot be entirely attributed to poor caloric intake. Insufficient oral intake is superimposed upon complex metabolic aberrations that lead to an increase in basal energy expenditure and culminate in a loss of lean body mass from skeletal muscle wasting. In contrast to simple starvation, which is characterized by a caloric deficiency that can be reversed with appropriate feeding, the weight loss of cachexia cannot be adequately treated with aggressive feeding.

This topic will review the definitions, pathogenesis, and clinical characteristics of cancer cachexia. Potential pharmacologic therapies for cancer-related anorexia/cachexia syndrome and a separate discussion of assessment and management of anorexia/cachexia in palliative care patients are discussed separately. (See "Management of cancer anorexia/cachexia" and "Assessment and management of anorexia and cachexia in palliative care".)

DEFINITION AND CLASSIFICATION OF SEVERITY — Historically, cancer cachexia has been most often defined by loss of weight (eg, involuntary weight loss >10 percent) [7]. However, the measurement of body weight may underestimate the frequency of cachexia in patients who are overweight/obese or who have gained weight because of edema or a growing tumor mass [8,9]. As an example, largely because of the obesity epidemic in industrialized nations, cancer patients who historically were visibly cachectic with a body mass index (BMI) <20 may not be discernible as cachectic and, in fact, may have a normal or increased BMI [10,11].

More recently, clinicians and researchers interested in cachexia gathered formally to consider the definition of cachexia and its underlying or component elements, as well as its diagnostic criteria. The concept of cachexia is expanding to encompass specific elements of body composition, functional consequences, and biochemical signs of specific metabolic change:

In 2007, at the Cachexia Consensus Conference, an expert panel agreed to the following definition [12]:

"Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. 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. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption, and hyperthyroidism and is associated with increased morbidity."

Common findings in cachectic patients include anorexia or reduced nutritional intake, a systemic inflammatory response, decreased muscle strength, and fatigue [8,13]. Taking all of these factors into consideration, another proposed generic definition for cachexia/wasting includes weight loss with or without fat loss, and as additional criteria (three of which are required for diagnosis), decreased muscle strength, reduced muscle mass, fatigue, anorexia, or biochemical alterations (anemia, evidence of an ongoing inflammatory response, low albumin) [12].

In 2011, an international group of researchers developed a definition and classification system for cachexia in cancer patients [8]. The criteria for cancer cachexia were weight loss >5 percent, or weight loss >2 percent in individuals already showing depletion according to current body weight and height BMI <20 kg/m2 or skeletal muscle mass (sarcopenia). These experts considered three stages, precachexia, cachexia, and refractory cachexia (figure 1), with the severity of nutritional depletion classified according to the degree of depletion of energy stores and body protein in combination with the degree of ongoing weight loss. The five domains to be assessed for classification and clinical management were anorexia or reduced food intake, catabolic drive, stores depletion, muscle mass and strength, and functional and psychosocial impact. However, due to the lack of formal validated cachexia assessment instruments based on these domains, malnutrition assessment tools can be used to assess cachexia. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Malnutrition assessment tools'.)

These guidelines were adopted by the European Palliative Care Research Collaborative, which defines cancer cachexia as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without the loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment [14]. On the other hand, palliative care guidelines from the National Comprehensive Cancer Network (NCCN) [15] do not provide a formal definition of cachexia.

Not all patients with cancer progress through all stages of cachexia. The risk of progression depends on factors such as cancer type, stage, food intake, presence of systematic inflammation, inactivity, lack of response or complications from systemic anticancer therapy, and/or sequelae of surgery [16].

Classifying severity — In 2015, some members of an international consensus group proposed diagnostic criteria for the classification of cancer-associated weight loss [17]. Existing definitions, including the grading scale of the National Cancer Institute (NCI) (table 1), do not take into account current trends towards obesity, and they include interventions such as artificial nutritional support, which are not appropriate in many patients with advanced cancer. The proposed diagnostic criteria were systematically developed from a contemporary population-based data set, which demonstrated the independent prognostic significance of both percent weight loss and body mass index (BMI) [17]:

Weight-stable patients (ie, weight loss ±2.4 percent) with a BMI ≥25.0 kg/m2 had the longest survival (29 months): proposed grade 0

