Cachexia is characterized by severe protein/calorie

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1 DETECTION AND MANAGEMENT OF CACHEXIA IN CANCER PATIENTS * Based on a presentation by Joanne Peter Finley, MS, RN Cachexia is characterized by severe protein/calorie malnutrition and is defined as a general weight loss with wasting that occurs as a result of chronic disease. The word cachexia is derived from 2 Greek words: cacos and hexis to mean bad condition. 1 Cancer cachexia is a complex syndrome involving anorexia, weight loss, wasting of muscle and adipose tissues, hyperlipidemia, and other metabolic abnormalities. The metabolic alterations of cancer cachexia resemble those observed in patients with sepsis or polytrauma rather than simple starvation. In starvation, decreased food intake results in decreased metabolism, and the body conserves vital tissues, with fat being catabolized before lean tissue. In cachexia, decreased food intake does not result in decreased metabolism. A vigorous breakdown of lean tissue and changes in fat and carbohydrate metabolism result from release of cytokines from the tumor. 2-4 Cachexia contributes to poor quality of life; efforts toward reversing or slowing its advancement are important, even if no gains in survival are made. ETIOLOGY OF CACHEXIA The etiology of cachexia is multifaceted and is related to (1) the tumor, (2) cancer treatment, and (3) psychological effects. 5 The tumor sites most commonly associated with cachexia include the pancreas, esophagus, stomach, colon, lung, and ovaries. Less common occurrences are observed in patients with tumors in the breast or with hematologic cancers. TUMOR-RELATED CAUSES *Based on a presentation given by Ms Finley at a satellite symposium held during the Oncology Nursing Society s 28th Annual Congress. Patient Education Coordinator, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland. Tumor-related causes of cachexia can be a function of tumor type, size, and location. 1,2 Mechanical obstruction of the alimentary canal via direct invasion of the tumor and obstruction of the lumen may result in dysphagia, early satiety, nausea and vomiting, difficulty with digestion, and malabsorption of food. Circulation of factors produced by the tumor itself, or by the host immune system in response to the tumor, may play a key role in cancer-related cachexia. 4-6 Several proinflammatory cytokines have been associated with the pathogenesis of cachexia in cancer: tumor necrosis factor-alpha (TNFα), Interleukins (ILs) 1 and 6, and interferon-alpha (IFN-α) and IFN-gamma (IFN-γ). Increased fat mobilization is implicated with TNF and IFN-γ via inhibition of the enzyme lipoprotein lipase. TNF, IL-1, and IL-6 are involved in protein metabolism and wasting of muscular tissue. Because the production of many cytokines is induced by other cytokines, it is difficult to identify which cytokine is primarily responsible for the cascade of metabolic changes resulting in cachexia. Most of the research on cytokines and cachexia has been conducted in animals and was not designed to evaluate changes in serum cytokine levels in cachectic patients. Despite these shortcomings, our understanding of the etiology and possible treatment options for cancer-related cachexia has grown due to this research. CANCER TREATMENT RELATED CAUSES The etiology of cachexia can be related to cancer treatment and may involve direct and indirect mechanisms. 2,7 Side effects of antineoplastic regimens may affect the nutritional status of patients, resulting in weight loss, an important component of cachexia. Nausea, vomiting, anorexia, mucositis, diarrhea, and taste alterations are commonly observed with chemotherapy and radiation therapy. Biotherapy can result in fever, fatigue, weakness, and decreased appetite. Nonpharmacologic treatment, such as surgery, may also contribute to cachexia by producing malabsorption, early satiety, dysphagia, and pain. PSYCHOLOGICAL CAUSES Patients with cancer commonly experience anger, anxiety, depression, and fear, which can contribute to 8 Vol. 1, No. 1 October 2003

