The Evolving Approach to Management of Cancer Cachexia

Weight loss is distressing to cancer patients and caregivers. Anorexia/cachexia syndrome is characterized by lipolysis and the loss of lean body mass, and is not reversible by increasing caloric intake. The pathophysiology of cancer cachexia is complex and includes symptoms that impact caloric intake, as well as chronic inflammation, hypermetabolism, and hormonal alterations. Cancer patients require routine screening for cachexia and, ideally, interventions should be initiated in the early stages of weight loss. No guidelines exist for the treatment of cancer cachexia. Appetite stimulants, such as megestrol acetate and glucocorticoids, have been shown to increase appetite and weight; however, single pharmaceutical interventions alone for cachexia do not result in meaningful functional outcomes. In the future, clinicians should consider multimodality treatment that is personalized for each patient. These interventions would include nutritional counseling, assessing and treating symptoms that have an impact on caloric intake, and a rational combination of pharmacologic approaches directed at underlying pathophysiology. Use of an appetite stimulant could be considered for patients who exhibit decreased appetite. Treatment with an anti-inflammatory agent should be considered for patients with elevated C-reactive protein, and hormonal alterations resulting from anti-cachexia therapy should be thoughtfully addressed.

Introduction

Cancer patients frequently develop loss of appetite and weight loss. Cachexia, defined by specific weight loss criteria, has a devastating physical and psychological effect on patients and caregivers. It results in a loss of muscle mass, altered body image, and associated decrease in physical functional level; it also often indicates the end of life. Cancer patients who have tumors responsive to chemotherapy often will regain weight. However, increased distress can result when cancer patients do not respond to treatment or experience treatment side effects, with weight loss sometimes eliciting requests from patients and their families for interventions to reverse cachexia.

In 2007, a panel of experts formalized the following definition: “Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass.”[1] Cancer cachexia cannot be easily reversed by increasing caloric intake and is distinct from starvation and age-related loss of fat-free mass. Before attributing weight loss to cancer, however, reversible contributing factors, such as depression, hyperthyroidism, or malabsorption, must be addressed. In a multi-institutional retrospective study of 3,047 cancer patients, weight loss occurring prior to the initiation of systemic chemotherapy, independent of disease stage and patient performance status, was predictive of disease progression and poor prognosis.[2]

Cancer cachexia is characterized by an inflammatory state, insulin resistance, and loss of skeletal muscle due to protein breakdown and lipolysis. In cancer patients, it is associated with decreased caloric intake, anorexia, decreased muscle strength, and increased fatigue.[3] Anorexia is common in cancer patients and results in decreased caloric intake, malnourishment, and weight loss. In advanced cancer, caloric intake is inadequate to support metabolic demands,[4] which are often elevated due to an increased frequency of hypermetabolism.[5]

In 2011, researchers in the field of cancer cachexia proposed a three-level distinct staging system consisting of pre-cachexia, cachexia, and a refractory stage.[6] In advanced non–small-cell lung or gastrointestinal cancers, patients classified as pre-cachectic and cachectic according to the proposed cancer cachexia staging system were clinically similar with respect to overall symptom burden, quality of life, tolerance of chemotherapy, and survival, whereas those in the refractory stage were unique and were noted to have deteriorating clinical outcomes.[7]

Estimates of the prevalence of cancer cachexia vary widely due to variable diagnostic criteria used in the past.[8] In one study, more than one-half of 644 ambulatory cancer patients reported anorexia and weight loss exceeding 5% of premorbid weight.[9] Cancer patients are often referred for cachexia intervention treatments late in their disease trajectory-that is, at a point where attempts to reverse the weight loss process may be less beneficial.[10] In addition, healthcare professionals frequently under-recognize the prevalence of cancer cachexia,[11] and this may contribute to delayed treatment of weight loss, often until the refractory stage.

Patient Assessment

A panel of experts recommended the following five domains in the assessment of cancer cachexia: depletion of fat stores, muscle strength and mass, caloric intake, underlying catabolic drivers, functional alterations, and psychosocial distress as a result of weight loss.[6] All cancer patients should be screened for nutritional status and weight loss; patient assessment should include a history of caloric intake; a physical examination assessing for evidence of muscle wasting, edema, and ascites; and serial measurements of body weight. Laboratory measurements of nutritional status, such as albumin levels, may be useful in certain cases.

