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JOURNAL OF PALLIATIVE MEDICINE Volume 9, Number 2, 2006 © Mary Ann Liebert, Inc. Symptom Control in Palliative Care—Part II: Cachexia/Anorexia and Fatigue EGIDIO DEL FABBRO, M.D., SHALINI DALAL, M.D., and EDUARDO BRUERA, M.D. 409 INTRODUCTION IN THE FIRST PART we addressed general symp-tom assessment, constipation, and chronic nau- sea. This part discusses cachexia/anorexia and fa- tigue, and once again most of the available research is cancer-related. CACHEXIA/ANOREXIA Cachexia may occur in up to 80% of patients with advanced cancer.1 This complex metabolic syndrome, characterized by profound loss of lean body mass, is the main cause of death in 20% of patients. Cachexia (involuntary loss of more than 10% of premorbid weight) is a marker for poor prognosis2 and is associated with anorexia (loss of appetite), asthenia and changes in body image. Cancer cachexia tends to occur in patients with solid tumors, in children, and in elderly patients. Cachexia is also common in acquired immune de- ficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), congestive heart fail- ure (CHF)3–6 and other chronic illnesses, such as dementia, tuberculosis, malaria,7 chronic kidney disease, liver disease,8 and rheumatoid arthritis. MECHANISMS Cachexia is caused by a complex interaction be- tween tumor by-products (proteolysis inducing factor, lipid mobilizing factor) and host cytokines (including interleukin [IL]-1, IL-6, tumor necrosis factor, interferon). Cachexia in experimental ani- mal models can be relieved by specific cytokine antagonists, such as monoclonal antibodies to IL- 6.9 The metabolic abnormalities are characterized by synthesis of acute phase proteins in the liver at the expense of muscle protein, proteolysis, lipolysis, insulin resistance, decreased lipogene- sis, elevated triglycerides and decreased high density lipoproteins (Fig. 1). Neuroendocrine ab- normalities and the production of anorexigenic10 compounds may further contribute to the devel- opment of cachexia. Nutritional supplementation and appetite stimulation alone cannot overcome the block in accretion of muscle mass. Similar mechanisms for cachexia in CHF, chronic kidney disease,11 COPD,12 and rheumatoid arthritis13 have been described. ASSESSMENT The patient’s subjective loss of appetite can be assessed with a numerical rating scale such as the Edmonton Symptom Assessment System (ESAS), or one of the other tools previously described. The clinical assessment includes a careful history that is focused on nutritional issues and a phys- ical examination. Body weight is the only test commonly used outside the research setting. Measuring mid upper arm circumference may have prognostic value.14 Whole-body impedence and electroconductivity is based on the principle that lean tissue conducts electricity better than fat. This has the potential for more widespread clin- ical use as the equipment becomes more easily Department of Palliative Care and Rehabilitation Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas. Palliative Care Reviews Feature Editors: Robert M. Arnold and Solomon Liao available. For research and for follow-up, the ef- fect of any intervention on related symptoms, such as fatigue and dyspnea, would be useful, as well as quality of life and functional assessments. MANAGEMENT The management of major contributors to this syndrome, such as chronic nausea, constipation, early satiety, taste alteration, dyspnea, decondi- tioning, and depression may result in significant improvement. Established pharmacologic treat- ment currently comprises either megestrol or cor- ticosteroids, which predominantly stimulate ap- petite, however will not reverse cachexia in most patients. Weight gain may be necessary to allevi- ate distress associated with changes in body im- age. The other therapies described below may delay or reverse the cachexia component, or alle- viate the symptom burden without major effects on body composition. Pharmacologic treatment Progestational agents. Megestrol acetate has demonstrated dose dependent improvements (starting at 160 mg/d) in appetite, fatigue, and general well-being in more than 60% of pa- tients.15–17 Approximately 480–800 mg/d is opti- mal for weight gain, but it is prudent to start at a lower dose and titrate upward, since adverse effects18 and expense are dose-related. Sympto- matic improvement in appetite occurs in less than 1 week; however, weight gain may take several weeks and it happens in less than