Introduction
Cachexia is a severe, multifactorial condition characterized by the significant loss of skeletal muscle mass and adipose tissue, commonly observed in patients with advanced cancer, chronic infections, and long-term illnesses such as chronic obstructive pulmonary disease (COPD), renal failure, heart failure, and late-stage, inflammatory autoimmune diseases. This condition is associated with increased proinflammatory factors and profound metabolic changes that differentiate it from simple starvation. In cachexia, fat stores are mobilized to replace glucose as the primary energy source, causing an altered metabolic state and an energy deficit. This metabolic dysregulation, combined with systemic inflammation, alimentary tract dysfunction, and anorexia, makes conventional nutritional support ineffective in reversing the condition. When significant anorexia accompanies cachexia, it is referred to as the anorexia-cachexia syndrome.
Cachexia's frequency and severity vary among different cancers. Patients with gastrointestinal, pancreatic, and lung cancers experience cachexia more frequently, whereas those with breast cancer, sarcomas, and hematologic malignancies are less commonly affected. Cachexia, regardless of its underlying cause, diminishes overall well-being, impairs tolerance to medical and surgical treatments, and is linked to reduced survival rates.[1][2]
Diagnosing cachexia involves a multifactorial approach, incorporating clinical, biochemical, and functional assessments. Professional organizations have developed overlapping diagnostic criteria and management recommendations, but no universally accepted guidelines exist. The American Society of Clinical Oncology (ASCO) defines cancer cachexia as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass not fully reversed by conventional nutritional support, leading to progressive functional impairment. The diagnostic criteria include weight loss of greater than 5% in 6 months or greater than 2% in individuals already exhibiting sarcopenia or a low body mass index (BMI) of less than 20 kg/m². In addition, the Society of Cachexia and Wasting Disorders has proposed diagnostic criteria for non–cancer-specific cachexia, including weight loss of 5% in 6 months with at least 3 of 5 clinical symptoms—fatigue, anorexia, decreased muscle strength, reduced fat-free mass, or systemic signs of inflammation.[3] The Asian Working Group for Cachexia criteria include the presence of an underlying chronic disease, weight loss of greater than 5% in 6 months or a BMI of less than 20 kg/m² with ongoing weight loss of greater than 2%, and at least 1 of the following—anorexia with loss of appetite or reduced food intake, decreased muscle strength measured by grip strength, and elevated inflammatory markers such as a C-reactive protein level greater than 5 mg/L.[4]
The pathophysiology of cachexia involves a complex interplay of systemic inflammation and metabolic derangements. These factors contribute to weight loss, muscle atrophy, and diminished physical function, worsening patients' prognosis. Recognizing and managing cachexia early is crucial, as its progression significantly impairs quality of life and treatment outcomes.[5]
This educational activity reviews the etiology, diagnosis, and management of cachexia. The activity provides healthcare professionals with essential knowledge and strategies for evaluating patients with cachexia, assessing their nutritional status, identifying the underlying causes, and implementing effective interventions. By enhancing understanding of the pathophysiology and prognosis of cachexia, this course aims to improve patient care and clinical outcomes.
Etiology
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Etiology
Underlying Causes of Cachexia
Cachexia occurs in the presence of chronic diseases, such as cancer, heart or renal failure, COPD, HIV and other infections, and advanced autoimmune conditions. Inflammation, tumor-induced metabolic disturbances, and hormonal changes trigger its onset. In cancer-related cachexia, the underlying cause is often the tumor itself, although chemotherapy and radiation treatments contribute to its development. Tumor-induced systemic inflammation, metabolic disruption, and physical factors, such as mechanical obstruction or organ dysfunction, play critical roles in the onset of cachexia. Key mediators include pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), proteolysis-inducing factor (PIF), and lipid-mobilizing factor that increase catabolism, muscle wasting, inflammation, and lipolysis, and inhibit muscle protein synthesis.[6][1][2]
The Warburg effect, characterized by increased aerobic glycolysis and lactate production by cancer cells in the presence of oxygen, contributes to cachexia by causing an energy imbalance and a higher demand for nutrients. Tumor cells consume large amounts of glucose, depleting the host's energy stores of glucose, fat, and protein. The lactate produced is transported to the liver, converted into glucose, with an associated energy cost to the host, and released back into the circulation, only to be taken up again by tumor cells. The cycle repeats, supporting rapid cancer cell proliferation at the host's expense, causing increased total energy expenditure and further tissue breakdown.[7]
Beyond cancer, cachexia occurs in other conditions characterized by severe systemic inflammation. Chronic infections such as tuberculosis, HIV, and other viral diseases cause immune dysregulation and persistent inflammation, contributing to the development of cachexia. Heart failure and COPD patients often experience elevated levels of inflammatory markers. Over time, these inflammatory responses trigger catabolic processes, leading to an energy imbalance and catabolism, with the loss of skeletal muscle and adipose tissue.
