Cachexia is a complex syndrome with loss of muscle mass as its prominent feature. It occurs in many disease states, such as cancer, chronic infections (human immunodeficiency virus [HIV], tuberculosis), and other chronic illnesses (rheumatoid arthritis; chronic obstructive pulmonary disease; renal, heart, and liver failure). Although anorexia and decreased intake often accompany cachexia, nutritional supplementation in oral or parenteral form does not reverse cachexia. Beyond this, there is inconsistency in the definition, which poses significant challenges to research and clinical care. For example, some claim that loss of fat tissue is invariably present in cachexia, whereas a recent consensus meeting of experts reported that loss of fat tissue may or may not be present. Recent attempts at standardizing the definition of cachexia have included cutoff levels of weight loss and calculations that include biologic markers for inflammation.
As challenging as the clinical definition appears to be, the meaning and impact of cachexia for patients, families, and caregivers is even more complex and layered. The fact that cachexia is not reversed by improved intake is confusing to patients, their caregivers, and some health care professionals. It is counter to the very human instinct that a good diet is disease fighting and life maintaining. In addition, feeding is an essential component of nurturing and perceived as a sign of competent caregiving. In some instances, these perceptions are reinforced by health care professionals who may say to patients that if they are able to gain weight and strength, they may be offered further chemotherapy. This message is particularly damaging, considering that our evolving understanding of cachexia tells us that gaining weight is often not in the patient’s or caregiver’s control. However, what is evident is that cachexia is associated with poor response to cancer therapy, decreased survival, and poor quality of life. One study showed that in a sample of 3047 patients with metastatic cancer, weight loss greater than 5% before chemotherapy was associated with decreased survival in a multivariate analysis that controlled for performance status, tumor type, and stage. Beyond survival, enjoyment of food and maintaining normal levels of activity are important to patients’ quality of life. Decreased levels of activity and altered body image may lead to social isolation. In many cultures with high prevalence of HIV disease, cachexia is stigmatized regardless of etiology. In images that are ubiquitous in society, cachexia is frequently mirrored in the skeletal forms used to depict the dead and dying and is therefore perceived as a metaphor for death itself.
Pathophysiology
The fundamental problem in cachexia syndrome is the combination of anabolic blockade and increased catabolism, which results in accelerated weight loss. This is where cachexia differs from a starvation state, in which decreased intake results in adaptive mechanisms of decreased metabolic rate and increased efficiency of energy utilization. Although our understanding of the underlying mechanisms that result in the metabolic disturbances of cachexia is incomplete, systemic inflammation has been consistently found to be a factor across many disease states, including cancer, heart failure, chronic obstructive pulmonary disease, and cachexia in the elderly. In cancer, cachexia is generally thought to be due to a varied and complex set of interactions between tumor and host that triggers a chronic inflammatory state ( Figure 9-1 ). Proinflammatory cytokines are mediators implicated in this process. This chronic inflammatory state, together with procachectic factors secreted by the tumor, results in protein and fat breakdown. It also causes a chain of related abnormalities in neuroendocrine function that result in an increased catabolic drive as a result of insulin resistance and elevated cortisol levels. Further compounding these metabolic defects are the upregulation of protein degradation pathways, such as the ubiquitin-proteosome system (UPS), and the disturbance of the dystrophin glycoprotein complex (DGC), which selectively consume muscle protein.
Assessment
The assessment of cachexia and its often related symptom of anorexia should begin with a detailed history and systematic search for potentially reversible causes. A scan of the social, cultural, economic, and emotional context of the patient and the family is a crucial step. Understanding the supports available for shopping, meal preparation, and social interaction at meal times may lead to practical strategies such as employing a personal support worker to assist with shopping or meal preparation. In home palliative care, a look in the kitchen and fridge of a socially isolated patient may reveal much about the adequacy of their home supports and financial resources to meet nutritional needs.
A comprehensive assessment of symptoms is required because symptoms like altered taste, mouth sores, difficulty swallowing, early satiety, nausea, and vomiting impact appetite and the patient’s overall nutritional state. Distress related to symptoms like pain, dyspnea, anxiety, and depression also affect appetite. The objective of this part of the assessment is to optimize the conditions that are needed for eating rather than to push the patient to eat more. Gauging the patient’s, family’s, or caregiver’s perspectives, anxieties, and fears about eating and feeding is important at this stage too. Depending on where the patient is during the trajectory of disease and in terms of their goals of care, it may be appropriate not to investigate cachexia further and to focus instead on improving the patient’s and family’s understanding of cachexia and teaching ways of nurturing other than feeding.