one quarter of treated patients. In a comparison study, meges- terol acetate (MA; 800 mg/d) was found to have fewer side effects than dexamethasone (0.75 mg four times daily [qid]), with a trend toward bet- ter weight gain.19 The authors concluded that for planned long-term use (weeks to months) it might be preferable to choose megestrol acetate. Consideration should also be given to cost (up to 20 times more expensive) and the higher risk for deep vein thrombosis (DVI). A recent review of the literature on MA20 showed that this drug was safe and effective in patients with cancer and AIDS. Megestrol has also been used in other noncancer conditions. A randomized double-blinded placebo controlled 8 week trial21 of either megestrol 800 mg daily or placebo in underweight patients with COPD demonstrated significant weight gain (mostly fat mass) in the megestrol group. Ventilation was stimulated (PaCO2 decreased), but there was no change in the 6-minute walk test. Side effects of megestrol include edema, hyperglycemia, and el- evated liver enzymes. Medroxyprogesterone22 at doses of 1000 mg/d (equivalent to megestrol 160 mg/d) has demon- strated significant improvements in appetite and body weight. Corticosteroids may stimulate appetite and decrease nausea as well.23,24 Randomized clini- cal trials have demonstrated that compared to placebo, corticosteroids can improve appetite and food intake.25 The effects of corticosteroids on ap- DEL FABBRO ET AL.410 FIG. 1. Metabolic abnormalities in primary cachexia. petite and food intake are usually limited to a couple of weeks, and the side effects of these drugs increase dramatically over time. Therefore, corticosteroids should be considered most useful for patients with a life expectancy of less than 6 weeks. Most authors have used prednisone doses ranging from 20–40 mg, or dexamethasone at an equivalent dosage. Cannabinoids. Dronabinol, a synthetic cannabi- noid, is Food and Drug Administration (FDA) ap- proved for anorexia related to AIDS and chemo- therapy-induced nausea and emesis. In a study of patients with AIDS-related cachexia, dronabi- nol showed significant improvement in nausea, appetite, and mood but no weight gain.26 Al- though some studies found beneficial effects of dronabinol on appetite in patients with advanced cancer,27,28 the effects of dronabinol on cachexia appear to be limited. In a more recent study com- paring dronabinol with megesterol acetate, the latter drug was found to be more beneficial as an orexigenic agent.29 A combination of both drugs was not better than MA alone. The use of dron- abinol is also limited by undesirable central ner- vous side effects, such as sedation, confusion, and perceptual disturbances.30 Thalidomide has immunomodulatory and an- tineoplastic effects and its use is being explored in a variety of conditions.31 Recent trials in pa- tients with advanced cancer have been encour- aging. Thalidomide was found to improve ap- petite, nausea and well-being32 after 10 days of treatment (100 mg daily) in patients with advanced cancer. A recent randomized placebo controlled trial33 of 50 patients with pancreatic cancer demonstrated that a dose of 200 mg daily for 24 weeks was well-tolerated and effec- tive at attenuating loss of weight andlean body mass. There was no significant difference in ap- petite symptom scores between thalidomide and placebo. Two patients developed peripheral neu- ropathy that resolved on cessation of the drug. Another open-label trial of thalidomide for 2 weeks in patients with esophageal cancer34 ap- peared to reverse loss of lean body mass, and al- though sedation was experienced by all patients, daytime somnolence was transitory and disap- peared after 2 or 3 days. Thalidomide also appears to benefit patients without cancer with cachexia. Patients with hu- man immunodeficiency virus (HIV) with aph- thous ulcers have demonstrated weight gain on doses of 200 mg daily.35 Low-dose (100 mg) thalidomide36 for 8 weeks in AIDS-associated cachexia was also associated with significant weight gain, half of which was fat-free mass. A trial of thalidomide in patients with active pul- monary tuberculosis37 was well tolerated and re- sulted in significant weight gain and reduction of tumor necrosis factor (TNF)-�. Testosterone and its derivatives, such as oxan- drolone,38 have been studied in patients with AIDS, neuromuscular disorders, and alcoholic cirrhosis. A recent review of oxandrolone con- cluded that improvements in body composition and muscle strength are