2 the anorexia/cachexia syndrome. 7 For most people, food has important social implications and is an important part of many social activities. Some cancer patients may feel isolated if they do not share meals with their families or attend family functions in which food plays a part. DETECTION OF CANCER CACHEXIA Detection early in the disease process is important in maintaining nutritional, body compositional, and functional status of the cancer patient. 2,5,8,9 A team of healthcare professionals is critical in the detection and management of cachexia. This team should include nurses, physicians, dietitians, and pharmacists, with referrals to social workers and physical and speech therapists as needed. A written nutritional plan that includes designation of responsibilities should be formulated. Reassessment of the patient and the nutritional plan should be conducted routinely to determine if the plan has produced good patient outcomes. If the patient s nutritional status has declined, problem areas should be addressed early. A variety of tools are available for the detection of cachexia; body weight is the most common and simple measurement used. When evaluating weight, comparisons should be made to usual or normal weight rather than to ideal body weight. Loss of up to 10% of body weight in 6 months or up to 5% in 1 month is cause for alarm; a loss of greater than 10% of body weight in 6 months is classified as severe weight loss. 10 Median survival is shorter in cancer patients who have experienced a weight loss of 5% or greater. 11 Other anthropometric measures used, which determine subcutaneous fat and muscle stores, are the skinfold test of the triceps and mid-arm muscle circumference (MAMC). 9 Normal values for the triceps skin-fold test are 18 mm in men and 22 mm in women. Normal MAMC values are 31.7 mm in men and 28.7 mm in women. Physical examination is also useful for evaluating the nutritional status of patients. Signs and symptoms associated with weight loss are presented in Table 1. Laboratory measurements affected by metabolism and malabsorption are helpful in determining nutritional status and include albumin, prealbumin, transferrin, urinary creatinine clearance, total lymphocyte count, nitrogen balance, and anergy panel (Table 2). 9 Evaluation of activities of daily living and diet may also be used in the assessment of cancer patients. A review of functional status is important because some patients may lack resources to obtain or prepare food. Patients should also be asked to provide a detailed dietary history for 3 days, including 1 weekend day. Several validated tools can assist oncology nurses in providing proactive nutritional support for patients. One commonly used tool is the Malnutrition Risk Assessment Tool (Figure). 2 This evaluation provides a quick assessment of categories that are significant for determining malnutrition. Patients and their families can complete this tool before being evaluated by a healthcare professional. Another tool that has been modified specifically for oncology patients is the Patient-Generated Subjective Global Assessment (PG-SGA). 10 The patient completes questions designed to evaluate weight, food intake, problems with eating, and functional capacity symptoms; the healthcare professional completes information regarding diagnosis, stage, age, and physical examination, then calculates an SGA rating. Table 1. Signs and Symptoms Associated with Weight Loss in Cancer Patients SIGNS Brittle hair/nails Diarrhea Dry mucosa Edema Fever Mucositis Muscle atrophy Nausea and/or vomiting Poor turgor Weakness (decreased hand-grip strength) Table 2. Laboratory Measurements Used to Assess Nutritional Status Laboratory Measures Normal Ranges Albumin 3.8 to 4.5 g/dl Prealbumin 17 to 40 mg/dl Transferrin 250 to 450 mg/dl Urinary creatinine clearance 1.2 g/24 hours Total lymphocyte count 2000/mm 3 Nitrogen balance Positive Anergy panel 5 mm induration is positive skin test Data from Tait. 9 SYMPTOMS Anorexia Anxiety Decreased immune response Decreased mental status Depression Fatigue Pain Advanced Studies in Nursing 9