The simplest objective screen for a change in nutritional status and cancer cachexia is serial measurements of body weight. Weight and height of cancer patients can be easily obtained, and the body mass index (BMI) can be calculated by obtaining the patient’s body weight (in kilograms) divided by his or her height (in meters) squared. The value of BMI is limited in this setting in that it fails to identify the proportion of bone, fat, and lean body mass. An international consensus group has incorporated BMI into diagnostic criteria used to stratify the severity of cancer cachexia.[12] The proposed grading system is as follows:

• Grade 0: Weight-stable patients (loss ± 2.4%) with BMI ≤ 25 kg/m² (median survival, 29 months).

• Grade 1: BMI 20 to 25 kg/m² and weight loss ≥ 2.4%, or BMI ≤ 28 kg/m² and weight loss of 2.5% to 6% (median survival, 14.6 months).

• Grade 2: BMI 20 to 28 kg/m² and weight loss of 2.5% to 6%, or BMI ≤ 28 kg/m² and weight loss of 6% to 11% (median survival, 10.8 months).

• Grade 3: BMI ≤ 20 kg/m² and weight loss < 6%, or BMI 20 to 28 kg/m² and weight loss of 6% to 11%, or BMI 22 to > 28 kg/m² and weight loss of 11% to 15%, or BMI ≤ 28 kg/m² and weight loss > 15% (median survival, 7.6 months).

• Grade 4: BMI ≤ 20 kg/m² and weight stable or loss of 6% to 11%, or BMI ≤ 22 kg/m² and weight loss of 11% to 15%, or BMI ≤ 28 kg/m² and weight loss > 15% (median survival, 4.3 months).

The prognostic discrimination of the grading system was clinically significant irrespective of the type of cancer or stage, age of patients, or performance status. Limitations of the study included the use of pooled datasets from multiple clinical trials in Canada and France and weight loss assessments at varying times in patients’ disease trajectory.

In the research setting, dual-energy x-ray absorptiometry scan, or DXA, provides a more accurate measure of weight that can distinguish lean body mass from fat-free mass and bone tissue. Bioelectrical impedance analysis represents a potential low-cost and clinically feasible method of weight assessment; however, in cancer patients it is reported to underestimate fat-free mass when compared with DXA.[13] Computed tomography and magnetic resonance imaging can be analyzed to determine body composition, but, due to their associated costs, these imaging techniques are used primarily in the research setting.

Caloric intake can be assessed either retrospectively with a 24-hour recall method, a prospective dietary record over a 3-day collection period, or by a trained nurse or volunteer estimating the percentage of food portions consumed by a cancer patient.[14] Screening tests that have been developed to assess for nutritional intake include the Patient-Generated Subjective Global Assessment (PG-SGA), the Malnutrition Universal Screening Tool (MUST), the Mini-Nutritional Assessment (MNA), and the Simplified Nutritional Appetite Questionnaire (SNAQ). The PG-SGA is validated for patients with cancer, but it requires 5 to 15 minutes to perform and must be completed by a well-trained person.[15] MUST predicts mortality and has been validated in cancer patients; it is a simple assessment tool that incorporates BMI, weight loss, and an acute disease score.[16]

Symptoms affecting appetite, termed secondary nutrition impact symptoms, should be assessed and can be easily treated; these include pain; xerostomia; nausea and vomiting; gastroparesis; constipation; and mood disorders, such as clinical depression.[10] In our experience, patients should be tested for reversible metabolic abnormalities that can result in weight loss (hyperthyroidism, adrenal insufficiency, and hypogonadism in men). For instance, cancer patients undergoing treatment with tyrosine kinase inhibitors are prone to thyroid abnormalities that, if not adequately treated, can contribute to weight loss.