A BMI 20 to 25 kg/m2 and weight loss ≤2.4 percent, or a BMI ≥28 kg/m2 and weight loss 2.5 to 6 percent (median survival 14.6 months): proposed grade 1

A BMI 20 to 28 kg/m2 and weight loss <6 percent, or a BMI ≥28 kg/m2 and weight loss 6 to 11 percent (median survival 10.8 months): proposed grade 2

A BMI 20 to 28 kg/m2 and weight loss 6 to 11 percent, a BMI 22 to >28 kg/m2 and weight loss 11 to 15 percent, or a BMI ≥28.0 kg/m2 and weight loss >15 percent (median survival 7.6 months): proposed grade 3

A BMI ≤20 kg/m2 and weight loss 6 to 11 percent, a BMI ≤22 kg/m2 and weight loss 11 to 15 percent, or a BMI ≤28 kg/m2 and weight loss >15 percent (median survival 4.3 months): proposed grade 4

Survival discrimination by grade was observed within specific cancers, stages, ages, and performance states, and within an independent validation sample. These data once again underscore the substantial prognostic impact of weight loss in cancer patients.

Importantly, the above definitions serve a more important role in a research setting than in a clinical setting. In a clinical setting, such definitions should not detract from providing patients with optimal therapeutic and palliative care.

Cachexia versus sarcopenia — Cachexia is distinct from sarcopenia, which is defined specifically based on loss of skeletal muscle mass, often by two standard deviations below sex-specific and age-adjusted values [18]. Whereas most people with cachexia are sarcopenic (here defined as a loss of muscle mass), most sarcopenic individuals are not considered to be cachectic. Muscle loss without loss in fat is known as sarcopenic obesity, which is prevalent in older adults [19,20] and is also noted in advanced cancer patients [21]. The causes of sarcopenia are multifactorial and can include disuse atrophy, changing endocrine function, chronic diseases, inflammation, insulin resistance, nutritional deficiencies, and some forms of cancer treatment (notably sorafenib and androgen deprivation). (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Malnutrition'.)

PATHOGENESIS — Cachexia is at times a hypercatabolic state that appears to be defined in part by an accelerated loss of skeletal muscle in the context of an inflammatory response. A number of studies have focused on the mechanisms underlying the metabolic and body composition changes observed in cancer cachexia. They suggest a potentially important role for cytokine activation and for several tumor-derived and potentially cachexia-inducing substances, the target of which appears to be skeletal muscle gene products [22].

Cytokines, inflammation, and the hypermetabolic state — Increases in resting energy expenditure (REE; also called basal metabolic rate) may contribute to the energy deficits that lead to wasting. An increase in REE, as measured by indirect calorimetry, has been observed in patients with lung cancer [23,24], hematologic malignancies, and sarcomas [25,26], and it is thought to contribute to the weight loss observed in cancer cachexia. In one series of patients with lung cancer, 74 percent had an elevation in REE, while 30 percent had a weight loss of 10 percent or more [24]. In contrast to this apparent hypermetabolic state, simple calorie restriction alone typically leads to a decline in REE [27-29].

A large number of observations point towards cytokines, polypeptides released mainly by immune cells, as responsible for some of the metabolic derangements associated with the hypermetabolic state that partially characterizes cancer cachexia. Because of their ability to increase REE [30,31] and induce anorexia [32,33], tumor necrosis factor (TNF) alpha, interleukin (IL) 1 beta, and IL-6 have been viewed as plausible mediators of cancer cachexia [34]. Initial studies provided conflicting data as to whether an increase in serum cytokines occurs in cancer cachexia; the majority of studies have detected elevations in peripheral blood mononuclear cell cytokine concentrations, especially TNF-alpha and IL-6, among weight-losing patients with cancer [35-39]. TNF-alpha has also been implicated in weight loss in other settings, such as chronic obstructive pulmonary disease. (See "Malnutrition in advanced lung disease".)

The possible role of cytokines in several different cancers has been demonstrated:

A study of 87 patients with non-small cell lung cancer found that 26 had lost more than 10 percent of their pre-illness weight [38]. The patients with weight loss manifested a significantly greater systemic inflammatory response characterized by increased plasma concentrations of soluble TNF receptor (TNFR) 55, IL-6, the acute phase reactant C-reactive protein (CRP), as well as other adhesion molecules.