3 MANAGEMENT OF CANCER CACHEXIA The management of cancer cachexia is centered on treating the underlying cancer to resolve the instigating problem; otherwise, care is focused toward symptom management. NONPHARMACOLOGIC MEASURES The most important nonpharmacologic measures in the management of cancer cachexia include the provision of education and support, utilizing the dietitian as a key member of the healthcare professional team. 2,5,10,12 These efforts are not only free from risk, but also are associated with increased caloric intake and improved quality of life. Counseling is clinically and economically effective and, in ideal situations, should be undertaken before weight loss or after only moderate weight loss (<5% of usual body weight). Counseling efforts should include the entire family and should be verbal and reinforced with written materials (eg, Web sites) that may be useful in supplementing discussions. Counseling efforts may include discussion of the complementary methods presented in Table 3. These methods, such as exercise, have been shown to improve immune function, mood, fatigue, muscle mass, physical performance, and quality of life in cancer patients. 13,14 To obtain an accurate picture of the patient s nutritional status, it is important to ask about the use of vitamins and herbs. PHARMACOLOGIC MEASURES No pharmacologic agents are approved by the US Food and Drug Administration (FDA) for the treatment of cancer cachexia; however, 5 different classes of agents will be discussed: progesterones, cannabinoids, corticosteroids, prokinetic agents, and investigational agents (Table 4). Current evidence suggests that progesterones, cannabinoids, corticosteroids, and prokinetic agents provide appetite stimulation but do not change the underlying metabolic processes in cancer cachexia. The investigation of newer agents is directed toward identifying pharmacologic measures that will alter the metabolic changes cancer patients experience. Progestogens. Progestogens were the first agents used in the management of cancer cachexia and are still commonly used in these patients. 6,11 Although the mechanisms are not fully elucidated, these agents may induce appetite stimulation via inhibition of the synthesis and release of IL-1, IL-6 and TNF-α. 6,11 Megestrol acetate, an oral synthetic progesterone associated with increased appetite and weight gain, is the most widely used progesterone for the management of cancer cachexia and has been evaluated in numerous randomized, double-blind, placebo-controlled trials. The appetite-stimulating benefits of megestrol acetate are dose related; 800 mg daily is the optimal dose. 6,10,11 Side effects include adrenal insufficiency, hyperglycemia, fluid retention, carpal tunnel syndrome, mood changes, and venous thromboembolism. 15 Figure. Malnutrition Risk Assessment Tool WEIGHT Today 6 months ago 1 year ago Change FOOD INTAKE (CHECK ONE) Unchanged More than usual Less than usual Very little of anything ACTIVITY LEVEL (CHECK ONE) Energetic Depressed Moderate fatigue Severe fatigue FUNCTIONAL ABILITY (CHECK ONE) Normal without limitations In bed or chair most of the day Need help with daily care Bedridden RESOURCES (CHECK ONE) Able to buy and prepare food Need financial help to buy adequate diet Need help with food preparation HABITS (CHECK ALL THAT APPLY) Use of alcohol greater than 6-pack of beer/week Use of alcohol less than 6-pack of beer/week Use of cigarettes Use of medicine for depression OTHER TREATMENTS (CHECK ALL THAT APPLY) Herbs and other supplements Large intake of vitamins Meditation/relaxation Support-group participation PHYSICAL SYMPTOMS (CHECK ALL THAT APPLY) No problems eating Constipation Diarrhea Difficulty swallowing Dry mouth Mouth sores Nausea No appetite Pain: Where? Smells that ruin appetite Taste changes Vomiting Reprinted with permission from Whitman. The starving patient: supportive care for people with cancer. Clin J Oncol Nurs. 2000;4(3): Vol. 1, No. 1 October 2003