significant in the major- ity of well-designed trials. Long-term safety (� 1 year) and dosage titration still need to be deter- mined. A prospective open-label study39 demon- strated a preferential increase of lean body mass in patients with COPD after 2 months of oxan- drolone. There was an increase in 6 minute walk- ing distance of more than 65 m in the majority of patients. Eighteen percent of patients withdrew because of side effects. Nandrolone has shown similar benefits in patients with COPD40 and AIDS, however, it can only be given parenterally and this limits its use. Other hormones, such as growth hormone, have demonstrated increases in lean body mass in patients with AIDS,41 and may have future ap- plications in the syndrome of frailty42 in the el- derly, but the cost is prohibitive. Ghrelin, a novel growth hormone-releasing peptide isolated from the stomach, may have future therapeutic poten- tial for cachexia43 of different causes (cardiac or cancer). Melatonin may inhibit cancer cell growth, im- prove survival and decrease chemotherapy in- duced side effects. In two studies with a large number of patients (total � 1640), the frequency of cachexia, asthenia, and thrombocytopenia was significantly lower in patients treated with 20 mg of melatonin at night.44 A randomized pilot trial in patients with cancer of fish oil, melatonin, or their combination did not induce major bio- chemical changes suggestive of a strong anti- cachectic effect, but may have produced a weight- stabilizing effect.45 This well-tolerated drug deserves further placebo-controlled trials. �-3 fish oil has few adverse effects and several benefits, including an immunomodulatory ac- tion and an antidepressant effect. Despite its SYMPTOM CONTROL: CACHEXIA, ANOREXIA, FATIGUE 411 promise,46 there was no nutritional or sympto- matic benefit in two randomized double-blinded controlled trials of advanced cancer patients.47,48 �-Antagonists and agonists. The possible role of the sympathetic nervous system in cardiac cachexia was illustrated by a study49 that mea- sured body weight, plasma norepinephrine, lep- tin, and insulin in both cachectic and noncachec- tic chronic heart failure patients. After 6 months of �-blocker therapy, patients with baseline cachexia demonstrated significantly greater weight gain, increase in leptin levels, and de- crease in norepinephrine levels compared to non- cachectic patients. The �-agonist Clenbuterol has an anabolic effect in normal and wasted muscles of animals. A single double-blinded placebo con- trolled trial50 of healthy postoperative orthopedic patients demonstrated increased muscle strength in the group treated with clenbuterol. Immunologic. A review51 of six clinical trials of various monoclonal antibodies to IL-6 in the treatment of cancer showed that the therapy was well tolerated and decreased the cancer-related symptoms of cachexia, pain, and fever. In most patients C-reactive protein levels decreased be- low detectable limits. A recent trial52 of a low-cost oral therapeutic HIV vaccine (V1) in patients with AIDS prolonged survival and increased body mass. Psychotropics. Antidepressants, such as mir- tazapine, and atypical antipsychotics, such as olanzapine, may be useful for the management of anorexia, nausea, and other symptoms in patients with cancer.53 Tricyclics, such as amitriptylline, may improve appetite but unfortunately have side effects, especially in the elderly. Nonpharmacologic treatment Nutritional support and counseling. Those pa- tients with a predominant starvation component resulting from obstructive gastrointestinal tu- mors or painful mucositis as a result of head and neck cancer treatment may benefit from nutri- tional interventions. Artificial nutrition via the enteral or parenteral routes is inappropriate for most patients with ad- vanced cancer and may hinder the transition to hospice. A meta-analysis54 of total parenteral nu- trition (TPN) in patients with cancer undergoing chemotherapy showed decreased survival and increased susceptibility to infection. A review of 70 prospective randomized trials of enteral and parenteral nutrition in cancer patients55 con- cluded that if there is any therapeutic benefit it is small and confined to a small subset of patients. In rare cases, home TPN can be associated with long-term survival. A retrospective single insti- tution study of home TPN56 identified 16 patients with cancer over a 20-year period who survived a year or longer. Most of the tumors were carci- noid and quality of