In the clinical setting, gastroparesis is common in patients with advanced disease and can result from treatment with opioid analgesics or anticholinergics, radiation enteritis, autonomic dysfunction, or a paraneoplastic syndrome. A history of early satiety suggests gastroparesis, which can be easily treated with metoclopramide. In cancer patients, a schedule of metoclopramide at a dose of 10 mg every 4 hours while the patient is awake can be titrated to 120 mg per day for the treatment of gastroparesis.[17] Metoclopramide can often control nausea but unfortunately does not lead to increased caloric intake.

Hypermetabolism, defined as an elevated resting energy expenditure (REE) > 110% of predicted REE, can contribute to the development of weight loss and occurs in approximately half of patients with cancer.[18] Quantitation by indirect calorimetry, as opposed to the Harris-Benedict equation, is needed to accurately measure REE in cancer patients and is currently limited to the research setting. In the future, cancer patients with cachexia and elevated REE may benefit from interventions to decrease hypermetabolism. Ibuprofen, polyunsaturated fatty acids, and beta-blockers have been reported in some preliminary studies to decrease REE, which may allow patients to meet their caloric needs and gain weight.

Pathophysiology

The pathophysiology of cancer anorexia/cachexia syndrome is complex. Anorexia is a tightly regulated process in the brain. As shown in Figure 1, the control center for appetite is located in the hypothalamic arcuate nucleus, where the prophagic neuropeptide Y/agouti-related peptide neurons and the anorexic pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript neurons each receive various peripheral mediators that regulate food intake over the course of the day. For instance, an increase in serum level of ghrelin, secreted by cells located in the gastric fundus before and during meals, leads to activation of neuropeptide Y neurons and inhibition of the pro-opiomelanocortin neurons, ultimately increasing appetite and gastric motility.

Cancer cachexia is characterized by an upregulation of muscle proteolysis and lipolysis that is often attributed to an increased inflammatory response mediated by cytokines, such as interleukins (IL-6 and IL-1) and tumor necrosis factor α (Figure 2). These inflammatory cytokines activate the ubiquitin-proteasome pathway via nuclear factor kappa B, resulting in a protein degradation pathway in the myocytes. At the same time, protein synthesis is downregulated by the human myogenic differentiation protein, MyoD. Further, increases in cytokine levels precipitate an overall hypermetabolic state with a loss of adenosine triphosphate, further shifting the balance toward catabolism.

Treatment of Cancer Cachexia

Unfortunately, no guidelines or standards of care for the treatment of cancer cachexia have been universally accepted. The following discussion highlights our group’s approach to the management of cancer cachexia.

General treatment

After treating nutrition impact symptoms and reversible underlying metabolic derangement, cancer patients with persistent symptoms of anorexia and weight loss should be assessed and treated sooner rather than later during the trajectory of weight loss. In general, doctors should recommend that patients eat small, frequent, calorie-dense meals. Because weight loss and alterations in body image can be distressing for patients and their caregivers, appropriate psychosocial support should be provided. The pleasure of eating and the social benefits of gathering at the dinner table should be emphasized over caloric intake. Liquid nutritional supplementation is often recommended; however, it should be made clear to patients that they should not use liquid supplements as replacements for regular meals, ideally prior to > 5% loss of baseline weight, but instead should drink them between meals to approximate normal dietary intake.[19] In advanced disease, patients and families should be counseled that increasing caloric intake alone does not reverse the underlying anorexia/cachexia; the syndrome is distinct from starvation, and represents a common sequela of dying with cancer.

Nutritional Interventions

Our group recommends that all cancer patients with anorexia/cachexia syndrome consult with a nutritionist who can provide useful information. Unfortunately, nutritional recommendations may not lead to meaningful clinical benefits of weight gain or improved functional status. Studies of intense nutritional interventions in patients with cancer have shown mixed results. In one study in the outpatient setting, colorectal cancer patients who received counseling regarding nutritional intake and supplementation were noted to have increased caloric intake, improved functional status, and better quality of life.[20] In contrast, while another study confirmed increased caloric intake in ambulatory cancer patients following nutritional counseling, improvements in body weight and quality of life were not observed.[21]

Cancer patients with anorexia/cachexia syndrome have increased energy needs, and increased proteolysis depletes essential as well as nonessential amino acids, the latter of which may become conditionally essential. Besides amino acids, other micronutrients, such as vitamins, may be beneficial for supplementing other agents used to treat cancer cachexia, but more research is needed.[22]