In a study of blood samples from 164 patients with prostate cancer, elevated serum IL-6 levels were observed in 38 patients with relapsed metastatic disease compared with those with newly diagnosed prostate cancer or disease in remission [40]. Among the entire study population, high IL-6 levels were associated with lower serum albumin, total protein, serum hemoglobin, and body mass index (BMI) and also were associated with poor performance status. Among patients with relapsed disease, an elevated serum IL-6 level correlated with significantly shorter survivals.

Similar observations were made in cachectic patients with pancreatic cancer [39]. Hypermetabolic patients with evidence of an acute phase response had higher concentrations of TNF-alpha and IL-6 in peripheral blood mononuclear cells than patients without an acute inflammatory response.

TWEAK (TNF-related weak inducer of apoptosis) is a cytokine that is related to the TNF/TNFR superfamily. In preclinical work, its receptor, Fn14 (also called TWEAKR), when expressed in malignancies, appears to be associated with the development of cachexia. Moreover, antibodies that target Fn14 appear to improve survival in animal models, preventing loss of fat and muscle with no evidence of an antineoplastic effect [41].

Additional evidence in support of the hypothesis that TNF-alpha, IL-1 beta, and IL-6 serve as mediators in cancer cachexia comes from animal studies:

Administration of any of these cytokines to laboratory animals induces cachexia [42-44].

Proinflammatory cytokines such as the IL-6 superfamily, TNF-alpha, IL-1, and others elicit anorexia, lipolysis, and muscle breakdown when injected systemically [1,45-47].

A large set of different transcription factors have been identified as playing important roles in tissue wasting; many are activated by proinflammatory stimuli [48-51].

The cachexia in tumor-bearing animals can be partially attenuated by the administration of anticytokine antibodies [52-56]. Similarly, transgenic IL-6 mice develop muscle atrophy, which can be reversed with anti-IL-6 receptor antibodies [55-57].

In knockout mice lacking the gene for the TNF-alpha receptor type I protein, tumor implantation is not associated with the protein breakdown and muscle wasting seen in wild-type mice [58]. In mice, TNF activates the transcription factor nuclear factor kappa B (NF-kB), which inhibits the expression of myoblast determination protein 1 (MyoD), a factor normally required for muscle function and repair [59]. The wasting effect of these proinflammatory cytokines appears to be targeted against the myosin heavy chain of skeletal muscle [60].

However, it should be noted that an etiologic role for TNF-alpha in cancer-associated anorexia/cachexia syndrome is not entirely supported clinically. Clinical trials have shown a lack of benefit from treatment with etanercept, a TNF-alpha inhibitor, as well as with infliximab, another TNF-alpha inhibitor, in randomized trials from the North Central Cancer Treatment Group (NCCTG). (See "Management of cancer anorexia/cachexia", section on 'TNF inhibitors'.)

Lipolysis and lipid-mobilizing factor — Although wasting of lean body mass is a major aspect of cancer cachexia, loss of fat mass also occurs. A tumor-produced lipid-mobilizing factor (LMF) may contribute to the wasting of fat tissue [61]. One study evaluated 50 patients: 24 with cancer, 10 with Alzheimer disease and weight loss, 9 with Alzheimer disease without weight loss, and 7 healthy individuals [62]. Using an assay for lipid mobilization that involves the incubation of human serum or urine with murine adipocytes and subsequent measurement of glycerol release from adipocytes, these investigators found that patients with cancer demonstrated significantly higher rates of lipid mobilization compared with other patient groups.

This factor has been isolated and characterized [63]. It appears to be a 43-kilodalton proteoglycan similar in its amino acid sequence to zinc alpha 2 glycoprotein (AZGP1), a ubiquitous protein whose function is largely unknown. In an animal model, administration of LMF-stimulated glycerol release led to weight loss and caused a 42 percent reduction in carcass adiposity [64]. In a series of 16 patients with cancer, only those with weight loss had detectable concentrations of LMF in their urine [63], a finding that suggests that this factor may play a role in the human cancer cachexia syndrome.

It is postulated that LMF acts to sensitize adipose tissue to lipolytic stimuli by increasing cyclic adenosine monophosphate (AMP) production in adipocytes [65]. This effect may be mediated through the beta-adrenergic receptor, with increased receptor number or G protein expression [61,65]. The lipolytic effect appears to be attenuated by eicosapentaenoic acid (EPA), which appears to directly inhibit adenylate cyclase activity [61,66].

