Assessment and management of anorexia and cachexia in palliative care

INTRODUCTION — This topic review will review the clinical assessment and management of anorexia and cachexia in palliative care patients. Other topics related to cancer anorexia and cachexia are discussed separately:

●(See "Pathogenesis, clinical features, and assessment of cancer cachexia".)

●(See "Management of cancer anorexia/cachexia".)

DEFINITIONS — Anorexia is defined as either loss of appetite or reduced caloric intake [1].

Cachexia is a hypercatabolic state that is defined by an accelerated loss of skeletal muscle in the context of a chronic inflammatory response. It has been best described in the setting of cancer but is also seen in older adults and patients with other advanced chronic illnesses including acquired immunodeficiency syndrome (AIDS), heart failure, chronic kidney failure, and chronic obstructive pulmonary disease (COPD) [2]. Although loss of appetite is common among patients with advanced serious illness, the profound weight loss seen with cachexia cannot be entirely attributed to poor caloric intake and is often due to systemic inflammation, metabolic alterations, and neurohormonal changes. In contrast to simple starvation, cachexia is not reversed by the supplementation of calories [3]. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Definition and classification of severity'.)

The combined symptom burden of anorexia, the loss of appetite, and cachexia, unintentional weight loss, is often referred to as the anorexia-cachexia syndrome.

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 [4]. Unlike cachexia, sarcopenia does not require the presence of weight loss. Muscle loss without the loss or gain of fat mass is known as sarcopenic obesity, which is prevalent in older adults [5,6] and is also noted in patients with advanced cancer [7].

EPIDEMIOLOGY

Anorexia — Anorexia is a common symptom in palliative care patients, especially among older adults [8]. In one observational series of 3030 palliative care patients with a variety of illnesses, the frequency of moderate or severe anorexia was 26 percent [9]. Anorexia usually results in reduced caloric intake, malnourishment, and weight loss. Poor nutritional intake is common across a variety of chronic disease states such as:

●Cancer – Anorexia is common in patients with advanced cancer. Nutritional intake is often inadequate to support basal metabolic demand in up to 40 percent of this population [10,11]. (See "Management of cancer anorexia/cachexia".)

●Chronic kidney disease – Anorexia is common in patients with 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 [12]. (See "Overview of the management of chronic kidney disease in adults", section on 'Malnutrition' and "Pathogenesis, clinical features, and assessment of cancer cachexia".)

●Heart failure – The majority of patients with heart failure do not obtain adequate caloric intake or nutrients [13].

●COPD – 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'.)

●Other conditions – The frequency of anorexia in other conditions such as end-stage liver disease and human immunodeficiency virus (HIV)/AIDS is discussed separately. (See "Issues in HIV/AIDS in adults in palliative care", section on 'Anorexia and tissue wasting' and "Palliative care for patients with end-stage liver disease", section on 'Other symptoms'.)

Cachexia — The prevalence of cachexia in palliative care populations varies widely (from 12 to 85 percent on one report [14]), 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 [15-17]. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)

Cachexia is also highly prevalent in moderate to advanced stages 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 [18]) and the presence of comorbid conditions such as heart failure, diabetes mellitus, or liver disease [19].

The incidence of cachexia in patients living with HIV has decreased with the introduction of effective antiretroviral therapy (ART). In the United States, during the era of effective ART, the prevalence of cachexia among patients living with HIV declined from approximately 30 percent to 18 percent between 2000 and 2022 [20-22]. Nevertheless, cachexia is more prevalent among individuals with later stages of disease (eg, AIDS) and those living in areas with limited access to antiretroviral medications. (See "The natural history and clinical features of HIV infection in adults and adolescents".)

PATHOGENESIS

Anorexia — The pathogenesis of anorexia is complex and related to multiple issues such as molecular alterations, lack of appetite, medications, and aging.

●Signaling molecules – 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 [23-27], including neurotransmitters (serotonin, dopamine, histamine), hormones such as ghrelin [28,29] and leptin [30,31], corticotropin-releasing factor, neuropeptide Y, alpha-melanocyte-stimulating hormone, and others (table 1). Aberrancies in these signaling pathways may contribute to anorexia.

●Lack of appetite – 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]). It is also seen in patients with local factors such as thrush or mouth sores and can be due to many chemotherapy agents. 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 [32,33].

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.)

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" [34]. 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" [35]. (See "Failure to thrive in older adults: Evaluation".)

