INTRODUCTION — Hippocrates described a syndrome of wasting and progressive inanition among patients who were ill and dying. Derived from the Greek words “kakos,” meaning “bad things,” and “hexus,” meaning “state of being,” the term cachexia has been used to describe weight loss. From “an,” meaning “without,” and “orexis,” meaning “appetite, desire,” the word anorexia is used to characterize loss of appetite. Cachexia, a hypercatabolic state that is defined by an accelerated loss of skeletal muscle in the context of a chronic inflammatory response, is best described in the setting of cancer but is also seen in other advanced chronic illnesses including AIDS, heart failure, and chronic obstructive pulmonary disease (COPD) [1]. Although body composition changes are not identical in all of these disease states, the term cachexia is used in all of these settings.
Loss of appetite and weight loss are common among patients with an advanced serious life-threatening illness such as cancer. However, 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, cachexia is not reversed by the supplementation of calories [2].
This topic review will cover the diagnosis, evaluation, and management of anorexia and cachexia in palliative care patients. A more detailed review of the clinical features, pathogenesis, and management of cancer-associated anorexia and cachexia is available elsewhere. (See "Pathogenesis, clinical features, and assessment of cancer cachexia" and "Management of cancer anorexia/cachexia".)
DEFINITIONS — Anorexia may be simply defined as either loss of appetite or reduced caloric intake [3].
Cachexia has historically been most often defined by weight loss (most often total involuntary weight loss of more than 10 percent of premorbid body weight [4]). However, the measurement of body weight may underestimate the frequency of cachexia in patients with overweight/obesity, or those who have gained weight because of edema or a growing tumor mass [5,6].
This has led to efforts to expand the definition:
●In 2007, an international expert panel agreed to the following formal definition [7]: “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, and malabsorption, and is associated with increased morbidity.”
●Common findings in cachectic patients include anorexia or reduced nutritional intake, systemic inflammation, decreased muscle bulk (sarcopenia) and strength, and fatigue [5,8]. Taking all of these factors into consideration, one proposed generic definition for cachexia/wasting includes weight loss with or without fat loss and, as additional criteria (three required for diagnosis), decreased muscle strength, reduced muscle mass, fatigue, anorexia, or biochemical alterations (anemia, inflammation, low albumin) [7].
●An international group of researchers has developed a definition and three-level staging system for cachexia in cancer patients [5], which needs further validation, particularly in patients with disease other than cancer. Preliminary studies in advanced non-small cell lung or gastrointestinal cancers have suggested clinical relevance for these cancer cachexia stages with respect to overall symptom burden, quality of life, tolerability for chemotherapy, body composition, and survival; however, patients in the precachectic and cachectic groups behaved in a similar manner [9]. Nevertheless, the cancer cachexia staging system has been adopted by the European Palliative Care Research Collaborative (EPCRC), 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 [5]. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)
The variable diagnostic criteria for cachexia are reflected in the wide variability in prevalence among palliative care populations [10]. (See 'Prevalence and clinical significance' below.)
Cachexia is distinct from sarcopenia, which is defined by loss of skeletal muscle mass to an amount that is two standard deviations below sex-specific normal values for young adults [11]. Unlike cachexia, sarcopenia does not require the presence of weight loss. Whereas most people with cachexia are sarcopenic, most sarcopenic individuals are not considered cachectic. Muscle loss without the loss or gain in fat is known as sarcopenic obesity, which is prevalent in older adults [12,13] and is also noted in advanced cancer patients [14].
The causes of sarcopenia are multifactorial and can include disuse; changing endocrine function; chronic diseases; inflammation; insulin resistance; nutritional deficiencies; some forms of cancer treatment, notably sorafenib and androgen deprivation therapy; and specific cancers, notably non-small cell lung cancer [15,16]. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Definition and classification of severity' and "Geriatric nutrition: Nutritional issues in older adults", section on 'Malnutrition'.)
PREVALENCE AND CLINICAL SIGNIFICANCE
Anorexia — Anorexia is a common symptom in palliative care patients, especially among older adults, and is associated with decreased overall survival in cancer patients [17].
In a European series of 3030 palliative care patients with a variety of illnesses, moderate or severe anorexia was present in 26 percent [18]. In a second report of 2382 inpatient palliative care consultations, adults 65 to 84 were significantly more likely to report anorexia than were younger adults (odds ratio 1.57, 95% CI 1.23-2.00) [19].
While very common in patients with advanced cancer, anorexia is also common in other chronic diseases, such as chronic kidney disease (CKD). Anorexia affects 30 to 40 percent of adult patients on maintenance hemodialysis and is associated with increased rates of hospitalization, poor quality of life, and increased mortality [20]. (See "Overview of the management of chronic kidney disease in adults", section on 'Malnutrition' and "Pathogenesis, clinical features, and assessment of cancer cachexia".)
Anorexia usually results in reduced caloric intake, malnourishment, and weight loss. Poor nutritional intake is common across a variety of chronic disease states:
●In the setting of advanced cancer, nutritional intake is inadequate to support basal metabolic demand in up to 40 percent of patients [21,22].
●The majority of patients with heart failure fail to obtain adequate caloric intake and range of nutrients [23].
●Among patients with chronic obstructive pulmonary disease (COPD), the prevalence of malnutrition is roughly 20 to 40 percent in outpatients and up to 70 percent for inpatients with respiratory failure. (See "Malnutrition in advanced lung disease", section on 'Frequency of malnutrition'.)
Cachexia — The prevalence of cachexia in palliative care populations varies widely (from 12 to 85 percent on one report [10]), in part because of variable diagnostic criteria. (See 'Definitions' above.)
The prevalence of cachexia also varies according to disease. Prevalence ranges from 5 to 20 percent in chronic heart failure to 60 percent in COPD and as high as 85 percent in advanced cancer, particularly certain types such as pancreatic, gastric, and lung cancer [24-26]. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)
Cachexia is also highly prevalent in moderate to advanced stages of CKD. Loss of weight affects between 18 to 75 percent of patients with CKD, and the prevalence depends in part on patient characteristics (eg, requirement for maintenance hemodialysis [27]) and the presence of comorbid conditions such as heart failure, diabetes mellitus, or liver disease [28]. In the setting of CKD, the term protein-energy wasting (PEW) is used to define earlier stages of a wasting syndrome [29]. The International Society of Renal Nutrition and Metabolism (ISRNM) suggests that the term cachexia be reserved for only the most severe forms of PEW [29]. This distinction is important because nutritional supplementation in adult patients with end-stage kidney disease (ESKD) may be helpful in patients with PEW to prevent progression to cachexia. (See 'Chronic kidney disease' below.)
The incidence of cachexia in patients infected with HIV has decreased with the introduction of effective antiviral therapy. However, in the United States, despite effective antiviral therapy, the prevalence of cachexia in HIV-infected patients is roughly 30 percent [30]. In non-developed countries where access to expensive antiviral medications is limited, weight loss is more prevalent. (See "The natural history and clinical features of HIV infection in adults and adolescents".)