Epidemiology
The epidemiology of cachexia depends upon the underlying chronic condition. In industrialized countries, the prevalence of cachexia is estimated at 9 million people, about 0.5% to 1% of the population, with prevalence expected to rise alongside the growing burden of chronic diseases. Cachexia affects approximately 50% to 80% of patients with advanced malignancies, with the highest prevalence observed in cases of pancreatic, stomach, and esophageal cancers. Gastrointestinal cancers tend to cause malnutrition and cachexia earlier than breast, lung, and renal cancers.[8][9][10] In end-stage heart and renal failure, the prevalence ranges from 5% to 15%, with annual mortality about 20% to 30%. The prevalence is similar for patients with advanced COPD, whose annual mortality rate is approximately 10% to 15%.[11] Approximately 40% of hospitalized patients with AIDS have malnutrition, a key component of cachexia, and treatment with antiretroviral medications is an additional risk factor for muscle wasting.[12][13]
These statistics underscore the impact of cachexia in cancer and other chronic illnesses, highlighting the critical need for early recognition and targeted interventions as the global population ages and the incidence of chronic diseases continues to rise.
Pathophysiology
Multiple chronic conditions trigger cachexia, sharing a common pathway involving systemic inflammation and energy-related dysfunction that cause significant weight reduction, muscle atrophy, and loss of adipose tissue.[1] The pathophysiology of cachexia includes several processes, including cytokine excess, hormonal dysregulation, and changes in metabolism.
Cachexia is associated with excessive resting energy expenditure, driven by heightened sympathetic nervous system activity and increased production of pro-inflammatory cytokines. These cytokines, such as TNF-α, IL-6, and IL-1β, exacerbate cachexia by promoting muscle protein degradation and inhibiting protein synthesis.[6] These factors lead to a maladaptive, catabolic state in which the body mobilizes energy stores, particularly from muscle and fat. Mediators of cancer-associated cachexia include cytokines, ciliary neurotrophic factor, leukemia inhibitory factor, and interferon-gamma. Both tumor and host immune cells produce these mediators, leading to anorexia, weight loss, muscle protein and fat breakdown, lower insulin levels, insulin resistance, elevated cortisol and glucagon levels, fever, anemia, and higher energy expenditure with a higher resting heart rate and body temperature. [14][15][10]
Host immune cells, including macrophages, helper T cells type 1, and myeloid-derived suppressor cells, produce procachectic cytokines. Tumor cells produce PIF, causing an elevated adrenergic state and increasing energy expenditure. The primary site of lean body mass depletion in states of persistent inflammatory response is skeletal muscle. Both TNF-α produced by host and cancer cells and PIF from cancer cells induce cachexia by activating the nuclear factor kappa B, a muscle transcription factor, which increases protein turnover without promoting protein synthesis.