●Medications – Anorexia is associated with medications such as amphetamines, antibiotics, cancer-directed therapies (especially many chemotherapy and targeted agents), opioids [36], antihistamines, digoxin, ranolazine, and certain antidepressants. Chemotherapy can also induce muscle wasting [37]. Chronic opioid use can result in hypogonadism and subsequent loss of lean body mass. 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 [38].

●Aging – Aging may also contribute to anorexia. 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 [39]. (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'.)

Cachexia — The pathogenesis of cachexia has been best studied in patients with cancer. Cytokines, or polypeptides released mainly by immune cells, are often associated with the hypermetabolic states seen with cancer cachexia. This inflammatory response may play a unifying role in the cachexia that occurs with injury, infection, and chronic illness other than cancer. Further details on these and other molecular mechanisms of cancer cachexia are discussed separately. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Pathogenesis'.)

In patients with non-cancer-related cachexia, the etiology is also multifactorial and not related to inflammation alone. As examples:

●Hypogonadism – Hypogonadism is a common endocrine cause of wasting in patients with advanced immunosuppression (eg, HIV). It is also associated with chronic opioid use [40]. Hypogonadism is associated with a higher symptom burden, markers of inflammation, and worse survival [41]. (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 disease – Cardiac cachexia is mediated by changes in catecholamines, cortisol, natriuretic peptides, and proinflammatory cytokines, including tumor necrosis factor (TNF) alpha, interleukin 1 (IL-1), and IL-6 [42,43]. Endocrine dysfunction, including activation of the renin-angiotensin-aldosterone-system, increased levels of ghrelin [44], and insulin resistance [45], also may play a role, as do other hormones such as adiponectin [46]. 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'.)

●Pulmonary disease – Malnutrition associated with advanced lung disease has been termed the “pulmonary cachexia syndrome.” It is a well-recognized feature of advanced COPD. 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 [47]. (See "Malnutrition in advanced lung disease", section on 'Contributing factors'.)

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 [48]. Myostatin levels correlated inversely with total body skeletal muscle mass and body mass index (BMI).

●Chronic kidney disease – 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 [49,50].

CLINICAL ASSESSMENT

History — 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. All patients with advanced incurable illness should be screened for loss of appetite or decreased caloric intake and unintentional weight loss. Screening can be performed either by clinicians or a licensed nutritionist. (See "Approach to symptom assessment in palliative care", section on 'Lack of appetite'.)

Contributing conditions — Patients should be evaluated for medical conditions and medications that can contribute to anorexia or cachexia. Notably, these also include metabolic abnormalities that are potentially reversible, which may go undetected and contribute to loss of appetite or decreased lean body mass.

●Hypogonadism – Hypogonadism is especially common in males with cancer [51,52]. In male patients without cancer, the clinical features of hypogonadism, including those that should prompt diagnostic evaluation, are discussed separately. (See "Clinical features and diagnosis of male hypogonadism", section on 'Candidates for testing'.)

●Adrenal insufficiency – We screen for adrenal insufficiency in cancer patients who have bilateral adrenal metastasis or in those without cancer and a clinical suspicion for adrenal insufficiency. (See "Clinical manifestations of adrenal insufficiency in adults".)

●Thyroid abnormalities – We screen all patients with unintentional weight loss for thyroid abnormalities (eg, hypothyroidism, hyperthyroidism). (See "Laboratory assessment of thyroid function".)

●Gastroparesis – Gastroparesis is common in patients who have diabetes mellitus; experience stress; have a history of surgery to the stomach, small bowels, or colon; and are critically ill. In addition, patients with cancer who have received chemotherapy or radiation therapy are at risk for developing gastroparesis.

In patients with cancer, 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 can sometimes be successfully treated. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Treatment of gastroparesis".)

●Medications – Among patients with cancer, some cancer-directed treatments are associated with sarcopenia (androgen deprivation therapy, sorafenib, bevacizumab), which may also contribute to decreased lean body mass. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Contribution of cancer treatment'.)

For patients without cancer, other medications may impair appetite. (See 'Anorexia' above.)

Secondary nutrition impact symptoms — Patients with anorexia and cachexia should also be assessed for secondary nutrition impact symptoms (S-NIS) or symptoms that may impact appetite and caloric intake. These may include symptoms 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 1). 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 [51,53]. 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 [51].

Psychosocial distress — Anorexia and/or cachexia often results in psychosocial distress for both patients and their caregivers [54-56]. (See "Overview of psychosocial issues in the adult cancer survivor", section on 'Caregivers'.)

Clinicians should assess patients for psychological distress such as depression and anxiety. 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) [54].

In a qualitative study, family caregivers universally noted changes in oral intake at the end of life [57,58]. 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 [57].