Research into the effects of amino acid supplementation for patients with cancer is ongoing, and is briefly summarized here:

• Supplementation with glutamine, which in catabolic states is considered conditionally essential, has been studied in cancer patients. Among lung cancer patients undergoing radiation treatment, those who received prophylactic powdered glutamine supplementation had less weight loss.[23]

• Low serum carnitine levels have been observed in cancer patients, and are attributed to decreased nutritional intake and diminished endogenous carnitine synthesis.[24] A prospective, multicenter, placebo-controlled, randomized, double-blind trial of L-carnitine (at a dosage of 4 g daily) in patients with advanced pancreatic cancer and cachexia reported increased weight, quality of life, and a trend toward improved survival.[25]

• Recently, supplementation with mixtures of various amino acids has been studied in cancer. In patients with advanced cancer, a combination of the leucine metabolite β-hydroxy-β-methylbutyrate (at 3 g/day), plus L-glutamine (at 14 g/day) and L-arginine (at 3 g/day) increased lean body mass.[26]

• A comparison of dietary essential amino acids with high leucine levels vs a mixture of essential and nonessential amino acids reported a higher anabolic potential in patients treated with 14 g of essential amino acids, independent of nutritional status, systemic inflammatory response, or disease trajectory.[27]

Omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), which are found in fish oil, have been investigated in cancer patients with cachexia. Early studies were inconclusive, as noted by a 2007 Cochrane database meta-analysis on whether or not supplementation with EPA is better than placebo for the treatment of cancer cachexia.[28] Recent studies evaluating supplementation of omega-3 fatty acids in cachectic patients[29] have been more promising, and the authors note that interventions to improve compliance and supplementation delivered earlier in the development of weight loss may have contributed to positive outcomes. In clinical practice, our group considers treatment with omega-3 fatty acids in patients with cachexia, since they have potential benefit with limited side effects, but more definitive research is needed.

Pharmacologic Interventions

Appetite stimulants

Glucocorticoids have been extensively studied in patients with advanced cancer, and are known to stimulate the appetite.[30] The ideal glucocorticoid and dose are unknown, but most studies have used prednisone (at 20 to 40 mg/day) or dexamethasone (at 3 to 4 mg/day). Problematic side effects include insulin resistance, immune suppression, muscle myopathy, and risk of adrenal insufficiency.

Megestrol acetate is an appetite stimulant with progestational and antigonadotropic effects. In cancer patients with weight loss, megestrol acetate has been reported to have beneficial effects on appetite and results in a slight increase in weight, but it has not produced improvements in lean body mass or quality of life.[31] Further, serious complications of its use have been reported, including increased risk for thromboembolism, adrenal insufficiency, and hypogonadism in male patients.[32] A Cochrane review of 35 trials in 2013 reported that megestrol acetate did improve appetite and was associated with a slight gain in weight, but the authors emphasized that patients should be informed about the risks prior to taking megestrol.[31]

Dronabinol, a constituent of cannabis, has been studied for appetite stimulation in cancer patients. In a placebo-controlled randomized trial of 243 patients with advanced cancer with cachexia, no difference in appetite or quality of life was reported.[33] In a study of 469 cancer patients with anorexia or weight loss, dronabinol yielded no benefit either when administered alone or in addition to megestrol acetate.[34]

In general, we recommend weighing risks and benefits of appetite stimulants for cancer cachexia. Use of either glucocorticoids or megestrol acetate administered at the lowest effective dose can be considered to improve appetite while minimizing potential side effects. Unfortunately, the use of appetite stimulants often does not translate to clinically meaningful improvements in lean body mass or functional outcomes.