Patients with cachexia exhibit altered hypothalamic control of appetite and satiety, and hormonal imbalances contribute to lower food intake and increased energy expenditure.[2] Cytokines such as TNF-α and IL-1β induce hypothalamic inflammation, further decreasing appetite and increasing energy expenditure. This inflammation affects the hypothalamic-pituitary-adrenal axis, leading to increased catabolic signaling and reduced orexigenic response to appetite-regulating neuropeptides such as neuropeptide Y. As a result, this causes poor appetite and nutrient intake.[16] In addition, low testosterone levels in patients with cachexia contribute to muscle wasting by reducing protein synthesis and increasing protein degradation, leading to further muscle atrophy. The hypothalamic-growth hormone-insulin-like growth factor-1 (IGF-1) axis is also affected in cachexia. Chronic inflammation leads to growth hormone resistance and reduced circulating levels of IGF-1, further impairing muscle protein synthesis and increasing muscle breakdown. This protein turnover continues, even with an energy and protein intake sufficient for a healthy, non-inflammatory state.[17]
Alimentary tract dysfunction also contributes to cancer-associated cachexia. Patients with cancer often have abnormalities of taste and smell sensation, and tumors of the mouth, neck, esophagus, and stomach can impair oral intake. Intestinal obstruction sometimes occurs in tumors of the bowel, pancreas, liver, and peritoneum. Reduced enzyme activity caused by pancreatic insufficiency predisposes to malabsorption. Slowing of peristalsis and delayed gastric emptying contribute to early satiety and decreased food consumption. Chemotherapy agents, such as cisplatin and doxorubicin, and immunotherapy often cause nausea, vomiting, mucositis, and taste and smell alterations, further interfering with eating. Stomatitis and xerostomia occur secondary to head and neck radiotherapy and limit oral intake. Abdominal radiation therapy can cause nausea, vomiting, anorexia, diarrhea, and malabsorption. All of these conditions exacerbate anorexia and cachexia in patients with cancer. Furthermore, many patients suffer from emotional stress due to their illness, contributing to poor appetite and further weight loss.[18][19][20][21][22]
In summary, the pathophysiology of cachexia involves a complex interplay of metabolic and inflammatory processes. Cytokines such as TNF-α, IL-1β, and IL-6 reduce appetite and induce hypothalamic inflammation. Metabolic alterations lead to catabolism and hormonal dysregulation. Regardless of the underlying cause, the pathophysiology of cachexia results in weight loss, muscle wasting, and depletion of adipose tissue.
History and Physical
As cachexia typically develops in the later stages of cancer or other chronic diseases, obtaining a detailed history and performing a thorough physical examination often reinforces an existing clinical suspicion. Although cachexia is a multifactorial syndrome, patients typically present with characteristic histories and report unintentional weight loss, poor appetite, and early satiety. Weight loss progresses, even with seemingly adequate or increased caloric intake. Patients complain of fatigue and a decline in their physical function, exercise capacity, and ability to perform their daily activities.[3][23] This fatigue may partly result from anemia caused by the underlying chronic illness, in addition to the effects of cachexia. The physical examination is notable for significant muscle wasting, particularly in the limbs, leading to a gaunt appearance and weak hand grip strength. A reduction in subcutaneous fat and the appearance of prominent bony landmarks, including shoulders, clavicles, ribs, hips, and cheeks, often accompany cachexia. Patients have a low BMI, typically less than 20 kg/m². Other physical findings include signs of underlying chronic illness, such as pallor, edema, or organomegaly, depending on the underlying etiology of the cachexia.
Evaluation
After obtaining a detailed history and performing a thorough physical examination, the next step is to determine the underlying cause and the extent of cachexia. Clinicians classify patients with cachexia into 3 distinct stages—pre-cachexia, cachexia, and refractory cachexia, based on the severity of weight loss, muscle wasting, and the response to treatment. These stages correlate with prognosis and assist the healthcare team in developing individually tailored interventions. Patients with pre-cachexia have anorexia, metabolic changes, and weight loss less than 5%. Individuals with cachexia show unintentional weight loss of greater than 5% or a BMI of less than 20 kg/m² with ongoing muscle loss, fatigue, anorexia, and a decline in physical function. The most advanced stage is refractory cachexia, in which weight loss and muscle wasting are severe, and the patient, often with late-stage cancer, no longer responds to treatment. Predicted life expectancy for patients with refractory cachexia is typically less than 3 to 6 months.[24]
A detailed nutritional assessment is essential to determine each patient’s baseline caloric and protein intake and to calculate their dietary needs, considering age, weight, activity level, and the increased resting energy expenditure associated with cachexia.