Assessing nutritional status

Subjective measures of nutritional status — Subjective measures of nutritional status can be measured using brief nutritional questionnaires that can be completed by the patient. These include dietary recalls, Edmonton Symptom Assessment System (ESAS, appetite score ≥3) or Visual Analog Scale (VAS, ≤70) for anorexia, and the Anorexia/Cachexia Subscale of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT-A/CS) [59]. 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 [60].

Malnutrition assessment tools — We endorse routine use of a brief assessment tool for malnutrition screening [61]. 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. At our institution, the PG-SGA is used as a malnutrition assessment tool.

●The PG-SGA is well established and validated with other objective nutritional measurements [62]. 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 [63]. 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 [53].

●The Nutritional Risk Screening (NRS) 2002 has two components: a screening assessment for undernutrition (estimated with three variables: body mass index (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) [64]. (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 [65-67].

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 2) [68].

These and other malnutrition screening tools are discussed in more detail separately. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Screening tools'.)

Nutritional intake diary — Nutritional intake dietary records kept by the patient at home (either with retrospective or prospective reporting) can be used to measure caloric intake. Retrospective reporting is limited by recall bias, while prospective recordings of dietary intake require several days of assessments to be reliable [69]. For prospective diet diaries, a three-day collection interval [70] 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 [71].

Physical examination — The physical examination focuses on evaluating for loss of subcutaneous fat, muscle wasting (temporal region, deltoids, and quadriceps with loss of bulk and tone by palpation), edema (sacral or ankle), and ascites. The initial stages of weight loss may be masked in patients with obesity. 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.

Objective measures — The most used objective measures of nutritional status are serial measurement of body weight, anthropometrics, biochemical, and laboratory measures, and functional measures including the six-minute walk and hand grip strength tests.

Laboratory tests — Laboratory measures (eg, albumin, transferrin) can be used to assess nutritional status, and some screening tools (eg, the Nutrition Risk Index) include a measurement of serum albumin (see 'Malnutrition assessment tools' above). In addition to screening for malnutrition, the presence of a low albumin can indicate increased risk of mortality.

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 their 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 [72], does not take into account age or sex, and fails to distinguish between proportions of bone, lean body mass, or fat. 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 [53,73].

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 [74]:

●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 timeframes 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'.)

Evaluating body composition — For patients who elect to have interventions for weight loss, it is important to have accurate assessment of lean body mass and body composition. At many centers, body composition can be initially assessed and monitored while on therapy using dual-energy x-ray absorptiometry (DXA), computed tomography (CT), or magnetic resonance imaging (MRI). In the absence of a clinical trial requirement, a weight and appetite diary is usually sufficient, more simple and convenient to obtain, and less expensive.

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 may underestimate fat-free mass when compared with DXA and the equipment is not readily available in most institutions [75].

TREATMENT

General dietary principles

Dietary and lifestyle modifications — Loss of appetite and alterations in appearance because 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 if the patient finds this to be important. The pleasure of tasting food, if it exists, should be emphasized over total caloric intake. In general, patients with anorexia-cachexia syndrome who can eat should have small, frequent meals that are dense in calories (eg, eggs, liquid nutritional supplements). Other strategies to enhance caloric intake include using straws to facilitate intake of fluids or nutritional supplements, 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 loss of appetite or unintentional weight loss are common symptoms. In addition, these symptoms are different from starvation and a natural process that occurs at the end of life. (See 'Indications for artificial nutritional support' below.)

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.

Nutritional consultation — Consultation with a nutritionist should be offered to 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 [76].

Treatment for gastroparesis — Gastroparesis and early satiety may be successfully treated with dietary modification (small, frequent meals, eg, five to six small meals throughout the day) and prokinetic agents, such as metoclopramide. Other options include erythromycin, and, where available, cisapride and domperidone. This is discussed in detail separately. (See "Treatment of gastroparesis".)

Indications for artificial nutritional support — Artificial nutrition is not offered to most palliative care patients. While nutrient supplementation might appear ideal to control or reverse malnutrition, there is no evidence that artificial nutrition, including hyperalimentation, prolongs life or improves functional status for the vast majority of chronically ill patients with an advanced life-threatening disease such as cancer or dementia [77].

For those patients with 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 is an option after deliberation among the health care staff, the patient, and family members [76,78,79]. 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.

Initiation and discontinuation of artificial nutrition and hydration near the end of life are discussed in detail separately. (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".)