If, on the other hand, a patient has a longer prognosis and the expectation that the disease may stabilize for a time, some further assessment may be appropriate for early recognition, to monitor effectiveness of management in the clinical setting, or as an endpoint for trials. As part of the history and physical examination, a bedside assessment of the extent and rate of weight loss is possible. Weight loss alone is a meaningful endpoint for assessing effectiveness of interventions for cachexia because it is related to quality of life. From the history or interval measurement of weight, the percent of weight loss in proportion to weight can be obtained. This serves as a baseline to compare subsequent rates of weight loss. In many instances, a favorable response to an intervention may be measured in a decreased rate of weight loss rather than a reversal of the cachexia.
Although rarely done in routine clinical practice, simple and inexpensive measures of nutritional status, body composition, and function exist. Hand dynamometry is a portable device that measures grip strength and has been shown to correlate to other nutritional parameters and function. Bedside anthropometry measures mid-arm muscle circumference and triceps skinfold thickness in comparison to age-adjusted reference values. Bioimpedance analysis (BIA) is a technique that measures total body resistance at different frequencies and calculates total body water, extracellular fluid, lean body mass, and fat mass. Although this requires specialized equipment, the equipment is portable and the test is safe and quick.
Impairment in physical functioning is closely related to cachexia and is another endpoint that is gaining favor. Performance status measurement using the Karnofsky Performance Status or the Palliative Performance Scale is one component of functional status that is familiar and easy to assess. There are more extensive assessments of physical activity, such as the Simmonds Functional Assessment, which includes a patient-reported questionnaire and nine physical tasks. Because the tasks include dressing and walking tests, the tool may preclude the participation of a significant number of palliative patients.
In addition, standardized tools for nutritional status are available that combine objective measures and patient-reported information. An example is the Subjective Global Assessment (SGA) tool, which generates categories of nutritional state and was found to be effective in identifying cancer patients at risk for cachexia. The Mini Nutritional Assessment (MNA) was originally developed to identify elderly patients at risk for malnutrition. It has been subsequently found to correlate with initial weight loss and C-reactive protein (CRP), a biomarker of inflammation, in advanced cancer patients receiving palliative chemotherapy. Admittedly these tools are difficult to implement without the resources of a fully staffed multidisciplinary clinic or research team; however, they appear to have a role in early identification of cachexia and as endpoints in clinical trials.
Biomarkers are being studied for both clinical and research applications. The evidence is most robust for CRP, a hepatic acute-phase reactant that is a marker for systemic inflammation. CRP has been associated with anorexia, accelerated weight loss, and decreased survival. A plasma CRP level greater than 10 mg/L, along with weight loss of greater than 10% and reduced food intake of less than 1500 kcal/day, has been proposed as criteria for diagnosis of cachexia. Although a variety of proinflammatory cytokines have been implicated in cancer cachexia, the findings across numerous studies are inconsistent. Cytokines that have been studied are tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-gamma (IFN-γ). Other potential biomarkers being studied include angiotensin II (involved in muscle catabolism) and leptin and ghrelin (peptides involved in control of food intake).
Management
In the majority of palliative patients, the main principle of management of cachexia is communication with the patient and family geared to listening to their fears, educating them about cachexia in the context of their advanced disease, helping them to come to terms with declining intake, and teaching them new ways of nurturing and caring. It is of course important to treat what is potentially reversible so that symptoms and factors that may interfere with eating and activity are minimized.
A 1989 position paper of the American College of Physicians, summarizing the results of a number of nutrition trials performed in the 1980s, stated that “parenteral nutritional support was associated with net harm, and no conditions could be defined in which such treatment appeared to be of benefit” in patients receiving chemotherapy. These studies may have had design flaws and were based on nutrition as the sole intervention, with regimens that may not meet current nutritional standards. However, there is still no evidence that either nutritional supplementation or artificial nutrition alone reverses cachexia.
More recently, a few studies have identified subsets of patients that may benefit from nutritional intervention. This has given rise to several guidelines regarding oral nutritional supplementation, enteral feeding, and parenteral nutrition, but the recommendations are inconsistent and difficult to apply in practice. The guidelines propose that a subset of patients with medical indications such as intestinal obstruction, high-output fistula, short-gut syndrome, combined with relatively good performance status (>50 on the Palliative Performance Scale) and longer prognosis (>3 months), may benefit from parenteral nutrition. Because prognostication is often inaccurate, identifying this subgroup may be challenging. In addition, parenteral nutrition is invasive, costly, and requires a high burden of care from families. Therefore, applying the proposed guidelines is fraught with problems.