Investigational Pharmacologic Interventions

Anabolic steroids and ghrelin

Testosterone and its derivatives, such as oxandrolone and enobosarm, are being studied in patients without cancer who are experiencing cachexia. In healthy individuals, a recent study reported that androgen deficiency was strongly associated with reduced lean body mass and strength, while estrogen deficiency resulted in an increased proportion of body fat, and both oxandrolone and enobosarm contributed to heightened libido.[35] Currently, enobosarm, a selective androgen receptor modulator with decreased potential for virilization, is under investigation for the treatment of cancer cachexia in a phase III clinical trial.[36] Preliminary unpublished reports suggest improvements in lean body mass with enobosarm; however, no functional improvement has been observed, thus limiting the potential for approval of this agent by the US Food and Drug Administration.[37] Fluoxymesterone, an anabolic steroid, has been studied in cancer patients with weight loss, and was shown to be less effective than megestrol acetate and dexamethasone as an appetite stimulant.[38]

The gastrointestinal neuropeptide ghrelin, known as the “hunger hormone,” is a strong appetite stimulant. In preliminary studies, long-term parenteral administration of ghrelin improved the appetites of patients who had cancers associated with significant weight loss.[39] The orally available ghrelin mimetic anamorelin has been studied in two large double-blind placebo-controlled trials in lung cancer–related cachexia (ROMANA 1 and 2); some anamorelin-treated patients had increased lean body mass but no significant improvement in handgrip strength.[40] As with enobosarm, lack of functional improvements may prevent the approval of anamorelin, and more research is needed.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

In a pilot study of cachectic cancer patients with head and neck or gastrointestinal malignancies, treatment with the NSAID celecoxib (at 200 mg twice daily) resulted in weight gain, increased BMI, and improved quality of life.[41] NSAIDs are frequently incorporated into combination drug therapy for cancer cachexia, which will be discussed later in this article. A recent systematic review identified four studies that reported some evidence for the therapeutic benefits of NSAIDs in terms of weight gain, survival, quality of life, and inflammatory markers, but evidence was lacking for widespread use of NSAIDs in clinical practice.[42]

Mirtazapine/olanzapine

The psychiatric drugs mirtazapine and olanzapine are both potent 5-hydroxytryptamine 3 blockers, with antinausea effects and potential as therapies for cancer patients with anorexia/cachexia syndrome. A phase II nonrandomized trial evaluating mirtazapine, a tetracyclic antidepressant, administered for 8 weeks to cancer patients without depression, reported that mirtazapine-treated patients gained weight and had an improved appetite.[43]

In an exploratory study, olanzapine treatment of cancer patients with cachexia who were receiving active chemotherapy showed a nonsignificant trend toward improved weight.[44] Olanzapine has also been used in combination with megestrol acetate in advanced cancer, with results suggesting benefit.[45] It may be useful for patients on chemotherapy who have difficult-to-control nausea and weight loss; further studies are warranted.

Thalidomide

Thalidomide, an inhibitor of the production of tumor necrosis factor α, has been considered a candidate for treatment of cachexia in cancer patients. An initial pilot study suggested a possible role for this agent, but a Cochrane review concluded that evidence is lacking for the use of thalidomide for weight loss.[46]

Exercise

Weight loss resulting in decreased muscle mass is accompanied by decreased strength and physical capacity in patients with cancer. Physical exercise has the potential to treat weight loss in cancer patients by modulating levels of inflammation and altering muscle metabolism; however, a recent Cochrane systematic review showed that no randomized controlled trials have been conducted that evaluate the role of exercise in cancer cachexia.[47] While exercise has therapeutic potential in the treatment of cancer cachexia, concerns about compliance with an exercise regimen can be problematic and limit the potential benefits of exercise in frail and chronically fatigued cancer patients. Researchers are exploring pharmaceutical interventions that mimic exercise as a potential treatment for cancer cachexia.

Combination Drug Therapy

Since current interventions have had minimal success in preventing or reversing the anorexia/cachexia syndrome in cancer patients, researchers have proposed combination pharmaceutical therapy targeting multiple aberrant pathophysiologic pathways simultaneously as a weight-loss treatment, with some success. Various combinations have been studied and are presented below.

In a randomized study of 73 patients, the NSAID ibuprofen (400 mg three times daily) and megestrol acetate (160 mg three times daily) were combined for a 12-week duration for the treatment of cachexia in patients with gastrointestinal tumors; significant improvement in weight (median weight gain, 2.3 kg) was reported for patients in the combination arm compared with those treated with megestrol alone, who experienced weight loss (median, 2.8 kg).[48] Notably, 46 patients (63%) dropped out of the study prior to the 12-week endpoint, suggesting a high attrition rate.