Anthropomorphic measurements provide information about muscle mass and fat stores using bioelectrical impedance analysis or dual-energy X-ray absorptiometry (DEXA). By measuring changes in muscle mass and fat distribution, DEXA quantifies the extent of cachexia and monitors its progression or response to treatment. Hand grip strength measures muscle function and correlates with muscle mass in cachexia. Specifically, a grip strength of less than 20 kg for men and less than 14 kg for women, measured using a hand dynamometer, indicates muscle function impairment and predicts poor clinical outcomes.[25] Other measures correlate with grip strength, including the Stair Climb Power, Timed Up and Go, and 6-Minute Walk tests to evaluate functional impairment in patients with cachexia.[26] The patient-generated Subjective Global Assessment and the Phase Angle Test are additional tools that correlate with grip strength and aid in the nutritional and functional assessment of cachexia. The Phase Angle Test uses bioelectrical impedance analysis to assess muscle mass and fluid status, with a low score indicating severe muscle wasting and malnutrition.[27]
Laboratory tests, including serum albumin, prealbumin, and transferrin levels, assess protein status and nutritional reserves. Elevated levels of C-reactive protein indicate an underlying inflammatory condition that contributes to muscle wasting and weight loss. These levels correlate with the severity of weight loss and overall prognosis. A complete blood count identifies anemia and may indicate inflammation or infection. Serum electrolytes and tests of liver and kidney function reflect malnutrition and organ dysfunction due to the underlying disease. Abnormal hormone levels, such as testosterone and thyroid hormones, can identify conditions that exacerbate weight loss, muscle wasting, and fatigue. Deficiencies of minerals and vitamins, particularly iron, vitamin D, vitamin B12, and folate, are common in chronic disease and may worsen cachexia symptoms.
In summary, the evaluation of cachexia includes classifying patients into stages, assessing nutritional needs, evaluating muscle function, and analyzing laboratory data to identify inflammation, anemia, organ dysfunction, and nutrient deficiencies. This information is used to determine the prognosis and guide individualized interventions.
Treatment / Management
Caring for patients with cachexia requires a multi-faceted approach, integrating nutritional interventions, tailored exercise regimens, and pharmacologic therapies. This section emphasizes the impact of early and comprehensive treatment on patient outcomes, reviews evidence-based treatment strategies and the limitations of current modalities, and discusses emerging therapies under investigation. No medical intervention completely reverses cachexia, and care must be individualized to meet each patient's needs.
Cachexia prevention in cancer patients begins with the removal of the tumor. When definitive treatment is impossible, multiple therapeutic modalities exist, comprising nutritional support, exercise, and pharmacotherapy.[28][29][30] Evidence suggests that prompt nutritional assessment and support in patients with pre-cachexia can improve outcomes, particularly in terms of nutritional status and well-being. The ASCO guidelines emphasize the importance of early intervention with dietary and pharmacologic treatments to optimize nutritional status and potentially enhance quality of life and survival.[3] The European Society for Clinical Nutrition and Metabolism (ESPEN) also advises early nutritional risk screening for cancer patients, incorporating assessments of body composition, inflammation levels, resting energy expenditure, and physical function. These data should guide the development of nutritional and exercise interventions tailored to each patient's needs.[30]
Nutritional Interventions
Nutritional interventions should focus on high-energy, high-protein diets with fortified foods and oral supplements when necessary. Commercially available oral supplements generally provide 200 to 300 kcal and 10 to 20 g of protein per 100 mL.[10][3] High-protein diets, typically providing 1 to 1.5 g/kg of body weight daily, help maintain adequate nutritional status and stabilize weight, improve lean body mass, and enhance overall quality of life. Patients with renal failure should consume less than 1.3 g of protein per kg of body weight daily.[31] Vitamin D supports muscle protein synthesis and metabolic health.[32] Addressing nutritional status before and during chemotherapy may lessen treatment-induced toxicities and improve survival outcomes.[33] However, in a randomized controlled study involving patients with colorectal cancer, although the group receiving high-protein supplementation demonstrated improved nutritional status as assessed by the Subjective Global Assessment and measurements of serum pre-albumen and albumen, the supplementation did not reduce the overall toxicity of the chemotherapy administered.(B3)