Psychosocial, functional, and prognostic impact — Anorexia-cachexia syndrome often results in psychosocial distress for both patients and their loved ones [31-33]. A prospective study of patients with advanced cancer found that patients who experienced weight loss of at least 10 percent during the previous six months reported higher deterioration of body image than did patients without such weight loss, and body image dissatisfaction had a strong association with psychosocial outcomes (anxiety, depression, decreased sexual interest and enjoyment) [31]. In a qualitative study, family caregivers universally noted changes in oral intake at the end of life [34,35]. Bereaved caregivers who were interviewed reported a sense of helplessness and guilt associated with a loved one losing weight and felt that not enough education and psychological support was provided by health care providers regarding hydration and nutrition at the end of life. Some caregivers accepted decreased intake as part of the dying process, while others preferred to support oral intake in their “battle” against illness [34].
Cachexia is 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 [36]. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Clinical consequences'.)
In addition to cancer, cachexia in the setting of other illnesses, such as heart failure, CKD, HIV disease, or COPD, has also been shown to increase the risk of death [37-40]. In addition to its prognostic value, loss of muscle mass is often associated with poor functional status, impaired quality of life, and an increased risk of hospitalization [41,42]. (See "Approach to symptom assessment in palliative care", section on 'Performance status, symptoms, and prognosis' and "Malnutrition in advanced lung disease", section on 'Effect on mortality and lung function'.)
ETIOLOGY AND PATHOGENESIS
Anorexia — Adequate caloric intake is dependent on multiple factors, including the palatability of food, which is controlled by the cranial nerves (the olfactory, glossopharyngeal, and facial), and the feeling of satiety, which is mediated by the autonomic sensory nerves innervating the proximal gastrointestinal tract and contained in the afferent arm of the vagus nerve. Nutritional intake is coordinated by the brain, primarily in the hypothalamic nuclei, which integrates signals from cognitive, visual, and sensory stimuli as well as activity of the gastrointestinal tract. A host of signaling molecules in the brain exert stimulating or inhibiting control of appetite [43-47], including neurotransmitters (serotonin, dopamine, histamine), hormones such as ghrelin [48,49] and leptin [50,51], corticotropin-releasing factor, neuropeptide Y, alpha-melanocyte-stimulating hormone, and others (table 1). The cellular signals that regulate intake of nutrition are not well understood.
Lack of appetite is frequently seen in patients with many kinds of advanced illness (eg, heart failure, cancer, chronic kidney disease [CKD], chronic obstructive pulmonary disease [COPD]). In fact, a chronic illness affecting any organ system can cause anorexia and weight loss. The symptom of anorexia in the setting of infection, trauma, or cancer may represent an important adaptive response that allows an organism to mobilize energy reserves in order to sustain the increased metabolism required to wage an immune response and heal injuries or repair the destruction from rapidly dividing malignant cells [52,53].
Lack of appetite can also be a consequence of chronic fatigue or nausea, which may be barely noticeable; altered taste, depression, pain, xerostomia, disorders of gastrointestinal motility (including gastroparesis), constipation, and food aversions can also contribute. These symptoms are referred to as "secondary nutrition impact symptoms." (See 'Secondary nutrition impact symptoms' below.)
Other common considerations include medications (amphetamines, antibiotics, opioids [54], antihistamines, digoxin, ranolazine, antidepressants) and chemotherapy which can induce muscle wasting [55]. Chronic opioid use can result in hypogonadism and subsequent loss of lean body mass. At least in the setting of end-stage kidney disease (ESKD), male patients tend to have increased symptoms of anorexia, suggesting a possible role for sex hormones [56].
Aging may also contribute. Food intake gradually diminishes with age, much of which is an appropriate response to decreased energy needs due to reduced physical activity and decreased resting energy expenditure. Changes in taste and smell can also lead to a decreased desire to eat [57]. (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'.)
Decreased appetite is a major component of the “failure to thrive” (FTT) syndrome, which is described by The National Institute of Aging as a “syndrome of weight loss, decreased appetite and poor nutrition, and inactivity, often accompanied by dehydration, depressive symptoms, impaired immune function, and low cholesterol” [58]. In geriatric practice, FTT describes a point further along a geriatric functional continuum that is closer to full dependence and death, with “frailty as a mid-point between independence and pre-death” [59]. (See "Failure to thrive in older adults: Evaluation".)
Cachexia — The pathogenesis of cachexia has been best studied in patients with cancer-related cachexia. A large number of observations point towards cytokines, polypeptides released mainly by immune cells, as the molecules responsible for some of the metabolic derangements associated with the hypermetabolic state that characterizes cancer-bearing states. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Pathogenesis'.)
This inflammatory response may play a unifying central role in the cachexia that occurs with injury, infection, and chronic illness other than cancer. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Cytokines, inflammation, and the hypermetabolic state'.)
●Proinflammatory cytokines such as interleukin 6 (IL-6) superfamily, tumor necrosis factor (TNF) alpha, IL-1, and others elicit anorexia, lipolysis, and muscle breakdown when injected systemically [1,60-62].
●A large set of different transcription factors have been identified to play important roles in tissue wasting; many are activated by proinflammatory stimuli [63-66].
However, the etiology of cachexia appears to be more complex and multifactorial than just inflammation alone, as evidenced by the following:
●In addition to cytokine activation, 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 several tumor-derived and potentially cachexia-inducing substances, the target of which appears to be skeletal muscle gene products. In particular, the ubiquitin-proteasome pathway may be the final common pathway mediating protein degradation in cancer-related cachexia. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Pathogenesis' and "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Contribution of cancer treatment'.)
●Hypogonadism is a common endocrine cause of wasting in patients with advanced immunosuppression (eg, HIV) and is also associated with chronic opioid use [67]. Hypogonadism is associated with a higher symptom burden, markers of inflammation, and worse survival [68]. (See "Hypogonadism in males with HIV" and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Neuroendocrine effects'.)
●Cardiac cachexia is mediated by changes in catecholamines, cortisol, natriuretic peptides, and proinflammatory cytokines, including TNF-alpha, IL-1, and IL-6 [69,70]. Endocrine dysfunction, including activation of the renin-angiotensin-aldosterone-system, increased levels of ghrelin [71], and insulin resistance [72], also may play a role, as do other hormones such as adiponectin [73]. Heart failure resulting in decreased bowel perfusion or edema may also contribute to nutritional deficiencies and fat malabsorption. (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Nausea and cachexia'.)
●Malnutrition associated with advanced lung disease has been termed the “pulmonary cachexia syndrome.” It is a well-recognized feature of advanced COPD, although its cause is poorly understood. A role for myostatin, a member of the transforming growth factor-beta superfamily that functions as a negative regulator of muscle growth, has been suggested by the finding of significantly elevated serum myostatin levels in patients with stable COPD compared with healthy controls [74]. Myostatin levels correlated inversely with total body skeletal muscle mass and body mass index (BMI).