Although preclinical data suggested the possibility that other mechanisms of loss of fat tissue may be operative (eg, tumor-induced impairment in the formation and/or lipid storage capacity of adipose tissue [67]), increased fat cell lipolysis, not reduced lipogenesis or adipocyte cell death, appears to be the primary cause of fat loss in this condition [68,69].

The ATP-ubiquitin-proteasome pathway — These multiple purported mediators of cancer cachexia raise questions as to what is happening at the muscle tissue level when wasting occurs. Activation of the adenosine triphosphate (ATP)-ubiquitin-proteasome pathway may play an important role in cancer-associated tissue wasting, as illustrated by the following observations:

Rats bearing the Yoshida AH-130 ascites hepatoma manifest notable muscle wasting after tumor implantation, including a 30 percent loss of the gastrocnemius and extensor digitorum longus muscles. By day 7 after tumor implantation, free ubiquitin and ubiquitin conjugates were higher in the gastrocnemius muscle of tumor-implanted rats than in muscles from control rats [70,71]. There was also an increase in ubiquitin messenger RNA levels in the skeletal muscle of tumor-bearing animals when compared with pair-fed animals [71].

Several proinflammatory cytokines, including TNF and IL-1, stimulate production of ubiquitin messenger RNA [72].

In an animal model of cancer cachexia, inhibition of the ubiquitin-proteasome pathway with the proteasome inhibitor MG132 attenuated weight loss, altered carbohydrate metabolism and muscle atrophy, and increased spontaneous activity and survival time for tumor-bearing mice [73].

Thus, the ubiquitin-proteasome pathway may be the final common pathway mediating protein degradation in cachexia [74]. Although the specific muscle receptors that trigger activation of the ATP-ubiquitin-proteasome system have not been elucidated, future treatment strategies for this entity might directly target this pathway in wasting tissues. One preliminary study with the proteasome inhibitor bortezomib did not result in reversal of the cancer anorexia/weight loss syndrome in patients with pancreatic cancer, but further studies of this approach are needed [75]. (See "Management of cancer anorexia/cachexia".)

Preclinical data further point to the importance of the ubiquitin-proteasome pathway in cancer-associated wasting and also provide insight into potential future therapeutic strategies. A 2010 animal study suggested that blockade of the activin receptor IIB (ActRIIB) pathway prevents further muscle wasting, reverses prior loss of skeletal muscle, and prolongs survival [76]. The prolongation of survival occurred independently of tumor growth. ActRIIB pathway blockade attenuated activation of the ubiquitin-proteasome system. These findings suggest that ActRIIB blockade might provide a new, innovative approach to treating cancer-associated weight loss; early clinical trials are ongoing.

JAK/STAT pathway — Janus kinases (JAKs) are a family of kinases that include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2); JAKs mediate cytokine signaling by activating signal transducer and activator of transcription (STAT) transcription levels. The JAK/STAT pathway is activated in a variety of disease states, including solid tumors [77], and it has also been implicated in cancer-induced muscle wasting [78]. Preliminary clinical data on the potential benefits of targeting this pathway were provided in a randomized phase II trial of capecitabine plus ruxolitinib (an inhibitor of JAK1 and JAK2) versus placebo in patients with advanced pancreatic cancer refractory to gemcitabine [79]. The addition of ruxolitinib did not significantly improve overall survival (the primary endpoint). However, in a prespecified subgroup analysis that included 50 percent of the cohort with evidence of increases in the inflammatory circulating biomarker CRP above the median value (13 mg/L), patients treated with ruxolitinib lived significantly longer (six-month survival rate 42 versus 11 percent). Furthermore, ruxolitinib-treated patients also gained weight. In the intention-to-treat analysis, approximately 20 percent of ruxolitinib-treated patients gained ≥5 percent of their body weight versus only 2 percent of those in the placebo group. Notably, the company that manufactures ruxolitinib has ceased its development in patients with pancreas cancer and, presumably, also in cachexia.