Dietary recommendations should always be individualized, considering appetite, weight, quality of life, risk of adverse effects, and the cost and availability of supplements. The ASCO guidelines highlight the importance of involving registered dietitians to provide practical and safe dietary advice, avoiding unproven or extreme diets that could further compromise the patient's nutritional status.[3] Patients and caregivers may benefit from counseling about dietary measures and oral supplements to manage cachexia. Practical advice includes recommending the consumption of frequent, small meals and snacks, focusing on foods high in caloric density but low in tropical oils, staying hydrated, and taking a supplement containing the usual recommended daily allowance of vitamins and minerals. Although in-vitro and animal studies suggest that the ketogenic diet may limit tumor cell metabolism, evidence supporting its effectiveness in humans with cachexia remains inconclusive. To date, no clinical trials have demonstrated a clear benefit of a ketogenic diet for patients with cachexia.[34] Some patients tolerate homemade food supplements better than commercial preparations, and for those with anorexia or a taste disorder, room-temperature or sour foods may be more palatable.[35] For cancer patients treated with aromatase inhibitors, vitamin D supports muscle protein synthesis and mitigates adverse effects such as bone loss.[32] No evidence supports routine enteral tube feeding supplementation or parenteral nutrition.[3] (B3)
Supplementation with eicosapentaenoic acid may help manage cancer cachexia by reducing the production of cytokines. Studies have shown increased body weight or muscle mass with an eicosapentaenoic acid dose between 1.8 and 2.2 g daily. However, adverse effects include gastrointestinal distress, liver dysfunction, and bleeding tendencies, which limit its use. ASCO guidelines note that although some evidence suggests the potential benefits of eicosapentaenoic acid and other omega-3 fatty acids, further research is needed before routinely recommending them.[3] The ASCO guidelines also advise against the routine use of total parenteral nutrition due to a lack of evidence of benefits and potential risks, such as the increased risk of abdominal and catheter-related infections. Although short-term TPN can be beneficial in specific clinical scenarios, such as gastrointestinal obstructions or severe malnutrition during chemotherapy, it has not been found to enhance the quality of life or prolong survival.[3][36](A1)
Exercise Regimens
Exercise plays a role in managing cachexia, as it counteracts the disordered metabolic pathways and negative protein balance that cause muscle atrophy and may help patients maintain their muscle mass.[37] Animal studies are inconsistent, but a combination of aerobic and resistance exercise has been shown to increase skeletal mass and strength in mice.[19] Evidence-based guidelines from ESPEN and the European Society for Medical Oncology recommend moderate physical training for patients with cachexia, including resistance and aerobic exercise, to maintain muscle mass and physical function.[19][38] Exercise is safe for cancer patients and can improve muscle strength, bone health, and quality of life while decreasing depression, fatigue, and psychosocial distress.[39] Physical activity can lessen the risks of comorbidities and may even reduce overall mortality. Exercise improves insulin sensitivity, modulates muscle metabolism, and decreases inflammation.[40] For maximum benefits, initiating an exercise regimen early in cancer treatment is crucial. Exercise has a low risk of adverse events, particularly when supervised by physical therapists or exercise professionals. Involving caregivers, designing individualized programs, and offering convenient locations enhance compliance.[39] Studies have shown that home-based, supervised resistance training programs are safe and feasible. In a report, therapist-assisted training at home increased adherence from 9% to 49% compared to an exercise program in a hospital setting.[41] Trials have also shown that while aerobic exercise improves overall fitness, resistance training is more effective in preserving muscle strength and lean body mass. In patients receiving chemotherapy for breast cancer, supervised exercise programs early in treatment have demonstrated benefits in maintaining physical function and cardiorespiratory fitness. However, effects on overall quality of life vary.[42][43] Although exercise benefits physical, psychological, and metabolic health, many individuals with cachexia face significant barriers to participation in fitness programs, including fatigue, bone pain, muscle weakness, mobility issues, low energy levels, and mental health challenges.[44][45] These findings emphasize the need for an individualized, cautious approach to exercise tailored to each patient's condition and treatment phase to optimize outcomes in individuals with cachexia.(A1)
Pharmacologic Treatments
The pharmacologic management of cachexia involves various medications that stimulate appetite, preserve muscle, and reduce inflammation and catabolism. Although no single therapy completely reverses cachexia, treatment can alleviate symptoms and improve quality of life. These agents are categorized based on their mechanisms of action.