Other potential contributory factors to the progressive reduction in lean body mass include changes in metabolism and caloric intake, aging, lack of exercise, fatigue, tissue hypoxia, inflammation, and medications [75]. (See "Malnutrition in advanced lung disease", section on 'Contributing factors'.)
●In CKD, anorexia and malnutrition may contribute to weight loss, but they are not responsible for the pathogenesis of cachexia. Factors such as systemic inflammation, alterations of hormones (including vitamin D deficiency), increased energy expenditure, insulin resistance, metabolic acidosis, and other mechanisms contribute to cachexia in CKD [76,77].
ASSESSMENT — All patients with advanced incurable illness should be screened for nutritional status and weight loss. The clinical assessment for patients with anorexia or cachexia includes a careful history that is focused on nutritional issues, including 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. Given that health care professionals, including clinicians and nurses, underrecognize the prevalence of cancer cachexia, routine use of a brief assessment tool for screening has been recommended [78]. (See 'Malnutrition assessment tools' below.)
In addition, the initial stages of weight loss may be masked in obese patients, as opposed to patients with a normal body mass index (BMI), contributing to cachexia being underrecognized by health care providers.
The most commonly used objective measures of nutritional status are serial measurement of body weight, anthropometrics, biochemical laboratory measures, and observed assessments of dietary intake, while subjective information on nutritional status can be provided by nutritional assessment tools including dietary recalls, Edmonton Symptom Assessment System (ESAS) or Visual Analog Scale (VAS) for anorexia, and the Anorexia/Cachexia Subscale of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT-A/CS) [79]. Recommended diagnostic criteria for anorexia include a cutoff value of ≤70 on the VAS for appetite and a cutoff value of ≤37 on the FAACT-A/CS [80].
Laboratory measures of nutritional status (eg, albumin, transferrin) are rarely needed for assessment of nutritional status, although some screening tools (eg, the Nutrition Risk Index) do include a measurement of serum albumin (see 'Malnutrition assessment tools' below). In addition, the presence of a low albumin can help find and document the presence of malnutrition to properly assess expected mortality.
Cachexia — 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 [5]. Due to the lack of formal validated cachexia assessment instruments based upon these domains (although one has been developed for cancer patients by the European Organisation for Research and Treatment of Cancer [EORTC] [81]), malnutrition assessment tools are generally in use to assess cachexia in cachexia clinics. (See 'Malnutrition assessment tools' below.)
Appetite — Although the reliability of subjective assessments of appetite is debated, they are probably the simplest and most practical measures available. Patient-rated assessment measures (eg, FAACT [82]) have been developed for clinical trials of orexigenic (appetite-stimulating) agents for cancer or HIV-related anorexia and should be considered for high-risk patient populations. In routine practice, the patient's subjective loss of appetite can be assessed with a numeric rating scale such as the ESAS or the revised ESAS (table 2). (See "Approach to symptom assessment in palliative care", section on 'Lack of appetite'.)
Secondary nutrition impact symptoms — A comprehensive assessment for anorexia and cachexia should also take into account other symptoms that may impact appetite and caloric intake, termed secondary nutrition impact symptoms (S-NIS). These include symptoms that may be related to the underlying illness, symptoms and syndromes that may contribute to reduced caloric intake, and symptoms that might be the consequence of cachexia (table 3). In particular, pain, xerostomia, nausea, constipation, and depression are frequent in patients with a chronic illness and may result in decreased caloric intake if not adequately treated [83,84]. In one study of 151 patients referred to a cancer cachexia clinic, the median number of S-NIS was three, and the most common were early satiety, constipation, nausea/vomiting, and depressed mood [83].
Other contributors to anorexia and cachexia — Potentially reversible metabolic abnormalities, including hypothyroidism, adrenal insufficiency, and hypogonadism (in male patients), may go undetected and contribute to loss of appetite or decreased lean body mass (table 3). Hypogonadism is especially common in men with cancer [83,85]. In the series of 151 patients referred to a cancer cachexia clinic described above, 52 of 71 males were hypogonadal (73 percent) [83].
The benefits of testosterone replacement in hypogonadal men with an advanced serious illness, at least in the setting of advanced cancer, remain uncertain [86]. Nevertheless, we screen all male patients for low testosterone in our cancer cachexia clinic and encourage enrollment in clinical trials evaluating the benefits of testosterone replacement on symptoms of fatigue and lean muscle mass. In addition, screening all cancer patients with weight loss for thyroid abnormalities, which are more common in patients treated with tyrosine kinase inhibitors that target the vascular endothelial growth factor, should be considered. (See 'Anabolic steroids' below and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Thyroid dysfunction'.)
We also screen for adrenal insufficiency in cancer patients who have bilateral adrenal metastasis or in those with a clinical suspicion for adrenal insufficiency.
Gastroparesis is fairly common in patients with a terminal disease, especially cancer, and it can contribute to weight loss because of inability to take in sufficient calories. In cancer patients, the etiology of gastroparesis and early satiety is often multifactorial and can include chemotherapy-induced autonomic dysfunction and medications such as opioids or anticholinergics, radiation enteritis, and tumor infiltration, or it can be the result of a paraneoplastic syndrome. It is easily diagnosed by history of early satiety and sometimes can be successfully treated. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Treatment of gastroparesis".)
Among patients with cancer, some treatments are associated with sarcopenia (androgen deprivation therapy, sorafenib, bevacizumab), which may also contribute to decreased lean body mass. (See 'Definitions' above and "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Contribution of cancer treatment'.)
Assessment of body weight and other anthropometric measures — Serial measurements of body weight offer the simplest screen for nutritional adequacy and change in nutritional status. The weight and height of a patient are easily obtainable and are used to formulate BMI, calculated by an individual’s body mass divided by the square of his or her height (kg/m2). Various values of low BMI (BMI <17, <18.5, or <20) have been used as markers for nutritional deficiency and cachexia. However, BMI accuracy is limited [87], does not take into account age or sex, and fails to distinguish between proportions of bone, lean body mass, or fat. Despite having a normal BMI, many chronically ill patients, including those with advanced cancer, have normal to high BMI values reflective of preexisting obesity, with decreased fat-free mass but increased fat mass [84,88].