4 Cannabinoids. Dronabinol, a cannabinoid, is FDAapproved for anorexia associated with weight loss in patients with acquired immune deficiency syndrome (AIDS) and for nausea and vomiting associated with cancer chemotherapy. 16 Cannabinoids exhibit complex effects on the central nervous system, including activity on the central sympathomimetic system. Cannabinoid receptors found in neural tissues may play a role in mediating the effects of cannabinoids. Dronabinol is a synthetic delta-9-tetrahydrocannabinol. It is orally active and is generally dosed at 2.5 mg twice daily, with gradual dose increases to a maximum of 20 mg daily. Side effects are dose related, and bedtime administration may help decrease some side effects. Chronic administration of dronabinol from days to weeks results in tolerance to subjective side effects (eg, easy laughing, elation, heightened awareness, sedation, and dizziness) and cardiovascular side effects (eg, palpitations and tachycardia). 17 Corticosteroids. The ability of corticosteroids to stimulate the appetite is thought to be mediated via an improvement in the sense of well-being or by inhibition of prostaglandin activity and suppression of IL-1 and TNF production. 6,10,18 Dosages of less than 1 mg/kg prednisone equivalent are recommended. Chronic administration of corticosteroids is limited by the significant side-effect profile of these agents (decreased immune function, hyperglycemia, gastrointestinal irritation) and their relatively short-lived (ie, weeks) beneficial effects on appetite. Prokinetic Agents. Prokinetic agents, such as metoclopramide, are used in an effort to increase gastric emptying time, therefore decreasing feelings of satiety. 6,18 The recommended dose of metoclopramide for the treatment of cancer cachexia is 10 mg by mouth 4 times daily 30 minutes before meals and at bedtime. 18 Common side effects include akathisia and dystonic extrapyramidal effects. 17 Investigational Agents. Several agents have recently been or are being investigated but are not currently FDA-approved for the management of cancer cachexia. 6 Thalidomide inhibits TNF-α production and has been shown to increase body weight in patients with AIDS. Evidence suggests that cyclooxygenase-2 (COX-2) and COX- 2 derived prostaglandins may play a role in the development of cancer via biochemical routes, including stimulating the growth of tumor cells; nonsteroidal anti-inflammatory drugs that selectively block COX-2 may have a chemopreventive benefit. These agents may reduce resting energy expenditure and stabilize weight and quality of life. Supplementation of omega-3 polyunsaturated fatty acids (fish-oil capsules) may block IL-1 and TNF-α. Long-term administration of eicosapentanoic acid has been shown to decrease serum levels of IL-1, IL-6, TNFα, and IFN-γ and stabilize body weight. Melatonin has been shown to reduce the extent of weight loss in patients with metastatic cancer. 19,20 The addition of melatonin to chemotherapy may improve response and survival rates with the benefit of a reduction in side effects associated with chemotherapeutic agents. Table 3. Complementary Methods Commonly Used for the Management of Cancer Cachexia Exercise Relaxation Hypnosis* Aromatherapy* Herbal and vitamin supplements* *Although commonly encountered in clinical practice, efficacy of these measures has not been thoroughly evaluated in the literature. Exercise and relaxation data from Tait. 9 Table 4. Pharmacologic Measures for Managing Cancer Cachexia* Class of Agent* Progesterones Cannabinoids Corticosteroids Prokinetic agents Anticytokines NSAIDs, COX-1 and COX-2 inhibitors Omega-3-polyunsaturated fatty acids Eicosapentanoic acid Serotonin antagonists Possible Mechanism of Action Inhibition of proinflammatory cytokines Central nervous system effects Suppression of TNF, IL-1, and prostaglandins Increased gastric emptying Neutralization of IL-1, IL-6, and TNF-α Inhibition of COX-2 derived prostaglandins Blockage of IL-1 and TNF-α Decreased IL-6 production Decrease in serotonin *No agent is currently approved by the US Food and Drug Administration for the treatment of cancer cachexia. TNF = tumor necrosis factor; IL = interleukin; NSAIDs = nonsteroidal anti-inflammatory drugs; COX = cyclooxygenase. Data from Mantovani et al. 6 Advanced Studies in Nursing 11