Appetite stimulants: Progesterone analogs, such as megestrol acetate and medroxyprogesterone acetate, stimulate appetite, modulate cytokine activity, and may increase fat mass in patients with cachexia. Megestrol acetate is associated with adverse effects of fluid retention, thromboembolic events, and an increased risk of death. Megestrol acetate is approved by the Food and Drug Administration (FDA) for AIDS-related cachexia and is frequently used off-label for cachexia associated with other conditions, particularly cancer.[3] Corticosteroids such as dexamethasone can improve appetite in the short term, but risks of immunosuppression, osteoporosis, fluid retention, and hypertension limit chronic use.[46][47] Anamorelin, a ghrelin receptor agonist, has shown promise in clinical trials by improving body weight, lean body mass, and patient-reported quality of life. Adverse effects include hyperglycemia, fatigue, and cardiovascular events. The FDA has not approved anamorelin for the treatment of cancer cachexia.[3][48][49] Serotonin and dopamine modulators are also associated with improved appetite. Olanzapine, an atypical antipsychotic medication, is a monoaminergic antagonist with an affinity for dopamine and serotonin receptors. This medication has been shown to increase appetite and weight when administered in small doses, with minimal adverse effects. In addition, its antiemetic properties can help manage chemotherapy-induced nausea and vomiting.[50][51] Mirtazapine is an antidepressant with appetite-enhancing properties that can be useful in patients with depression-related anorexia. Still, evidence for the overall efficacy of mirtazapine in treating cancer cachexia is more limited compared to olanzapine.[52](A1)
Anabolic agents: Nandrolone decanoate, a synthetic anabolic-androgenic steroid, has been shown to promote muscle growth, reduce weight loss, and improve physical function in cachexia associated with cancer and HIV without significant benefits to the length of survival. Adverse effects include fluid retention, liver toxicity, and cardiovascular risks.[3][53] Enobosarm is a selective androgen receptor modulator with tissue-specific anabolic effects on muscle and bone. Early clinical trials have demonstrated that it significantly increases lean body mass and improves physical function in cancer patients. Enobosarm has not been approved by the FDA and remains an investigational therapy.[3] Recombinant human growth hormone can increase lean body mass and total body weight and improve physical function in individuals with HIV-associated cachexia and animal studies of chronic kidney disease-associated cachexia. Adverse effects include hyperglycemia, edema, and arthralgias; its high cost may limit its usefulness.[54][55](A1)
Anti-inflammatory and cytokine-targeting therapies: Thalidomide, which suppresses TNF production, has shown benefits when combined with other therapies, such as megestrol acetate or L-carnitine, to improve lean body mass and appetite. Thalidomide is not approved by the FDA and is associated with significant adverse effects, such as drowsiness and constipation.[56][3] Infliximab and adalimumab are anti-TNF-α monoclonal antibodies that have been investigated for their potential to mitigate cachexia by targeting the inflammatory pathways involved in muscle wasting and weight loss. Monoclonal antibody targeting interleukin-1 alpha is a human monoclonal antibody that targets and neutralizes interleukin-1 alpha, an inflammatory cytokine observed in cachexia. Early clinical trials of this antibody have shown promise, resulting in increased lean body mass, reduced inflammatory markers, and improved patient-reported outcomes, including decreased pain, fatigue, and anorexia. Further studies are needed to confirm its efficacy and safety for the treatment of cachexia.[57][58] Indomethacin and celecoxib, nonsteroidal anti-inflammatory medications, have also been investigated to treat cachexia, but evidence is lacking to recommend their routine use outside of clinical trials.[59][3] Eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid with anti-inflammatory properties, has shown a potential to improve lean body mass, increase appetite, and reduce inflammation in cancer cachexia. Still, the clinical benefits appear modest and not consistently significant across studies.[60][61](A1)
Metabolic Modifiers