These issues were taken into account in the development, by an international consensus group, of a set of proposed diagnostic criteria for the classification of the severity of cancer-associated weight loss, which was developed from a contemporary population-based data set and showed the independent prognostic significance of both percent weight loss and BMI [89]:
●Weight-stable patients (ie, weight loss ± 2.4 percent) with BMI ≥25.0 kg/m2 had the longest survival (29 months): proposed grade 0
●BMI 20 to 25 kg/m2 and weight loss ≤2.4 percent, or BMI ≥28 kg/m2 and weight loss 2.5 to 6 percent (median survival 14.6 months): proposed grade 1
●BMI 20 to 28 kg/m2 and weight loss 2.5 to 6 percent, or BMI ≥28 kg/m2 and weight loss 6 to 11 percent (median survival 10.8 months): proposed grade 2
●BMI ≤20 and weight stable or loss of <6 percent, BMI 20 to 28 kg/m2 and weight loss 6 to 11 percent, BMI 22 to >28 kg/m2 and weight loss 11 to 15 percent, or BMI ≥28.0 kg/m2 and weight loss >15 percent (median survival 7.6 months): proposed grade 3
●BMI ≤20 kg/m2 and weight loss 6 to 11 percent, BMI ≤22 kg/m2 and weight loss 11 to 15 percent, or 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 underscore the important prognostic impact of weight loss as well as BMI in cancer patients. Limitations of the study include the variable time frames used when assessing weight loss and BMI, which pooled data from multiple clinical trials conducted in Canada and France. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Classifying severity'.)
Other anthropometric indicators of nutritional status, such as mid-upper arm circumference and skinfold measurement, can be used to objectively document muscle wasting and loss of subcutaneous fat. However, these are more often used in the research setting and are rarely needed in the clinic.
Nutritional intake — Standard measures for assessment of caloric intake rely upon retrospective reporting or prospective dietary record keeping. Retrospective reporting is limited by recall bias, while prospective recordings of dietary intake require several days of assessments to be reliable [90]. For prospective diet diaries, a three-day collection interval [91] seems to be a feasible and accepted approach to determining caloric intake. An alternative approach used in research, which estimates the percentage of food portions consumed by patients by trained proxies (either a nurse or a volunteer), has shown good correlation with actual caloric intake and is more reliable than a 24-hour recall method [92].
Malnutrition assessment tools — Several screening tests have been developed to assess for malnutrition, including the Patient-Generated Subjective Global Assessment (PG-SGA), the mini nutritional assessment (MNA), the Malnutrition Universal Screening Tool (MUST), and the Simplified Nutritional Appetite Questionnaire (SNAQ). No single screening tool has been universally agreed upon as the best way to detect malnutrition in patients with cancer or other chronic illnesses.
●The PG-SGA is well established and validated with other objective nutritional measurements [93]. It incorporates information from patients (weight history, food intake, functional status, symptoms affecting food intake), assessments made by health care professionals (comorbid conditions, corticosteroid use, fever), and assessments made by physical examination [94]. PG-SGA is validated in cancer patients of all ages and in hospitalized patients, but it does take time and a well-trained person to complete. In one review, the average time required to complete the PG-SGA by a patient and responsible evaluator was 5 to 15 minutes [84].
●The Nutritional Risk Screening (NRS) 2002 has two components: a screening assessment for undernutrition (estimated with three variables: BMI, percent recent weight loss, and change in food intake) and an estimate for disease severity (which ranges from a score of zero for those with chronic illnesses or a hip fracture to three for those in the intensive care unit with an Acute Physiology and Chronic Health Evaluation [APACHE] score of 10) [95]. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Screening tools'.)
●The MUST has been validated in cancer patients and hospitalized patients who are acutely ill and predicts length of stay and mortality. It is a simple tool that incorporates BMI, weight loss, and an acute disease effect score [96-98].
The specific cachexia domains covered by some of these screening tools include stores depletion, muscle mass and strength, anorexia or reduced food intake, catabolic drivers, and functional/psychosocial defects (table 4) [6]. At our institution, the PG-SGA is used as a malnutrition assessment tool.
These and other malnutrition screening tools are discussed in more detail elsewhere. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Screening tools'.)
Evaluating body composition — Dual-energy x-ray absorptiometry (DXA) is a highly accurate measure of weight that can differentiate fat, lean body mass, and bone tissue but is used mainly in the research setting. Computed tomography (CT) and magnetic resonance imaging (MRI) have also been used to distinguish body composition, but the high cost limits their use to the research setting.
Bioelectrical impedance analysis (BIA) is a convenient, portable, and low-cost measure of weight and can estimate fat-free mass and fat mass. However, in cancer patients, BIA was shown to underestimate fat-free mass when compared with DXA [99]. Furthermore, the equipment is not readily available in most institutions.
TREATMENT
General aspects — Loss of appetite and alterations in appearance as a result of cachexia are distressing to both patients and their loved ones. The social benefits of being at the dining table with other family members should be encouraged. The pleasure of tasting food should be emphasized over total caloric intake. In general, patients with anorexia-cachexia syndrome who are able to eat should be recommended to have small, frequent meals that are dense in calories (eg, eggs, liquid nutritional supplements). Other strategies to enhance caloric intake include eating meals that require little preparation (eg, microwaveable) and resting before meals.
While some patients may benefit from nutritional supplementation, patients and families should be counseled that increasing caloric intake does not reverse the underlying process and that anorexia/cachexia is a common symptom, different from starvation, and a natural process that occurs at the end of life. (See 'Artificial nutritional support' below.)
Consultation with a nutritionist should be considered for all patients with cachexia in the setting of an advanced life-threatening illness. A dietician may provide important support to patients and their caregivers by helping individual patients meet estimated protein and caloric needs as much as possible and by discouraging potentially harmful dietary supplement use and unproven, or extreme diets [100]. Research on intermittent fasting is ongoing, and pilot studies on ketogenic diet have failed to show improvements in treatment response for patients with glioblastoma [101,102], but the diet was tolerated in a group of mixed advanced cancer patients who reported mixed benefits on quality of life [102].
Optimizing management of major contributors to anorexia, such as chronic nausea, constipation, taste alterations, dyspnea, and depression, may result in significant improvement. For patients with persistent anorexia, pharmacologic treatments are available that predominantly stimulate appetite; however, they will not reverse cachexia in most patients.
Pharmacologic interventions — Several classes of drugs have the capacity to stimulate appetite, including progestin (a synthetic progesterone derivative), megestrol acetate, glucocorticoids, and, in some settings, cannabinoids.
Clinically proven treatments
Megestrol acetate — A short trial of megestrol is reasonable if there are no contraindications (eg, recent or high risk for thromboembolic events). However, if there is no improvement in appetite within two weeks, we discontinue the drug.
Megestrol acetate is a progesterone derivative with predominantly progestational and antigonadotropic effects [103]. Among patients with cancer-related anorexia and cachexia, megestrol acetate has modest beneficial effects on appetite and overall weight; however, it has no effect on overall quality of life, lean body mass, or enhanced survival [104-106]. (See "Management of cancer anorexia/cachexia", section on 'Progesterone analogs'.)