Genomics and its emerging role in studying cachexia — In another study using RNA profiling to better understand cachexia in patients with upper abdominal malignancies, rectus abdominis muscle biopsies were obtained from 65 cancer patients, and RNA profiling was performed on a subset (n = 21) using the Affymetrix U133+2 platform [80]. An 83-gene RNA signature identified patients with greater than 5 percent weight loss. Selected genes that were associated with weight loss were validated with quantitative real-time polymerase chain reaction (PCR) and were studied as cachexia biomarkers in a second cohort of gastrointestinal cancer patients (n = 13). Two specific genes, CaMKIIbeta and TIE1, both of which appear to also be activated with exercise, were directly associated with weight loss.

While these data are preclinical, studies such as these open new avenues for understanding cancer cachexia and for potentially identifying novel therapeutic targets.

Growth differentiation factor 15 (GDF15) — GDF15, a peptide hormone, is a member of a superfamily related to transformed growth factor beta. Emerging data reveals that elevation of this hormone correlates with cancer-associated cachexia and reduced survival in such patients [81-83]. Efforts are ongoing to study drugs that were specifically developed to block the activity of this substance in patients with cancer-associated anorexia/cachexia [81,82,84-86].

Contribution of cancer treatment — Cancer treatment may also contribute to loss of lean body mass (sarcopenia) in patients with advanced cancer. Examples include the muscle wasting seen with androgen deprivation therapy in men with advanced prostate cancer, and a similar loss of skeletal muscle mass that has been reported in patients treated with sorafenib, a multitargeted tyrosine kinase inhibitor, and bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). (See "Side effects of androgen deprivation therapy", section on 'Body composition and metabolism' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Muscle wasting/sarcopenia'.)

Reduced dietary intake or absorption — Anorexia and poor oral intake contribute to the energy deficits observed in cancer cachexia [87]. In one of the studies noted above, caloric intake was significantly lower (300 kcal/day) in weight-losing cancer patients [24]. Chemotherapy-related alterations in taste and smell may contribute to this loss of appetite [88-90]. One study suggests that weight-losing cancer patients appear to maintain the same relative food preferences but consume all foods in lesser amounts [91].

A number of nonspecific factors associated with cancer may contribute to decreased nutrient intake or absorption. These include diminished food intake due to dysphagia, abdominal pain, or abdominal distention; early satiety due to an enlarged spleen or liver, an abdominal mass, or abdominal distention (ascites); diminished gastrointestinal motility; and malabsorption resulting from tumor invasion of the gastrointestinal tract (especially the pancreas [92]) or intestinal resection.

Other symptoms that may impact appetite and caloric intake, termed secondary nutrition impact symptoms, may be related to the underlying illness or the consequence of cachexia (table 2). In particular, pain, fatigue, xerostomia, nausea, constipation, and depression are frequent in patients with advanced cancer and may result in decreased caloric intake if not adequately treated [11,93]. In one study of 151 patients referred to a cancer cachexia clinic, the median number of secondary nutrition impact symptoms was three, and the most common were early satiety, constipation, nausea/vomiting, and depressed mood [11]. It is not clear, however, if depression is more a cause or an effect of cancer cachexia.

Anorexia may also be a result of the central and peripheral influences of proinflammatory cytokines [1]. Centrally, inflammatory cytokines act at the level of the hypothalamic nuclei, which control feeding behavior. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Anorexia'.)

Finally, appetite may also be influenced by medications, food aversions, and aging. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Inadequate dietary intake' and "Approach to the patient with unintentional weight loss", section on 'Etiologies'.)

Despite the frequency of anorexia in advanced cancer, the profound weight loss suffered by patients with cachexia cannot be entirely attributed to poor caloric intake. In contrast to simple starvation, which is characterized by a caloric deficiency that can be reversed with appropriate feeding, the weight loss of cachexia cannot be adequately treated with aggressive feeding [94]. Insufficient oral intake is superimposed upon complex metabolic aberrations that lead to an increase in basal energy expenditure and culminate in a loss of lean body mass from skeletal muscle wasting [22].

In a study utilizing the Lewis lung carcinoma model, tumor-derived parathyroid-hormone-related protein (PTHrP) appeared to have a role in cancer-induced weight loss, possibly by inducing expression of genes involved in thermogenesis in adipose tissues [95]. When PTHrP was neutralized in tumor-bearing mice, various aspects of cachexia were improved, and the animals manifested improvement in muscle mass and strength. These findings have been observed only in an animal model, and the relevance of PTHrP in the clinical setting of cancer anorexia-cachexia syndrome is not yet determined. Further study appears to be warranted.