Myostatin is a protein produced in skeletal muscle that actively inhibits muscle growth. The inhibition of myostatin has been explored as a possible treatment for cachexia. Preclinical animal studies have demonstrated attenuation of muscle wasting and improved muscle function, but trials are needed to evaluate the efficacy and safety of myostatin inhibitors in humans.[62][63] Another metabolic modifier is bimagrumab, a monoclonal antibody that binds to activin type II receptors, inhibiting myostatin. Bimagrumab promotes muscle growth, reduces muscle wasting, and shows promise as a safe therapy for cachexia, but it is another investigational agent not yet approved by the FDA.[64][65] Beta-hydroxy-beta methylbutyrate (HMB), a metabolite of the amino acid leucine, has an anabolic effect on muscle protein metabolism, making it a potential treatment for cachexia. Experimental models have demonstrated that it promotes muscle growth, suppresses protein degradation, and activates signaling pathways that precede muscle protein synthesis. Further study is needed to determine the safety and efficacy of HMB in treating cachexia.[66](A1)
Supportive Therapies
The ASCO guidelines suggest that cannabinoids, such as marijuana, dronabinol, and nabilone, do not significantly improve appetite, weight, or quality of life compared to placebo or megestrol acetate in patients with cachexia, and further clinical trials are needed.[67] Cyproheptadine, an antiserotonergic agent, has been evaluated for its appetite-stimulating properties but has not been shown to improve weight gain in cancer patients with cachexia, and the ASCO guidelines do not recommend its routine use. However, it may be helpful in pediatric cancer patients with cachexia.[68] Metoclopramide, a prokinetic and antiemetic agent, is often prescribed to manage nausea and vomiting in cancer patients. However, it does not address the underlying metabolic disturbances of cachexia. Although the ASCO guidelines include it for managing symptoms of cachexia, it is not recommended as a primary treatment. Metoclopramide may be helpful for patients with delayed gastric emptying or gastroparesis, aiding them in maintaining adequate food intake.[69][3]
In conclusion, treatments for cachexia aim to alleviate symptoms, stabilize weight, and improve quality of life, but must be tailored to individual patient needs, considering efficacy, adverse effects, and availability. Early intervention, particularly during precachexia, in combination with nutritional support, may improve outcomes and reduce treatment-related complications. No single medication completely reverses cachexia, and no drug therapies are currently approved as a standard of care.[2] Clinicians may elect not to prescribe specific therapies for cachexia, or they may advise a trial of progesterone analogs or short-term corticosteroids to improve appetite and weight gain. The ASCO guidelines note that the use of these medications is based on clinical practice rather than formal FDA approval.[3] Future therapies targeting specific metabolic and inflammatory pathways are under investigation and offer hope for more effective management.
Differential Diagnosis
The differential diagnosis of cachexia includes several other conditions characterized by weight loss and muscle wasting with distinct etiologies and clinical features. Patients with anorexia nervosa and other eating disorders may present with severe weight loss, but they lack the muscle wasting and metabolic abnormalities associated with cachexia.[70] Individuals with starvation, caused by inadequate caloric intake, experience a reduction in adipose tissue and lean body mass but do not display the metabolic disturbances and inflammation observed in cachexia. Most patients with starvation recover with adequate nutritional support.[71] Patients with chronic diseases such as heart or renal failure, cancer, and COPD may exhibit signs of malnutrition without the inflammatory profile characteristic of cachexia. However, as their underlying conditions worsen, they may progress to cachexia.[72]
Cachexia is distinct from sarcopenia, defined as the loss of skeletal muscle mass by 2 SD below sex-specific and age-adjusted values. The latter is primarily associated with aging, and individuals exhibit muscle loss and functional decline without the inflammation or significant weight loss observed in cachexia. Sarcopenia may also occur in patients with chronic disease, physical inactivity, and malnutrition.[73] The majority of individuals with cachexia are sarcopenic, but most with sarcopenia do not have cachexia.
Other conditions in the differential diagnosis include endocrine diseases, malabsorption, and psychiatric disorders. However, clinicians can typically distinguish between cachexia and other diagnoses by obtaining a detailed history, performing a thorough physical examination, and assessing pertinent laboratory results.