Megestrol has also been used to treat anorexia in other non-cancer conditions, but data regarding efficacy are more limited [107,108]. A 2013 Cochrane review of megestrol acetate for treatment of anorexia-cachexia syndrome concluded that compared with placebo, megestrol improves appetite and is associated with slight weight gain in cancer, HIV/AIDS, and other underlying pathology [107]. However, edema, thromboembolic phenomena, and deaths were more frequent in the patients treated with megestrol acetate. The authors concluded that use of megestrol increased mortality (relative risk 1.42, 95% CI 1.04-1.94), an effect that appeared to be higher with doses ≥800 mg/day. However, none of the trials was designed to investigate mortality at a time point, so further research was needed to draw any firm conclusions. Megestrol acetate may also cause adrenal insufficiency and hypogonadism in male patients [109].
To minimize adverse effects, it is recommended to start at the lowest effective dose (starting at 160 mg daily) and titrate to a maximum of 800 mg/day [110]. Consideration must also be given to cost. Megestrol acetate is expensive (USD $162 to $290 for a 14-day supply of 625 mg/5 mL liquid; USD $17 to $29 for a 14-day supply of 40 mg tablets [91]).
Symptomatic improvement in appetite may be seen in less than one week, but weight gain (which only occurs in one-fourth of treated patients) may take several weeks. If it is being prescribed for appetite, we give a 14-day supply and only refill if it is of benefit.
Glucocorticoids — Glucocorticoids stimulate appetite; almost all of the data are in cancer patients with anorexia-cachexia syndrome, and there is no evidence for the use of these agents in anorexia due to end-stage nonmalignant conditions. For patients with cancer-associated anorexia-cachexia syndrome, a short-term trial of a glucocorticoid is a reasonable alternative to a trial of megestrol acetate.
Glucocorticoids are well known to stimulate appetite. A 2014 systematic review of eight studies concluded that corticosteroids improved appetite in palliative care patients with malignancies [111]. However, there was insufficient evidence to recommend any particular glucocorticoid over another or to recommend a specific dosing regimen. Furthermore, almost all of the data were derived in patients with advanced cancer, and there was no evidence for their use in anorexia due to end-stage nonmalignant disease.
Consideration must also be given to cost and treatment-related toxicity; in general, glucocorticoids are less expensive than megestrol acetate, and there is a higher risk for venous thromboembolism with megestrol. Although clear recommendations do not exist on optimal dosing and duration of various glucocorticoids for the symptom of anorexia, and more research is needed, most studies have used prednisone at doses of 20 to 40 mg/day, or equivalent doses of dexamethasone (3 to 4 mg/day in divided doses). This subject is discussed in more detail elsewhere. (See "Management of cancer anorexia/cachexia", section on 'Glucocorticoids'.)
Anabolic steroids — Testosterone supplementation may be beneficial for hypogonadal men who have advanced HIV/AIDS or are receiving long-term opioid therapy. The benefits of testosterone replacement in hypogonadal men with an advanced serious illness, at least in the setting of advanced cancer, remain uncertain. Nevertheless, we screen all male patients for low testosterone in our cancer cachexia clinic and encourage enrollment in clinical trials evaluating the benefits of testosterone replacement on symptoms of fatigue and lean muscle mass.
Testosterone and its derivatives, such as oxandrolone, have been studied in patients with HIV/AIDS, neuromuscular disorders, chronic obstructive pulmonary disease (COPD), and alcoholic cirrhosis. A 2004 review concluded that improvements in body composition and muscle strength were significant with oxandrolone in the majority of well-designed trials, although long-term safety and optimal dose have yet to be determined. In one prospective study in patients with COPD, there was a preferential increase in lean body mass after two months of oxandrolone (10 mg twice daily) [112]. Nandrolone has shown similar benefits in patients with COPD, but it can only be given parenterally, and this limits use (see "Malnutrition in advanced lung disease", section on 'Medications'). If testosterone is prescribed, patients should understand that changes in lean body weight and muscle mass may take 12 to 16 weeks to develop [113].
Testosterone supplementation may be beneficial for men with hypogonadism, such as is frequently present in advanced HIV/AIDS or in individuals receiving long-term opioids. In such men, physiologic testosterone supplementation has been shown to increase lean body mass and, in some studies, improve muscle strength [114-116]. (See "Hypogonadism in males with HIV" and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Neuroendocrine effects'.)
However, the benefits of testosterone replacement in hypogonadal men with advanced cancer remain uncertain [86], and further study is needed in this area. Nevertheless, we screen all male patients for low testosterone in our cancer cachexia clinic and encourage enrollment in clinical trials evaluating the benefits of testosterone replacement on symptoms of fatigue and lean muscles mass. A selective androgen receptor modulator, enobosarm, is undergoing a phase 3 clinical trial for the treatment of cancer cachexia, and preliminary reports suggest a modest 1 kg weight gain but note no improvements in strength or functional outcomes [117]. (See "Management of cancer anorexia/cachexia", section on 'Androgens and selective androgen receptor modulators'.)
Treatment for gastroparesis — Gastroparesis and early satiety may be successfully treated with dietary modification (small, frequent meals; five to six small meals throughout the day) and prokinetic agents, such as metoclopramide and erythromycin, and, where available, cisapride and domperidone. In cancer patients, early satiety can be treated with scheduled metoclopramide 10 mg every four hours while awake and can be titrated up to 120 mg/day. In some countries, a controlled release formula is available, and it was found to be safe and effective in managing chronic nausea [118]. (See "Treatment of gastroparesis".)
Treatments needing further study
Cannabis and cannabinoids — We suggest not using synthetic cannabinoids, either as a single agent or in combination with megestrol, for most palliative care patients with anorexia and/or cachexia. We also suggest not using inhaled marijuana or ingested cannabidiol (CBD) oil for anorexia and cachexia given the lack of evidence supporting benefit and the potential risk (which includes psychosis, anxiety, and palpitations [119], and cardiovascular effects, including myocardial infarction, serious arrhythmias, and postural syncope [120]).
For the purpose of this review, marijuana (cannabis) refers to naturally grown plant materials that are not regulated by the US Food and Drug Administration (FDA) and are procured by patients from legal marijuana dispensaries or street suppliers. The primary psychoactive ingredient is tetrahydrocannabinol (THC).
The term “cannabinoids” refers to several different entities:
●CBD is a naturally occurring molecule without psychoactive properties that is found in the cannabis plant. It can be procured by patients from legal marijuana dispensaries or street suppliers (often as CBD oil), and a purified form is available by prescription (Epidiolex) in the United States and is approved for treatment of refractory epilepsy. (See "Dravet syndrome: Management and prognosis" and "Lennox-Gastaut syndrome".)
●There are three marketed drug products that contain synthetic THC. The United States-approved synthetic cannabinoid dronabinol (delta-9-THC) is approved only for chemotherapy-induced nausea and vomiting. Outside of the United States, nabiximols, an oromucosal spray containing dronabinol plus CBD and smaller concentrations of other compounds (Sativex), is available and approved to relieve the spasticity associated with multiple sclerosis. Nabilone, another synthetic cannabinoid, is no longer available in the United States but may be available elsewhere.