Patients with cancer — The pharmacologic management of cachexia in patients with cancer involves initial therapy with low-dose olanzapine. Progesterone agents and steroids are alternative options for those who cannot tolerate olanzapine. Further details on the efficacy of these agents are discussed separately. (See "Management of cancer anorexia/cachexia", section on 'Pharmacologic treatments'.)

Patients without cancer

HIV/AIDS

Antiretroviral therapy — When possible, the primary therapy of HIV wasting is treatment of the underlying HIV infection with antiretroviral therapy (ART). In most patients, tissue wasting responds rapidly to ART. (See "Issues in HIV/AIDS in adults in palliative care".)

Megestrol acetate — For patients living with HIV or AIDS with anorexia or cachexia despite appropriate ART and addressing other treatable causes of weight loss (eg, malignancy, infection, malabsorption, endocrine disease, kidney disease, psychiatric disorder, hypogonadism), we suggest the addition of megestrol acetate to other supportive measures. Megestrol acetate is approved by the US Food and Drug Administration (FDA) for treatment of anorexia, cachexia, or unexplained significant weight loss in patients with AIDS [80].

Patients should be counseled that the effect of this medication on appetite is limited, that it may not fully restore the lost weight, and that it may not improve survival or quality of life. Patients should also be counseled about risks of this medication, including edema, thromboembolic events, and death.

We initiate megestrol acetate at the lowest effective dose (80 to 160 mg/day) and titrate to a maximum of 800 mg/day to minimize toxicity [81]. 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; $17 to $29 for a 14-day supply of 40 mg tablets [70]).

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 provide a 14-day supply and only refill if it is of benefit and without evidence of toxicity [82].

There are limited data for the efficacy of megestrol acetate to treat anorexia in patients with HIV/AIDS. In a trial of 100 patients with AIDS and cachexia conducted prior to the availability of modern antiretroviral treatment, megestrol acetate resulted in increased daily caloric intake compared with placebo at eight weeks (difference 474 calories, 95% CI -68 to 880 calories) as well as greater weight gain (difference 4.32 kg, 95% CI 2.42 to 6.22 kg) [83]. In a similar trial of 195 patients, a greater percentage of those receiving megestrol acetate gained 5 pounds or more compared with placebo at 12 weeks (64.2 versus 21.4 percent) [84]. However, in a meta-analysis of patients with cachexia related to cancer, HIV/AIDs, and other conditions, megestrol acetate was associated with toxicities including edema and thromboembolic phenomena as well as increased mortality, especially at doses ≥800 mg/day [85].

Cardiac cachexia — Treatment for anorexia and cachexia in heart failure includes optimizing heart failure management. Nutritional support and physical exercise is often recommended to prevent muscle loss. Cardiac rehabilitation programs in patients with heart failure have been reported to improve functional outcomes and quality of life [86]. This subject is covered in detail separately. (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Nausea and cachexia'.)

Chronic obstructive pulmonary disease — Nutritional treatment of pulmonary cachexia syndrome typically includes providing sufficient calories to meet basal energy expenditure and induce weight gain. Treatment options are discussed separately. (See "Malnutrition in advanced lung disease", section on 'Nutritional interventions' and "Malnutrition in advanced lung disease", section on 'Medications'.)

Exercise has also been shown to improve the effectiveness of nutritional therapy and to stimulate appetite [87]. (See "Malnutrition in advanced lung disease", section on 'General measures for prevention and treatment' and "Pulmonary rehabilitation".)

Chronic kidney disease — Nutritional supplementation may be helpful in patients with protein-energy wasting to reverse the progression to cachexia in adult patients with end-stage kidney disease (ESKD). This is discussed in detail separately. (See "Pathogenesis and treatment of malnutrition in patients on maintenance hemodialysis", 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 separately. (See "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake'.)

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, 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'.)

Treatments needing further study

Cannabis and cannabinoids — For most palliative care patients with anorexia and/or cachexia unrelated to cancer, we do not use synthetic cannabinoids, inhaled marijuana, or ingested cannabidiol oil either as a single agent or in combination with megestrol acetate given the limited evidence supporting benefit and the potential risks [88-91]. The limited role of cannabis in treatment of anorexia and cachexia in patients with cancer is discussed separately. (See "Management of cancer anorexia/cachexia", section on 'Cannabis and cannabinoids'.)

In the United States, the availability and regulation of medical cannabis and cannabinoids varies by state (see "Medical use of cannabis and cannabinoids in adults", section on 'Medical cannabis policy in the United States'). Nevertheless, there are insufficient data for the efficacy of these agents for the treatment of anorexia and cachexia in patients using palliative care [92]. Potential toxicities including hallucinations and psychosis, which is especially concerning for older adults, frail patients, or those who take multiple medications. Further information on cannabis and cannabinoids are presented separately. (See "Medical use of cannabis and cannabinoids in adults".)