life data were not assessed. One recent randomized prospective study57 of patients with primarily gastrointestinal tumors suggested a trend toward increased survival in patients who received TPN. Counseling. Compassionate communication is re- quired to address the benefits and burdens of nu- trition and to reframe the condition from that of “starving to death” to the more complex one of ir- reversible (usually) metabolic abnormalities. The psychological component is also important to con- sider, because eating meals together is important for social integration. Families of patients who are able to eat should be advised that frequent small meals may be more tolerable than three large meals daily. Nutritional counseling has been reported to improve nutritional intake in patients undergoing chemotherapy but not to influence symptom dis- tress or survival.58 In patients with advanced can- cer, this increased nutritional intake may last for only a few weeks.59 Unfortunately, there has been only limited research on the value of nutritional counseling in palliative care. FATIGUE Fatigue is one of the most common symptoms encountered in palliative care patients.60,61 It has been ranked as the longest lasting and most dis- ruptive of symptoms,62 having the greatest im- pact on quality-of-life parameters.63 Fatigue, sim- ilar to other symptoms, is a subjective sensation, which manifests with varying dimensions of im- paired physical, cognitive, and affective func- tioning.64 The physical dimension is usually de- scribed as a perception of muscle weakness or decreased energy. The cognitive and affective di- mensions include difficulty in concentrating or maintaining attention and lack of motivation or interest in activities. DEL FABBRO ET AL.412 Frequency rates as high as 96% for fatigue have been reported in association with chemotherapy and radiotherapy,65 and severe fatigue is almost universal in patients receiving biological re- sponse modifiers, such as interferon-� and IL- 2.66–68 In cancersurvivors, fatigue has also been reported as a disruptive symptom months or years after cancer treatment ends.69–71 A qualita- tive study of patients with severe heart failure re- vealed difficulties with walking and extreme fa- tigue similar to that of patients living with advanced cancer.72 In a study of 427 ambulatory patients with AIDS,73 fatigue was found to be present in 54%, and its presence correlated strongly with the number of AIDS-related phys- ical symptoms, anemia and pain. The patients with fatigue were also observed to have relatively poorer physical functioning and quality of life and greater psychological distress than those with no fatigue. MECHANISMS Multiple etiological factors may coexist and be interrelated. The common contributors to fa- tigue in advanced cancer include the tumor, the treatments and the proinflammatory cytokines produced (interleukin-1, IL-6, and TNF-�). Cy- tokines are the likely mediators of anemia, fever, pain, cachexia, and depression. Comorbidities such as congestive heart failure, kidney, and liver failure exacerbate fatigue as do electrolyte endocrine and mood disorders These factors are shown in Figure 2. ASSESSMENT Fatigue is assessed much like any other symp- tom, namely by characterizing the severity, tem- poral features (onset, course, duration, and daily pattern), exacerbating and relieving factors, asso- ciated distress, and impact on daily life,74 while searching for contributing factors. Additional in- formation is obtained from the history and phys- ical examination and laboratory data. In pallia- tive care practice, patients present with multiple symptoms, which can be simultaneously assessed by the ESAS. The presence of other symptoms such as pain, sleep, depression, and anxiety, are strongly correlated with fatigue. A more rigorous method, used for research purposes and validated for internal consistency, Functional Assessment of Cancer Therapy-Fa- tigue Subscale (FACT-F).75 The Brief Fatigue In- ventory (BFI) has also been used and validated as a measure of fatigue in patients with cancer,76 as has the Memorial Symptom Assessment Scale- Short Form (MSAS-SF). A study of patient re- SYMPTOM CONTROL: CACHEXIA, ANOREXIA, FATIGUE 413 FIG. 2. Contributors to fatigue. sponses to BFI, FACT-F, and the lack of energy item yielded similar information for assessing fa- tigue.77 MANAGEMENT Figure 3 shows an approach to management of fatigue and is discussed below. Specific measures Anemia is frequent in patients with cancer and may