Anecdotal reports and small studies suggest that marijuana stimulates appetite, prompting interest in the use of cannabinoids in patients with anorexia/cachexia. Unfortunately, synthetic cannabinoids such as dronabinol have not been demonstrated to have activity against anorexia and cachexia patients with advanced cancer, although nabilone, which has better absorption than dronabinol, has preliminary findings reporting increased caloric intake [121]. (See "Management of cancer anorexia/cachexia", section on 'Cannabis and cannabinoids'.)
The benefit of dronabinol is limited to increased appetite and not weight gain [122-124], and at least two trials suggest dronabinol is inferior to megestrol in this setting [125-127]. Furthermore, the incidence of wasting in HIV/AIDS has declined since the introduction of effective antiretroviral therapy (ART). Tissue wasting responds rapidly to ART, and the primary therapy of HIV wasting is treatment of the underlying HIV infection with ART and not appetite stimulation. (See "Issues in HIV/AIDS in adults in palliative care".)
There are limited data on the efficacy of inhaled marijuana or ingested CBD oil for palliative care patients with anorexia, and well-designed clinical trials are needed before widespread adoption [128,129].
Omega-3 fatty acids/EPA and DHA — Omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are found in fish oil and are known to reduce inflammation. The evidence for the beneficial effect of supplementation of omega-3 fatty acids on cancer cachexia is inconclusive. Early small, uncontrolled, nonrandomized studies reported potential benefits of supplementation of EPA on appetite and weight gain [130-133], but subsequent larger, randomized trials reported no benefit of supplementation of EPA on lean body mass, and a 2007 Cochrane database meta-analysis concluded that there were insufficient data to establish that EPA was better than placebo [134]. However, other more recent studies have been encouraging, at least in patients receiving active cancer therapy [135]. The inconsistent results may be at least in part explained by the latest attempts to improve compliance with fish oil supplementation and provide interventions earlier in the progression of cancer cachexia. These data are discussed in more detail elsewhere. (See "Management of cancer anorexia/cachexia", section on 'Omega-3 fatty acids'.)
Amino acids/carnitine supplements — Protein depletion is a hallmark feature of cachexia. Anorexia-cachexia and increased proteolysis in patients with advanced illness result in depletion of both essential and nonessential amino acids, which may become conditionally essential. The following studies have evaluated supplementation with amino acids in cachectic patients:
●Glutamine is identified as a nonessential amino acid; however, in catabolic states of injury or illness, glutamine is argued to be conditionally essential [136]. A preliminary study of glutamine supplementation with prophylactic powdered glutamine supplementation had fewer complications of radiation-induced esophagitis and weight loss in patients with lung cancer [137].
●L-carnitine is a quaternary ammonium compound derived from the amino acids methionine and lysine [138] and is required for the transport of fatty acids to the mitochondria, where they are utilized to generate metabolic energy. In cancer patients, low serum levels of carnitine have been attributed to decreased caloric intake as well as diminished endogenous synthesis [139]. Benefit from carnitine supplements is suggested by a randomized, placebo-controlled, double-blind trial of 4 g of carnitine daily in 72 advanced pancreatic cancer patients with weight loss, which reported an increase in body mass index (BMI) and quality of life and a trend toward improved survival [140].
NSAIDs/COX-2 selective inhibitors — In a small placebo-controlled pilot study of cachectic patients with either head and neck or gastrointestinal malignancies, celecoxib (200 mg twice daily) was associated with weight gain of 1.0 kg, compared with a 1.3 kg loss with placebo, increased BMI, and improved quality of life scores [141]. A larger prospective randomized study comparing megestrol plus either placebo or ibuprofen reported weight loss in the placebo arm, while the megestrol/ibuprofen group had gain in weight and improvements in quality of life scores [142]. (See 'Combination therapy' below.)
Olanzapine — Olanzapine is an atypical antipsychotic often used off-label for the treatment of chemotherapy induced nausea. Preliminary studies report that olanzapine may improve caloric intake [143], and in a trial of 80 cancer patients, the combination of megestrol acetate with olanzapine resulted in greater weight gain, appetite improvement, and quality of life [144]. However, hyperglycemia and increased seizure risk were associated with chronic use [145].
Mirtazapine — Mirtazapine, a tetracyclic antidepressant, has been associated with weight gain but was not better than placebo at improving appetite in a trial among patients with cancer-associated anorexia and cachexia [146].
Thalidomide — The use of thalidomide, a potent inhibitor of tumor necrosis factor (TNF) alpha production, has been associated with weight gain in patients with tuberculosis or HIV infection [147-151]. A possible role in cancer patients has also been suggested in a small trial [152]. However, a Cochrane review concluded that there is insufficient evidence to support or refute the use of thalidomide for the management of cachexia in patients with advanced cancer [153]. Larger, more definitive studies are needed to clarify the role of this agent in this setting.
Growth hormone and ghrelin — In a small study of seven malnourished patients with COPD, subcutaneous injections of recombinant growth hormone (0.05 mg/kg/day) resulted in substantial weight gain after only three weeks of treatment [154]. However, the use of recombinant growth hormone in critically ill adults has been associated with high mortality rates, perhaps because of a diversion of amino acids and energy to skeletal muscle and away from the acute phase response, thus blunting host defenses [1,155].
However, promising results have been seen with ghrelin, a growth hormone-releasing peptide that induces a positive energy balance by decreasing fat utility and stimulating feeding through growth hormone-independent mechanisms, and with anamorelin, an oral ghrelin mimetic. Some studies in cachectic patients with COPD suggest that repeated intravenous administration of ghrelin lessens muscle wasting and improves body composition, functional capacity, and sympathetic augmentation. However, the risk and benefits of ghrelin are still undergoing investigation. (See "Malnutrition in advanced lung disease", section on 'Medications' and "Ghrelin".)
A combined report of two large, double-blind, placebo-controlled trials of anamorelin in patients with lung cancer-related cachexia (the ROMANA 1 and ROMANA 2 studies) noted significantly increased lean body weight but no significant improvement in handgrip strength with anamorelin compared with placebo [156]. Anamorelin is not yet approved by any regulatory agency or commercially available in any country. Whether the 1 to 1.5 kg weight gain, with no change in muscle strength or other important outcomes, whether it will be “worth it” may be dependent on the cost of the drug. Data from these and other anamorelin trials are presented elsewhere. (See "Management of cancer anorexia/cachexia", section on 'Growth hormone and ghrelin analogs (anamorelin)'.)
Combination therapy — Since the underlying mechanism of anorexia-cachexia syndrome is complex, an argument has been made that a single therapeutic agent, such as an appetite stimulant, would be ineffective in reversing weight loss. A better approach would be to incorporate a personalized or practical multimodal therapy, which would target simultaneously the multiple underlying pathophysiological processes that contribute to anorexia-cachexia syndrome, but compliance with multiple interventions has been problematic.