5 PARENTERAL NUTRITION Parenteral nutrition is not indicated in primary cachexia, but may be useful in preoperative treatment of malnutrition in surgically resectable tumors, bone marrow transplants, and cancers of the head and neck. 21 When managing the nutritional status of cancer patients, it is best to use the gut if possible, followed by enteral supplements and then parenteral nutrition if necessary. 22 Parenteral nutrition is characterized by high caloric and protein content; however, data are inconclusive that it is associated with any benefit in the treatment of cachexia. 18,21 The increased infection rate observed with the use of central venous lines is a serious complication of parenteral feedings. IMPACT OF TREATMENT ON QUALITY OF LIFE By addressing cancer cachexia and issues surrounding nutrition in the cancer patient, an improvement in quality of life may be achieved. 10 Psychosocial needs addressed by nurses include counseling the patient and family on the importance for the patient to participate in family activities, including those that contain food. The family needs to be sensitive to changes occurring in the patient s body and not force the patient to eat. Even if no improvement in survival is achieved, improvements in social interactions, body image, and performance status that may be achieved are important for the patient s psyche. Other important benefits of improved nutritional status are decrease in fatigue, weakness, and depression. SUMMARY Appropriate education of the cancer patient and his or her family regarding weight loss and cachexia is critical. The anorexia/cachexia syndrome is a leading cause of death in patients with cancer and is present in 80% of cancer patients at death. 6,18 Nurses play a pivotal role in the early detection and management of cancer cachexia, with educational efforts directed toward the patient, family, and caregivers. Communication with the multidisciplinary healthcare team is vitally important and should include a written plan. REFERENCES 1. Ohnuma T. Anorexia and cachexia. In: Bast Jr RC, Kufe DW, Pollack RE, et al, eds. Cancer Medicine. 5th ed. Hamilton, Ontario: B.C. Decker Inc; 2000: Whitman MM. The starving patient: supportive care for people with cancer. Clin J Oncol Nurs. 2000;4(3): Jatoi A Jr, Loprinzi CL. Current management of cancer-associated anorexia and weight loss. Oncology. 2001;15: Moldawer LL, Copeland EM. Proinflammatory cytokines, nutritional support, and the cachexia syndrome. Cancer. 1997;79: Finley JP. Management of cancer cachexia. AACN Clin Issues. 2000;11: Mantovani G, Maccio A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs. 2001;61(4): Nutrition. National Cancer Institute Web site. Available at: Accessed February 8, Ottery FD. Cancer cachexia: prevention, early diagnosis, and management. Cancer Pract. 1994;2(2): Tait NS. Anorexia-cachexia syndrome. In Yarbro CH, Frogge MH, Goodman M, eds. Cancer Symptom Management. Sudbury, MA: Jones and Bartlett, Publishers; 1999: Ottery FD. Supportive nutrition to prevent cachexia and improve quality of life. Semin Oncol. 1995;22(2 suppl 3): Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin. 2002;52(2): Tchekmedyian NS. Pharmacoeconomics of nutritional support in cancer. Semin Oncol. 1998;25(suppl 6): Dimeo F. Exercise for cancer patients: a new challenge in sports medicine. West J Med. 2000;173: Dimeo FC. Effects of exercise on cancer-related fatigue. Cancer. 2001;92(suppl 6): Megace [package insert]. Bristol-Myers Squibb Company. Princeton, NJ. July Marinol [package insert]. Unimed Pharmaceuticals, Inc. Deerfield, IL. January Nausea and Vomiting. National Cancer Institute Web site. Available at: Accessed February 8, Nelson KA. The cancer anorexia-cachexia syndrome. Semin Oncol. 2000;27(1): Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non small cell lung cancer patients in a poor clinical state. J Pineal Res. 1997;23: Lissoni P, Tancini G, Barni S, et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer. 1997;5: Nelson KA. Modern management of the cancer anorexiacachexia syndrome. Curr Pain Headache Rep. 2001;5(3): Langer CJ, Hoffman JP, Ottery FD. Clinical significance of weight loss in cancer patients: rationale for the use of anabolic agents in the treatment of cancer-related cachexia. Nutrition. 2001;17(suppl 1):S1-S Vol. 1, No. 1 October 2003