An exploratory study by Bozzetti et al. enrolled 69 advanced cancer patients, the majority of whom had intestinal obstruction or “were almost aphagic”, to receive parenteral nutrition. The results suggest some stabilization of nutritional parameters but are limited by not having a control group. Another study, by Lundholm et al., involved 309 patients with solid tumors and prognoses longer than 6 months as estimated by the clinician. Patients were randomized to receive multimodal treatment consisting of indomethacin, erythropoietin (when indicated by hemoglobin cutoffs), and nutritional support (when indicated by study targets) or base treatment consisting of indomethacin and erythropoietin (when indicated by hemoglobin cutoffs). Of interest, patients did not have the typical medical indications for parenteral nutrition but were being provided parenteral support to maintain target intakes. Initially the nutritional intervention consisted of dietetic consultation and oral supplements to achieve a target intake of 30 kcal/kg body weight/day. If voluntary intake fell below 70% of these targets, parenteral nutrition was instituted. The results of this study suggest improvements in survival and total body fat and greater maximum power output during exercise.
Our current knowledge of cachexia suggests that providing increased substrate alone is ineffective because cachexia is a disturbance in both the use of substrate to build new tissue as well as an accelerated breakdown of existing muscle and tissue. Nutritional interventions are likely to be important in combination with therapies to correct the metabolic disturbances underlying the cachexia. It is clear that the management of cachexia involves a complex set of decisions that requires a multidisciplinary team to implement effectively. Within this team, the role of a nutritionist is important in optimizing the presentation, texture, taste, nutritional quality, and enjoyment of food.
Cachexia has inspired a flurry of research activity with a remarkable number of high-quality clinical trials in the last two decades. Despite this, few agents have shown benefit. In cancer patients, megesterol acetate, a progestational agent, has shown modest improvement in appetite and increase in weight as a result of increases in fat stores but not lean body mass. These gains do not seem to translate to improved survival, and no overall conclusion about improvement in quality of life could be drawn because of statistical heterogeneity. The 2009 Cochrane Review search yielded studies that tested doses ranging from 100 mg to 1600 mg daily of megestrol acetate. The evidence is lacking to make any specific recommendations regarding optimal dosing; however, ranges of 400 mg to 800 mg daily of the standard oral formulation of megestrol acetate are commonly used in clinical practice. The recommended duration of treatment is 6 weeks or more. Corticosteroids have shown modest benefit in improving appetite and well-being, but they are limited by side effects in prolonged use. Both megestrol and steroids appear to provide transient benefit. The concern with steroids, in particular, is the potential for steroid-induced myopathy and for a net catabolic effect.
Eicosapentanoic acid (EPA), an N-3 fatty acid, thought in preliminary trials to have beneficial effects on appetite and on underlying metabolic abnormalities, has not proven efficacious in phase III clinical trials. Cannabinoids are another class of agents hypothesized to have an appetite-stimulating effect, but a well-conducted three-arm trial of oral cannabis extract versus delta-9-tetrahydrocannabinol (dronabinol) versus placebo showed no statistical difference in appetite or quality of life in any of the treatment arms. Anabolic androgens, such as the synthetic oxandrolone, have been tested in preliminary trials, but their efficacy in cachexia is unknown. Etanercept, which belongs to yet another class of agents, one that blocks tumor necrosis factor-alpha, was tested in a phase III trial after preclinical and clinical studies showed promise. This was a study of etanercept versus placebo in 63 cancer patients. There were no significant differences in appetite and weight gain across both groups.
Future Directions
Further work is needed in developing a standardized definition of cachexia that is useful clinically and for research. The development of robust biomarkers for precachexia will lead to earlier targeted and individualized interventions. Models of multimodal therapy that include nutritional support, exercise, best supportive care, correction of secondary factors, and combination therapy are being proposed. Some preliminary trials of combinations of agents that target multiple mechanisms in cachexia are showing promise. Such trials have tested megesterol acetate in combination with ibuprofen, high-protein oral nutritional supplementation with eicosapentanoic acid, oral nutritional supplements with indomethacin and erythropoietin. These early results await confirmatory clinical trials. Such multimodal therapy requires the collaborative and coordinated efforts of a multidisciplinary care team. Notwithstanding the disappointing results of agents tested to date, research in cachexia has been invaluable in elucidating underlying metabolic pathways, many that have informed research in the area of fatigue as well.
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Cachexia shortens survival and quality of life.
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Early recognition and early treatment may reduce suffering.
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As a multifactorial syndrome, cachexia requires an individualized, multimodal approach to treatment.
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Confusion about definition and classification hinders treatment and research.
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Isolated nutritional intervention does not reverse cachexia.
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Cachexia has no predictable course or outcomes.
Summary
Cachexia significantly impacts survival and quality of life. Early identification and education are likely to reduce suffering. Cachexia is a complex, multifactorial syndrome that requires individualized, multimodal management. This, in turn, requires the work of a coordinated multidisciplinary team.
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