CLINICAL CHARACTERISTICS

Changes in body composition — A disproportionate and excessive loss of lean body mass is the hallmark of cancer cachexia. One study evaluated 50 patients with hematologic, pulmonary, gastrointestinal, and head and neck malignancies [96]. Patients were studied with tritiated water, prompt gamma neutron activation, and total body potassium measurement; these body composition measurements were compared with those of age- and sex-matched controls. Weight-losing patients with solid tumors suffered a loss of both fat and lean body mass. However, the loss of lean body mass, most notably skeletal muscle, was more dramatic. This response contrasts with that of simple starvation, where from a teleologic standpoint, the host preserves lean body mass in an effort to survive [97].

Alterations in nutrient metabolism — Cancer cachexia is often associated with important changes in nutrient metabolism. Many patients have a constellation of findings consisting of hyperglycemia, hypertriglyceridemia, and an exaggerated insulin response to a glucose load [98]. Hypertriglyceridemia occurs in combination with increases in very low-density lipoprotein production and lipolysis, and reduced activity of adipose tissue lipoprotein lipase.

These changes may be a result of the interaction between increased cytokine release and insulin resistance [99,100]. As an example, tumor necrosis factor (TNF) alpha, which is often increased in patients with cancer cachexia (see 'Cytokines, inflammation, and the hypermetabolic state' above), has been implicated in the insulin resistance associated with obesity and type 2 diabetes [101-104]. (See "Pathogenesis of type 2 diabetes mellitus".)

Protein breakdown is increased in patients with cancer cachexia, leading to enhanced amino acid release from skeletal muscle despite the reduction in muscle mass and negative nitrogen balance. The plasma concentration of certain amino acids tends to be elevated, perhaps in part because of decreased skeletal muscle uptake due to insulin resistance [105].

Clinical consequences — The anorexia-cachexia syndrome is often associated with psychosocial distress for both patients and family [106-108].

In addition, weight loss and cachexia are also associated with a poor prognosis in patients with advanced disease:

In a National Hospice Study of terminal cancer, the symptoms of anorexia, weight loss, xerostomia, and dysphagia were all predictive of decreased survival [109].

In a multi-institutional, retrospective review of 3041 clinical protocol cancer patients from the Eastern Cooperative Oncology Group (ECOG), weight loss of more than 5 percent of premorbid weight prior to the initiation of chemotherapy was predictive of early mortality. Weight loss was independent of disease stage, tumor histology, and patient performance status in its predictive value [110]. There was also a trend towards lower response rates with the use of chemotherapy among weight-losing patients, but this trend reached statistical significance only among patients with breast cancer. In addition to contributing to poor prognosis and impaired response to therapy, cachexia may be a direct cause of death. A retrospective autopsy study found that approximately 1 percent of 486 patients with cancer died from no cause other than cachexia itself [111].

As noted above, measurement of actual body weight may underestimate the frequency of cachexia in patients who are overweight/obese. At least some data support the view that weight loss, muscle depletion, and low muscle attenuation (Hounsfield units) by computed tomography (CT) scan evaluation portend a poor prognosis independent of actual body weight [112-114]. In one of these studies, despite some patients being obese, those with all three of these characteristics lived for approximately eight months, compared with approximately 28 months for patients without any of these characteristics (p<0.001) [112-114].

Although the evidence that weight loss is associated with a poor prognosis in patients with advanced, incurable cancer is convincing, efforts to counteract cancer anorexia/cachexia via increasing caloric supplementation or the provision of agents to increase appetite have not been shown to improve patient outcomes.

In addition to their prognostic value, weight loss, cachexia, and loss of muscle mass are often associated with poor functional status, impaired quality of life, and an increased risk of hospitalization [115-118]. (See "Approach to symptom assessment in palliative care", section on 'Performance status, symptoms, and prognosis'.)

ASSESSMENT — The clinical assessment for patients with cancer cachexia includes a careful history that is focused on risk factors that compromise the ability to obtain or take in nutrition, and a physical examination focusing on loss of subcutaneous fat, muscle wasting (temporal region, deltoids, and quadriceps with loss of bulk and tone by palpation), edema (sacral or ankle), or ascites. The most commonly used objective measure is serial measurement of body weight. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Assessment'.)