be secondary to bleeding, treatment-related myelosuppression, chronic disease, and malnutri- tion. Severe anemia (hemoglobin � 8 g/dL) is known to cause profound fatigue; however, a higher hemoglobin may also be associated with fa- tigue. Using a hemoglobin value of 12 g/dL or less to define anemia, anemic cancer patients requiring chemotherapy were found to have significantly higher levels of fatigue and impaired physical and functional well-being.78 There is a clear relationship between anemia and fatigue in patients with can- cer receiving chemotherapy,79 and treatment of these patients with red blood cell transfusion and/or erythropoetin alpha80 has shown to im- DEL FABBRO ET AL.414 FIG. 3. Approach to fatigue management in palliative care. prove quality of life and energy.81 Although ther- apy with erythropoetic agents is relatively safe, the disadvantages include the cost and the delay of 4–8 weeks before an increase of 1–2 g/dL and symp- tom improvement occurs. Recent data suggest that erythropoietin leads to an increase risk of deep ve- nous thrombosis and may, in certain populations, increase mortality. Moreover, data82 supporting erythropoetin’s usefulness in patients not on che- motherapy are less clear. In a recent retrospective study of 147 patients with cancer receiving pallia- tive care, anemia was not found to be indepen- dently associated with fatigue. Because the num- ber and severity of other comorbid conditions increase with advancement of disease, the relative contribution of anemia to fatigue likely decreases progressively.83 Infection. Fatigue is frequently associated with in- fection. It may predate the episode of infection and may outlast the infection by weeks or months. Anxiety, depression, or other mood distur- bances are common in patients with cancer.84 There is an association between depression and fatigue in patients with cancer; however, a causal relationship has not been established Hypogonadism may also contribute to fatigue. Much of the research on the role of hypogo- nadism in fatigue has been done on HIV-positive men. Testosterone deficiency is associated with loss of muscle mass, fatigue, reduced libido, and anemia.85 In patients with HIV with testosterone deficiency, treatment with androgenic anabolic steroids, including testosterone and its deriva- tives, has been found to increase muscle mass, energy levels, and libido.86–89 A randomized 10- week trial of 47 patients with COPD with testos- terone deficiency showed that testosterone plus resistance training had additive benefits.90 Both lean body mass and leg muscle strength increased significantly. Recently published studies have found a high prevalence of hypogonadism in pa- tients with cancer91 and in patients receiving high doses of opioids.92 In both these studies, the pres- ence of hypogonadism was associated with fa- tigue. Therapeutic trials of androgen replacement therapy in these patients for fatigue management are currently in progress. Pharmacologic Medications such as MA and dexamethasone may alleviate some of the symptoms of fatigue in patients with advanced cancer.93,94 Corticoste- roids have been shown to decrease fatigue via un- known mechanisms.95 The duration of benefit is between 2–4 weeks, and treatment may be suit- able for patients with a short life expectancy. Pro- longed use may induce myopathy and infection, thereby further contributing to fatigue. The usual starting dose in most studies is prednisone 20–40 mg per day or its equivalent. Psychostimulant medications have been shown in studies to ameliorate fatigue in patients with AIDS and multiple sclerosis.96,97 In a ran- domized double-blinded placebo-controlled trial of ambulatory patients with HIV, two psycho- stimulants—pemoline and methylphenidate— were shown to improve fatigue scores and qual- ity of life. In patients with cancer, the most commonly used psychostimulant is methyl- phenidate. Dextroamphetamine, pemoline, and modafinil have also been used, although there have been no controlled comparisons of any of these drugs. Methylphenidate has been used in cancer patients to treat opioid induced somno- lence, reduce pain intensity, treat depression, and improve cognition.98 Preliminary evidence sug- gests that psychostimulants may have a role in fatigue management in patients with cancer.99 Clinical trials are in progress. Modafinil, which is licensed for treatment of narcolepsy, is a novel psychostimulant that has been shown to be ef- fective for management of fatigue in multiple