Other agents — Other therapies have been investigated in the treatment of anorexia and cachexia in patients receiving palliative care. Further studies are necessary prior to incorporating these approaches into routine practice. These are discussed separately. (See "Management of cancer anorexia/cachexia", section on 'Insufficient evidence to recommend for or against'.)

PROGNOSIS — 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 [93]. (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, chronic kidney disease (CKD), HIV, or chronic obstructive pulmonary disease (COPD), has also been shown to increase the risk of death [94-97]. 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 [98,99]. (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'.)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topi^c. We en^courage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Malnutrition (The Basics)" and "Patient education: Malnutrition – Discharge instructions (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Anorexia is defined as either loss of appetite or reduced caloric intake. Cachexia is a hypercatabolic state defined by an accelerated loss of skeletal muscle. Both conditions are common in palliative care patients, including those with and without cancer. (See 'Definitions' above.)

●Prognosis – Cachexia is associated with a poor prognosis in patients with advanced disease. (See 'Prognosis' above.)

●Clinical assessment

•History – The history focuses on nutritional issues, including factors such as pain, xerostomia, nausea, constipation, and depression that may compromise the ability to take in nutrition. (See 'History' above.)

Patients should be evaluated for other conditions that can contribute to anorexia or cachexia include potentially reversible metabolic or endocrine abnormalities, medication use, and gastroparesis. (See 'Contributing conditions' above.)

•Assessing nutritional status – Various brief assessment tools for nutritional status and malnutrition are available. Nutritional intake dietary records kept by the patient at home can also be used to measure caloric intake. (See 'Assessing nutritional status' above.)

•Physical examination and objective measures – We evaluate for loss of subcutaneous fat, muscle wasting (temporal region, deltoids and quadriceps with loss of bulk and tone by palpation), edema (sacral or ankle), and ascites. The initial stages of weight loss may be masked in patients with obesity. (See 'Physical examination' above.)

Objective measures include serial measurement of body weight, anthropometrics, biochemical, and laboratory measures (eg, albumin, transferrin), and functional measures including the six-minute walk and hand grip strength tests. (See 'Objective measures' above.)

●Treatment

•Dietary modifications – Patients should have small, frequent meals that are dense in calories (eg, eggs, liquid nutritional supplements). Other strategies to enhance caloric intake include using straws to facilitate intake of fluids or nutritional supplements. (See 'Dietary and lifestyle modifications' above.)

•Nutritional consult – Consultation with a nutritionist should be offered to all patients with cachexia in the setting of an advanced life-threatening illness. (See 'Nutritional consultation' above.)

•Treatment of gastroparesis – Gastroparesis may also be treated with dietary modification (small, frequent meals, eg, five to six small meals throughout the day) and prokinetic agents. This is discussed in detail separately. (See "Treatment of gastroparesis".)

•Indications for nutritional support – Artificial nutrition is not offered to most palliative care patients, as there is no evidence it prolongs life or improves functional status. (See 'Indications for artificial nutritional support' above.)

•Patients with cancer – The pharmacologic management of cachexia in patients with cancer is discussed separately. (See "Management of cancer anorexia/cachexia", section on 'Pharmacologic treatments'.)

•Patients with HIV/AIDS – The primary therapy of HIV wasting is treatment of the underlying HIV infection with antiretroviral therapy (ART). (See "Issues in HIV/AIDS in adults in palliative care".)

For patients living with HIV or AIDS with anorexia or cachexia despite appropriate ART and addressing other treatable causes of weight loss (eg, malignancy, infection, malabsorption, endocrine disease, kidney disease, psychiatric disorder, hypogonadism), we suggest the addition of megestrol acetate to other supportive measures (Grade 2C). (See 'Megestrol acetate' above.)

•Patients with other non-cancer conditions – The management of cachexia for the following non-cancer conditions are discussed separately:

-Cardiac cachexia (see "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Nausea and cachexia')

-COPD (see "Malnutrition in advanced lung disease", section on 'Nutritional interventions' and "Malnutrition in advanced lung disease", section on 'Medications')

-CKD (see "Pathogenesis and treatment of malnutrition in patients on maintenance hemodialysis", section on 'Nutritional supplements')

-End-stage liver disease (see "Palliative care for patients with end-stage liver disease", section on 'Other symptoms')