As noted above, an international consensus group recommended that five domains be encompassed in cachexia assessment: stores depletion, muscle mass and strength, anorexia/reduced food intake, catabolic drivers, and functional/psychosocial effects [8]. However, there are no formal validated cachexia assessment instruments based on these domains. Malnutrition assessment tools are sometimes used by others. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Malnutrition assessment tools'.)

The extent or severity of cachexia can be classified [17]. (See 'Classifying severity' above.)

While classification such as these may be useful for prognostication, they do not provide any information as to whether early interventions improve outcomes in patients with more severe cachexia grades. Intervention trials in advanced cancer (using parenteral nutrition, appetite stimulants such as megestrol acetate, anabolic agents such as ghrelin analogs, or other forms of pharmacologic intervention) have not been shown to improve survival or, for the most part, quality of life. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer" and "Management of cancer anorexia/cachexia".)

Another important aspect of assessment is asking about items that have been termed "nutrition impact symptoms"; these include such things as depression, severe pain, excessive drowsiness, nausea, dysgeusia, and constipation (table 2). In a retrospective analysis of patients in a clinic designed for patients with cancer cachexia, one-half of the patients with advanced malignancies noted two to four of these nutrition impact symptoms; 15 percent had more than five of them. With attention paid to reversing these symptoms, follow-up evaluations of patients revealed evidence of improved appetite and body weight [11]. (See "Management of cancer anorexia/cachexia", section on 'Treating nutrition impact symptoms'.)

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SUMMARY

Definition and pathogenesis

Cachexia, a hypercatabolic state defined as accelerated loss of skeletal muscle in the context of a chronic inflammatory response, frequently occurs in the setting of cancer. While loss of appetite with weight loss is common among cancer patients, the profound weight loss suffered by patients with cachexia cannot be entirely attributed to poor caloric intake. Insufficient oral intake is superimposed upon complex metabolic aberrations that lead to an increase in basal energy expenditure and culminate in a loss of lean body mass from skeletal muscle wasting [22]. (See 'Introduction' above.)

A number of studies focusing on the mechanisms underlying the metabolic and body composition changes observed in cancer cachexia suggest a potentially important role for cytokine activation and for several tumor-derived and potentially cachexia-inducing substances, the target of which appears to be skeletal muscle gene products. (See 'Pathogenesis' above.)

In some cases, cancer treatment may also contribute to loss of lean body mass in patients with advanced cancer. Examples include the muscle wasting seen with androgen deprivation therapy in men with advanced prostate cancer, and a similar loss of skeletal muscle mass (sarcopenia) that has been reported with sorafenib, a multitargeted tyrosine kinase inhibitor used for the treatment of advanced renal cell and liver cancer. (See 'Contribution of cancer treatment' above.)

Other contributors include reduced dietary intake/absorption, which may be influenced by several factors related to the cancer or its treatment (eg, nausea, fatigue, pain), depression, medications, and aging. (See 'Reduced dietary intake or absorption' above.)

Clinical characteristics

A disproportionate and excessive loss of lean body mass is the hallmark of cancer cachexia. Weight loss and cachexia are associated with psychosocial distress for both patients and family and are also associated with poor prognosis. (See 'Clinical characteristics' above.)

Cancer cachexia is often associated with important changes in nutrient metabolism, including hyperglycemia, hypertriglyceridemia, and an exaggerated insulin response to a glucose load.

Assessment

The clinical assessment for patients with cancer cachexia includes a careful history that is focused on risk factors that compromise the ability to obtain or take in nutrition, the presence of symptoms (including "nutrition impact symptoms" (table 2)), and a physical examination focusing on loss of subcutaneous fat, muscle wasting (temporal region, deltoids, and quadriceps with loss of bulk and tone by palpation), edema (sacral or ankle), or ascites.

The most commonly used objective measure of cachexia is serial measurement of body weight, but assessment of dietary intake and the use of malnutrition assessment tools might also be helpful. (See 'Assessment' above and "Assessment and management of anorexia and cachexia in palliative care", section on 'Secondary nutrition impact symptoms'.)

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