sclerosis.100 Further research is warranted to eval- uate its role in fatigue management in advanced chronic disease. Donepezil, a centrally acting acetylcholin- esterase (AChE) inhibitor approved for use in Alzheimer’s disease, may have a role in some pa- tients with fatigue. Preliminary studies in pa- tients with cancer have suggested at least short- term benefit in treating opiate-related sedation,101 as well as improvement in fatigue scores.102 Randomized controlled trials are currently in progress. Nonpharmacologic approaches A multidisciplinary approach to management benefits patients with advanced cancer and other disease such as CHF.103 Patients with heart failure have a wide array of options104 should standard medicaltherapy (di- uretics, angiotensin-converting enzyme [ACE]- inhibitors, beta blockers, aldosterone antagonists, SYMPTOM CONTROL: CACHEXIA, ANOREXIA, FATIGUE 415 digoxin) fail to improve fatigue and functional capacity. However, more invasive emerging therapies, such as ventricular assist devices or re- synchronization pacing should be carefully dis- cussed with the primary team before implemen- tation, because of their considerable impact on complexity of care and hospital discharge. Patient education. Patients with symptoms of fa- tigue need to be counseled about the nature of symptoms, likely etiology of their fatigue, options for management, and the expected outcome. This will help patients and their families set realistic expectations. As the disease progresses, patients will need to adapt to progressive limitations in physical function and activity. Patient prefer- ences for information and willingness to partici- pate in exercise and other treatment options should be ascertained. Exercise programs. In patients with cancer, mus- cle abnormalities have been found even when lean body mass is constant and caloric intake normal. Excessive amounts of lactate have been found in tumor-free muscle tissues and it is unclear whether lactate is part of the pathogenic mechanism or con- sequent to it.105 Tumor-free muscle from tumor- bearing animals show alterations in the activity of various enzymes, distribution of isoenzymes, and synthesis and breakdown of myofibrillar and sar- coplasmic proteins.106 Patients with breast cancer who underwent electrical stimulation of the ab- ductor pollicis muscle via the ulnar nerve were found to have impaired maximal strength, de- creased relaxation velocity, and increased fatigue compared to normal controls.107 In addition, med- ications such as corticosteroids and cyclosporine may contribute to myopathy.108 Deconditioning resulting from inactivity and prolonged bed rest results in loss of muscle mass and reduced cardiac output. This in turn decreases endurance and ac- tivities of daily living.109,110 There is good evi- dence111 to support the effectiveness of exercise in patients with fatigue.112–117 Exercise improves fa- tigue through an adaptive cardiorespiratory re- sponse, maintenance of muscle mass, improve- ment in mood, and quality of sleep. Several studies have shown that endurance exercise training im- proves fatigue and physical performance in pa- tients with cancer undergoing chemotherapy or in those who have undergone bone marrow or stem cell transplantation.118–120 Patients with multiple sclerosis121 who underwent an 8-week progressive resistance training program reported decreased fa- tigue and disability. There are also similarities122 between COPD and CHF with regard to muscle dysfunction and the impact of exercise. Although there is abundance of data to sup- port exercise, selection of the most appropriate program for patients with various types of ad- vanced disease and different levels of perfor- mance status are not well defined. Any exercise program should be initiated gradually. Psychosocial interventions. Patients should be counseled about stress management and methods to deal with depression and anxiety, which are commonly associated with fatigue. Clinical stud- ies testing interventions to reduce stress and in- crease psychosocial support in cancer patients have shown reduction in fatigue levels, although in many of these studies fatigue was a secondary endpoint.123–126 Nutrition and hydration. Patients may have de- creased oral intake due to a variety of causes re- lated to their illness or treatment. Referral to a nu- tritionist for dietary planning may be indicated if decreased intake is judged to be one of the causes of fatigue. 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