Alternatively, a randomized noninferiority trial of 60 cancer patients with anorexia/cachexia syndrome reported that the two-drug combination of L-carnitine (4 g/day) and celecoxib (300 mg/day) with or without megestrol acetate reported improved weight and increased physical activity as tested by grip strength and a 6-minute walk test in both arms, suggesting a limited benefit to adding megestrol acetate to L-carnitine and celecoxib. Patients in both arms also received antioxidants, including polyphenols (300 mg/day); lipoic acid (300 mg/day); carbocysteine (2.7 g/day); and vitamins E, A, and C for a 4-month duration.[49]

In a randomized study, 332 patients with cancer cachexia were randomly assigned to a 4-month duration of monotherapy with medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); EPA; L-carnitine (4 g/day); or thalidomide (200 mg/day)-or to combination therapy with all five agents. Combination therapy was reported to be significantly superior to the individual interventions with respect to appetite and performance status, with toxicity similar to the toxicity profiles observed in the monotherapy arms of the trial.[50] Another combination trial in 104 cachectic patients with gynecologic malignancies evaluated a combination of megestrol acetate, L-carnitine, celecoxib, and antioxidants vs treatment with megestrol acetate alone, reporting improvements in lean body mass, fatigue, and global quality of life in the combination arm.[51]

Cachexia Clinics

Arguably, the additional levels of assessment and expertise needed to personalize therapy for cancer patients with anorexia/cachexia syndrome-with the healthcare team including a nutritionist, nursing personnel trained in assessing patients with weight loss, and clinicians with expertise in cancer cachexia-would be best coordinated in specialty cancer cachexia clinics.[10] Cancer cachexia clinics could evaluate patients who are anticipated to experience decreased caloric intake and weight loss (for example, those undergoing chemotherapy and/or radiation treatment to the neck and chest, putting them at risk for mucositis) in order to offer prophylactic treatment to minimize or prevent weight loss. Since beneficial therapies for treatment of cancer cachexia are limited, patients should be encouraged to enroll in clinical trials.

Conclusions

The cancer anorexia/cachexia syndrome is prevalent in patients with cancer, often precedes a decline in functional status, and is an indicator of poor prognosis. Weight loss results in psychological distress for both patients and their caregivers who feel the need to intervene in order to “fight” the illness. Cachectic patients and their families need additional psychosocial support and sensible nutritional advice in order to decrease their feelings of distress.

Since the anorexia/cachexia syndrome in cancer involves multiple pathophysiologic derangements, careful systematic patient assessment is needed. Figure 3 outlines the components of the multimodality treatment for cancer anorexia/cachexia syndrome. The foundation of multimodality treatment, and also the least harmful of interventions, consists of “best supportive care,” which encompasses careful attention to the assessment and treatment of nutritional impact symptoms, nutritional counseling and psychosocial support, and the potential addition of an exercise regimen for motivated cancer patients.

Currently, there are no guidelines for the treatment of cancer cachexia. To stimulate appetite, the administration of appetite stimulants such as glucocorticoids and megestrol acetate has been extensively studied; while these agents may improve caloric intake, they often do not improve functional outcomes. In the future, depending on the results of an assessment of the underlying pathology that is unique to each patient, appropriate pharmaceutical interventions or drug combinations could be initiated after thoughtful consideration of their potential benefits vs side effects. For example, for cancer patients with predominantly poor appetite, clinicians could consider treatment with an appetite stimulant such as a ghrelin mimetic, megestrol acetate, or a glucocorticoid. For male patients with low testosterone levels, androgen replacement therapy or use of an androgen receptor modulator could be considered. For patients with evidence of elevated C-reactive protein, suggestive of inflammation, consideration of treatment with an omega-3 fatty acid or addition of an NSAID to the combination therapy would be rational. Carefully tailored combination therapy for cancer cachexia may maximize the potential for reversal of weight loss while minimizing the potential for toxicities from multiple pharmacologic interventions.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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