Prognosis
Cachexia is a significant predictor of morbidity and mortality across a range of chronic diseases, with its impact varying by the underlying condition. Cachexia affects 50% to 80% of patients with advanced cancer and is associated with an annual mortality rate of approximately 80%. Similarly, cachexia affects 5% to 15% of patients with COPD, with mortality rates ranging from 10% to 25% per year. In chronic heart failure, cachexia impacts 5% to 15% of patients with end-stage disease and carries an annual mortality rate of 20% to 40%, making it an independent predictor of all-cause mortality in these patients, with a prevalence of up to 31%.[74] Cachexia affects 20% to 30% of patients in advanced stages of chronic kidney disease, with a comparable mortality rate.[9] Although less common in rheumatoid arthritis and other autoimmune diseases, cachexia still contributes to increased morbidity and carries a higher mortality risk.[9] The poor prognosis of patients with cachexia reflects its complex pathophysiology, driven by inflammatory mediators, metabolic imbalances, and catabolic processes. These factors worsen the quality of life and underscore the need for targeted therapeutic strategies to improve outcomes in affected patients.
Complications
Complications of cachexia profoundly impact patients' overall health and prognosis. Cachexia-related sarcopenia limits patients' mobility, increases fall and fracture risks, and causes disability in activities of daily living, such as stair climbing, bathing, and transferring from bed to chair. The systemic inflammation of cachexia contributes to cardio-metabolic comorbid conditions, respiratory failure, and thromboembolic events. Immune dysfunction, including impaired T- and B-cell responses, makes individuals more vulnerable to severe infections.[10] These complications contribute to a poorer quality of life, encompassing physical, emotional, and social domains, with additional use of healthcare resources and economic burdens due to prolonged hospital stays and decreased disability-free survival.[2][75][2] Alarmingly, nearly 20% of cancer deaths are due to cachexia and its sequelae, with the syndrome being a significant driver of treatment toxicity, therapeutic complications, and a markedly elevated 6-month mortality risk.[76]
Deterrence and Patient Education
Deterrence and patient education are crucial in managing cachexia, given its profound impact on quality of life and survival. Clinicians should focus on the early identification of patients with a high risk of cachexia and associated mortality, particularly those with cancer, COPD, AIDS, and chronic heart and kidney failure. Educating patients and their caregivers about the mechanisms and manifestations of cachexia, including systemic inflammation, metabolic imbalances, and muscle wasting, fosters understanding and adherence to treatment plans. Counseling should emphasize the importance of adequate nutritional support, physical activity tailored to an individual's capacity, and early reporting of new symptoms. Healthcare team members can help deter progression by addressing modifiable risk factors, optimizing management of the underlying disease, providing proactive support for mental health, and identifying social determinants of health barriers. Clear communication about treatment goals, such as improving quality of life, maintaining functional capacity, and slowing disease progression, empowers patients to take an active role in their care even when cachexia is irreversible.
Enhancing Healthcare Team Outcomes
Effective management of cancer cachexia requires a comprehensive, interprofessional team approach to improve patient outcomes and quality of life. The team typically comprises primary care clinicians, oncologists, other medical and surgical specialists, nurses, dietitians, social workers, pharmacists, physical therapists, and mental health counselors, with each member contributing to a coordinated care plan.
Oncologists play a central role in early recognition and intervention for cancer patients, as timely treatment improves the likelihood of success. Oncology nurses serve as key advocates to manage symptoms, educate patients, and support family caregivers while ensuring adherence to follow-up appointments and encouraging patients to report new concerns.[28] Registered dietitians and nutrition specialists develop individualized plans to address malnutrition and weight loss, whereas physical therapists, exercise physiologists, and personal trainers focus on preserving muscle mass and physical function. Pharmacists reconcile medications, identify potential drug interactions, and recommend pharmacological interventions to boost appetite or manage symptoms. Social workers address social determinants of health, such as access to care and financial barriers, and mental health counselors support emotional well-being, improving patients' ability to cope with their condition.
Collaboration with palliative care teams further enhances symptom management, mitigates treatment-related adverse effects, and aligns care with the patient's expectations. Despite the poor prognosis of cachexia, this holistic approach ensures that symptom relief, nutritional support, and quality of life remain central to the goals of supportive and individualized care.
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