Combinations that have been tested include ibuprofen with or without megestrol [142], and carnitine (4 g/day) plus celecoxib (300 mg/day) with or without megestrol [157]; these and other even more complex combinations are being investigated in cancer-related anorexia-cachexia syndrome, but more research is needed weighing the potential benefits and harms before any of these approaches can be considered standard. (See "Management of cancer anorexia/cachexia", section on 'Combination therapy'.)
Nonpharmacologic treatment
Artificial nutritional support — While nutrient supplementation might appear ideal to control or reverse malnutrition, for the vast majority of chronically ill patients with an advanced life-threatening disease such as cancer, there is no evidence that artificial nutrition, including hyperalimentation, prolongs life or improves functional status [158], and it is not recommended, with the following exceptions listed below:
●For highly selected patients (eg, high-grade bowel obstruction or malabsorption from advanced cancer) who might otherwise have a prognosis that is measured in months and good functional status, a short-term trial of home parenteral nutritional support may be considered after extensive deliberation among the health care staff, the patient, and family members [100,159,160]. After initiation, the use of parenteral nutrition needs periodic reevaluation; if the benefits are outweighed by excessive harms, it should be discontinued. In addition, when death appears imminent, any previously initiated nutritional support should be discontinued.
●For other terminal diseases such as dementia, or neuromuscular or other neurodegenerative diseases in which the patients will not or cannot eat, the benefits of nutritional support remain controversial. Long-term tube feeding is most often achieved by the placement of a percutaneous endoscopic gastrostomy (PEG) tube. Purported benefits for tube feeding in diseases such as advanced dementia include prolonging life, preventing aspiration, improving malnutrition and its sequelae (ie, pressure sores), and alleviating symptoms of hunger or thirst. However, a systematic review in 2009, which included seven observational studies, found that the available evidence failed to demonstrate that enteral tube feeding achieved any of these outcomes in patients with advanced dementia [161]. It is important to note, however, that there have been no randomized trials of tube feeding versus continued oral feeding in advanced dementia, and intervention with a PEG tube may be considered in selected patients. Maintaining or improving a patient’s quality of life, even in the short-term; reducing pain and suffering; and providing access for hydration or medication delivery may be reasonable goals of PEG tube placement, even in patients with ultimately terminal diseases.
These issues, as well as issues surrounding discontinuation of artificial nutrition and hydration near the end of life, are all discussed in detail elsewhere. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer" and "Gastrostomy tubes: Uses, patient selection, and efficacy in adults" and "Care of patients with advanced dementia" and "Symptom-based management of amyotrophic lateral sclerosis", section on 'Management of swallowing and nutrition' and "Stopping nutrition and hydration at the end of life".)
Specific treatment issues in selected diseases
Cardiac cachexia — Treatment for anorexia and cachexia in heart failure includes optimizing heart failure management. This subject is covered in detail elsewhere. (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Nausea and cachexia'.)
Chronic obstructive pulmonary disease — For patients with pulmonary cachexia syndrome, nutritional treatment is appropriate due to the increased risk for mortality demonstrated in COPD patients in this weight range and the (modest) benefits that have been associated with nutritional support in clinical trials. (See "Malnutrition in advanced lung disease", section on 'Efficacy of nutritional support'.)
Nutritional treatment of pulmonary cachexia syndrome typically includes providing sufficient calories to meet basal energy expenditure and induce weight gain. (See "Malnutrition in advanced lung disease", section on 'Nutritional interventions'.)
Exercise has been shown to improve the effectiveness of nutritional therapy and to stimulate appetite. We encourage patients to participate in a pulmonary rehabilitation program to increase their exercise endurance. (See "Malnutrition in advanced lung disease", section on 'General measures for prevention and treatment' and "Pulmonary rehabilitation".)
For patients with pulmonary cachexia syndrome who are unable to increase their weight with the above interventions, a trial of megestrol acetate or oxandrolone is reasonable. These agents enhance weight gain, although they have little or no effect on exercise capacity. (See 'Megestrol acetate' above and "Malnutrition in advanced lung disease", section on 'Medications'.)
Chronic kidney disease — Nutritional supplementation may be helpful in patients with protein-energy wasting (PEW) to reverse the progression to cachexia in adult patients with end-stage kidney disease (ESKD). (See "Pathogenesis and treatment of malnutrition in maintenance hemodialysis patients", section on 'Nutritional supplements'.)
However, the desire to maintain adequate nutrition among patients with ESKD clearly competes with attempts to slow the progression of kidney failure with the use of a low-protein diet. This issue is discussed elsewhere. (See "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake'.)
In addition, for patients with slow or delayed gastric emptying, prokinetic agents such as metoclopramide or erythromycin may be beneficial. (See "Pathogenesis and treatment of malnutrition in maintenance hemodialysis patients", section on 'Evaluate and treat comorbid conditions' and "Treatment of gastroparesis", section on 'Prokinetics'.)
On the other hand, experience does not support the use of megestrol acetate in patients with anorexia and ESKD. In a small, double-blinded, crossover study, megestrol acetate was administered to patients with ESKD and symptoms of anorexia, and it reported no significant increase in albumin or lean body mass but did result in a number of side effects, including headaches, dizziness, confusion, diarrhea, hyperglycemia, thromboembolism, peripheral edema, and adrenal insufficiency [162,163].
There is conflicting evidence about the effects of exercise and physical activity on lean body mass and functional status in patients with ESKD. One study comparing 12 weeks of high-intensity progressive resistance training versus usual care in patients receiving hemodialysis reported no statistical improvements in lean body mass but did show improvements in muscle strength and mid-thigh and mid-arm circumference in the intervention group [164]. However, a second, larger, randomized, controlled trial of exercise with or without nandrolone, an anabolic steroid, demonstrated that exercise did not significantly increase lean body mass, although it improved strength and self-reported physical function [165]. More research is needed before it can be concluded that exercise and physical activity result in long-term improvements in muscle mass or survival in patients with chronic kidney disease (CKD).
Limited data have evaluated the efficacy and adverse effects of androgenic anabolic steroids in dialysis patients. Although an increase in body weight, muscle mass, and serum albumin have been reported, the long-term efficacy and risk for adverse effects with these agents is unclear, and these agents therefore cannot be recommended in this setting. (See "Pathogenesis and treatment of malnutrition in maintenance hemodialysis patients", section on 'Experimental methods'.)
Other therapies undergoing investigation to prevent cachexia in patients with CKD include correction of acidosis using alkali supplements such as NaHCO3 (which unfortunately carry the risk of sodium and fluid overload), administration of recombinant human growth hormone ghrelin agonists, and ubiquitin-proteasome inhibitors. Management of malnutrition and recommendations concerning correction of acidosis in patients with CKD on maintenance dialysis are discussed in more detail elsewhere. (See "Pathogenesis and treatment of malnutrition in maintenance hemodialysis patients" and "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease", section on 'Improved nutritional status and lean body mass'.)
End-stage liver disease — Protein-calorie malnutrition is common in individuals with end-stage liver disease. Anorexia and cachexia are often anticipated findings in patients who are near death and are receiving palliative care, but these issues need to be handled differently in the palliative care patient hoping to receive a liver transplant. (See "Palliative care for patients with end-stage liver disease", section on 'Other symptoms'.)
HIV/AIDS — Historically, weight loss and tissue wasting were common in HIV/AIDS, particularly in the later stages of the disease. The incidence of wasting has declined since the introduction of effective ART. Tissue wasting responds rapidly to ART. When possible, the primary therapy of HIV wasting is treatment of the underlying HIV infection with ART. (See "Issues in HIV/AIDS in adults in palliative care".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)
SUMMARY AND RECOMMENDATIONS
●Anorexia and cachexia are common in palliative care populations. Anorexia is defined as either loss of appetite or reduced caloric intake. Cachexia is a multifactorial syndrome that is defined by a continuous loss of skeletal muscle mass, with or without loss of fat mass, that cannot be fully reversed by conventional nutritional support. While loss of appetite (anorexia) with weight loss can contribute to cachexia, the profound weight loss suffered by patients with cachexia cannot be entirely attributed to poor caloric intake. (See 'Definitions' above.)
●There is a high prevalence of anorexia-cachexia syndrome in patients with advanced cancer, but it also can occur in the setting of other chronic illnesses including advanced HIV/AIDS, heart failure, chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). (See 'Prevalence and clinical significance' above.)
●Lack of appetite and cachexia is common in patients with advanced illness. Contributory factors include chronic fatigue or nausea, altered taste, depression, pain, xerostomia, disorders of gastrointestinal motility, constipation, medications, and aging. (See 'Secondary nutrition impact symptoms' above.)
●A large number of observations point towards cytokines as the molecules responsible for some of the metabolic derangements associated with the hypermetabolic state that characterizes cancer-bearing states, and the inflammatory response may play a unifying central role in the cachexia that occurs with injury, infection, and chronic illness other than cancer. However, the etiology of cachexia appears to be more complex and multifactorial than just inflammation alone. As an example, in patients with cancer cachexia, studies suggest a potentially important role for several tumor-derived and potentially cachexia-inducing substances, the target of which appears to be skeletal muscle gene products. Chemotherapy can also contribute to muscle wasting, and chronic opioid use can result in hypogonadism and subsequent loss of lean body mass. (See 'Cachexia' above.)
●All palliative care patients should be screened for nutritional status and weight loss. The clinical assessment for patients with anorexia or cachexia includes a careful history that is focused on nutritional issues, including 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 measures of nutritional status are serial measurement of body weight and observations of dietary intake, while subjective information on nutritional status can be provided by Edmonton Symptom Assessment System (ESAS) or Visual Analog Scale (VAS) for anorexia, Anorexia/Cachexia Subscale of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT-A/CS), or other malnutrition assessment tools. No screening tool has been universally agreed upon to detect malnutrition in cancer patients or in those with other chronic illnesses. (See 'Assessment' above.)
●For most hypogonadal men, the benefits of testosterone replacement are unclear and need more robust clinical trials. We do not routinely screen men with cancer cachexia for low testosterone except in those patients for whom there is a clinical trial available to evaluate the benefits of testosterone replacement. We screen all cancer patients with weight loss for thyroid abnormalities, which are more common in patients treated with tyrosine kinase inhibitors that target the vascular endothelial growth factor. We also screen for adrenal insufficiency in cancer patients who have bilateral adrenal metastasis or in those with a clinical suspicion for adrenal insufficiency. (See 'Other contributors to anorexia and cachexia' above.)
●A nutrition consult should be considered for patients with anorexia-cachexia syndrome. In general, patients with anorexia-cachexia syndrome who are able to eat should be recommended to have small, frequent meals that are dense in calories. While some patients may benefit from nutritional supplementation, patients and families should be counseled that increasing caloric intake does not reverse the underlying process and that anorexia and cachexia are not uncommon symptoms but a natural process that occurs at the end of life. Optimizing management of major contributors to anorexia, such as chronic nausea, constipation, taste alterations, dyspnea, and depression, may result in significant improvement. (See 'General aspects' above.)
●For patients with persistent anorexia, pharmacologic treatments are available that predominantly stimulate appetite; however, they will not reverse cachexia in most patients. For patients with anorexia related to cancer, HIV/AIDS, or other underlying pathology (but not end-stage kidney disease [ESKD]), we suggest a short trial of megestrol acetate (Grade 2A). However, the benefits of therapy (appetite stimulation, modest weight gain) must be balanced against the risk of edema, the risk of thromboembolic phenomena, and an increased risk of death. If patients elect to pursue treatment, a two-week trial of megestrol to assess for improvement in appetite may be considered, and if ineffective, discontinued. To minimize adverse effects, it is recommended to start at the lowest effective dose (starting at 160 mg/day) and titrate to a maximum of 800 mg/day. (See 'Megestrol acetate' above.)
●Glucocorticoids stimulate appetite; almost all of the data are in cancer patients with anorexia-cachexia syndrome, and there is no evidence for the use of these agents in anorexia due to end-stage nonmalignant conditions. In the setting of cancer-associated anorexia-cachexia syndrome, a trial is reasonable for patients with a poor short-term prognosis (life expectancy less than six to eight weeks) because of the unfavorable long-term side effect profile of glucocorticoids. (See 'Glucocorticoids' above.)
●We suggest not using synthetic cannabinoids, either as a single agent or in combination with megestrol, for most patients with anorexia and/or cachexia. We also suggest not using inhaled marijuana for anorexia and cachexia given the lack of evidence supporting benefit. (See 'Cannabis and cannabinoids' above.)
●Testosterone supplementation may be beneficial for hypogonadal men who have advanced HIV/AIDS or are receiving long-term opioid therapy. The benefits of testosterone replacement in hypogonadal men with other advanced serious illness, at least in the setting of advanced cancer, remain uncertain. (See 'Anabolic steroids' above.)
●For patients with pulmonary cachexia syndrome who are unable to increase their weight with nutritional supplementation and exercise, a trial of megestrol acetate or oxandrolone is reasonable. These agents enhance weight gain, although they have little or no effect on exercise capacity. (See 'Anabolic steroids' above and 'Chronic obstructive pulmonary disease' above.)
●Treatment for anorexia and cachexia in heart failure includes optimizing heart failure management. (See 'Cardiac cachexia' above.)
●Nutritional supplementation and exercise may be helpful to reverse the progression to cachexia in adult patients with ESKD. (See 'Chronic kidney disease' above.)
