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.
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.” 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.
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. 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, which are often elevated due to an increased frequency of hypermetabolism.
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. 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.
Estimates of the prevalence of cancer cachexia vary widely due to variable diagnostic criteria used in the past. In one study, more than one-half of 644 ambulatory cancer patients reported anorexia and weight loss exceeding 5% of premorbid weight. 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. In addition, healthcare professionals frequently under-recognize the prevalence of cancer cachexia, and this may contribute to delayed treatment of weight loss, often until the refractory stage.
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. 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. 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. 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. 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. 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.
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. 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. 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. 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.
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.
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. 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.
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. 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.
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.
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.
• Low serum carnitine levels have been observed in cancer patients, and are attributed to decreased nutritional intake and diminished endogenous carnitine synthesis. 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.
• 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.
• 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.
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. Recent studies evaluating supplementation of omega-3 fatty acids in cachectic patients 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.
1. Evans WJ, Morley JE, Argilés J, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793-9.
2. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980;69:491-7.
3. Strasser F. Diagnostic criteria of cachexia and their assessment: decreased muscle strength and fatigue. Curr Opin Clin Nutr Metab Care. 2008;11:417-21.
4. Hutton JL, Martin L, Field CJ, et al. Dietary patterns in patients with advanced cancer: implications for anorexia-cachexia therapy. Am J Clin Nutr. 2006;84:1163-70.
5. Bosaeus I, Daneryd P, Svanberg E, Lundholm K. Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients. Int J Cancer. 2001;93:380-3.
6. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489-95.
7. Vigano A, Del Fabbro E, Bruera E, Borod M. The cachexia clinic: from staging to managing nutritional and functional problems in advanced cancer patients. Crit Rev Oncog. 2012;17:293-304.
8. Wallengren O, Lundholm K, Bosaeus I. Diagnostic criteria of cancer cachexia: relation to quality of life, exercise capacity and survival in unselected palliative care patients. Support Care Cancer. 2013;21:1569-77.
9. Tchekmedyian NS. Costs and benefits of nutrition support in cancer. Oncology (Williston Park). 1995;9(11 suppl):79-84.
10. Del Fabbro E, Hui D, Dalal S, et al. Clinical outcomes and contributors to weight loss in a cancer cachexia clinic. J Palliat Med. 2011;14:1004-8.
11. Del Fabbro E, Jatoi A, Davis M, et al. Health professionals’ attitudes toward detection and management of cancer-related anorexia-cachexia syndrome, and a proposal for standardized assessment. J Community Support Oncol. 2015;13:181-7.
12. Martin L, Senesse P, Gioulbasanis I, et al. Diagnostic criteria for the classification of cancer-associated weight loss. J Clin Oncol. 2015;33:90-9.
13. Ellegård LJ, Ahlén M, Körner U, et al. Bioelectric impedance spectroscopy underestimates fat-free mass compared to dual energy X-ray absorptiometry in incurable cancer patients. Eur J Clin Nutr. 2009;63:794-801.
14. Bruera E, Chadwick S, Cowan L, et al. Caloric intake assessment in advanced cancer patients: comparison of three methods. Cancer Treat Rep. 1986;70:981-3.
15. Kwang AY, Kandiah M. Objective and subjective nutritional assessment of patients with cancer in palliative care. Am J Hosp Palliat Care. 2010;27:117-26.
16. Cansado P, Ravasco P, Camilo M. A longitudinal study of hospital undernutrition in the elderly: comparison of four validated methods. J Nutr Health Aging. 2009;13:159-64.
17. Bruera ED, MacEachern TJ, Spachynski KA, et al. Comparison of the efficacy, safety, and pharmacokinetics of controlled release and immediate release metoclopramide for the management of chronic nausea in patients with advanced cancer. Cancer. 1994;74:3204-11.
18. Dev R, Hui D, Chisholm G, et al. Hypermetabolism and symptom burden in advanced cancer patients evaluated in a cachexia clinic. J Cachexia Sarcopenia Muscle. 2015;6:95-8.
19. Wilson MM, Purushothaman R, Morley JE. Effect of liquid dietary supplements on energy intake in the elderly. Am J Clin Nutr. 2002;75:944-7.
20. Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Dietary counseling improves patient outcomes: a prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy. J Clin Oncol. 2005;23:1431-8.
21. Ovesen L, Allingstrup L, Hannibal J, et al. Effect of dietary counseling on food intake, body weight, response rate, survival, and quality of life in cancer patients undergoing chemotherapy: a prospective, randomized study. J Clin Oncol. 1993;11:2043-9.
22. Mochamat, Cuhls H, Marinova M, et al. A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project. J Cachexia Sarcopenia Muscle. 2016 Jul 16. [Epub before print]
23. Topkan E, Yavuz MN, Onal C, Yavuz AA. Prevention of acute radiation-induced esophagitis with glutamine in non-small cell lung cancer patients treated with radiotherapy: evaluation of clinical and dosimetric parameters. Lung Cancer. 2009;63:393-9.
24. Vinci E, Rampello E, Zanoli L, et al. Serum carnitine levels in patients with tumoral cachexia. Eur J Intern Med. 2005;16:419-23.
25. Kraft M, Kraft K, Gartner S, et al. L-carnitine-supplementation in advanced pancreatic cancer (CARPAN)—a randomized multicentre trial. Nutr J. 2012;11:52.
26. May PE, Barber A, D’Olimpio JT, et al. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg. 2002;183:471-9.
27. Engelen MP, Safar AM, Bartter T, et al. High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer. Ann Oncol. 2015;26:1960-6.
28. Dewey A, Baughan C, Dean T, et al. Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev. 2007;1:CD004597.
29. Murphy RA, Mourtzakis M, Chu QS, et al. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with
nonsmall cell lung cancer receiving chemotherapy. Cancer. 2011;117:1775-82.
30. Miller S, McNutt L, McCann MA, McCorry N. Use of corticosteroids for anorexia in palliative medicine: a systematic review. J Palliat Med. 2014;17:482-5.
31. Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, et al. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2013;3:CD004310.
32. Dev R, Del Fabbro E, Bruera E. Association between megestrol acetate treatment and symptomatic adrenal insufficiency with hypogonadism in male patients with cancer. Cancer. 2007;110:1173-7.
33. Cannabis-In-Cachexia-Study-Group, Strasser F, Luftner D, et al. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006;24:3394-400.
34. Jatoi A, Windschitl HE, Loprinzi CL, et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol. 2002;20: 567-73.
35. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369:1011-22.
36. Crawford J, Prado CM, Johnston MA, et al. Study design and rational for the phase 3 clinical development program of enobosarm, a selective androgen receptor modulator, for the prevention and treatment of muscle wasting in cancer patients (POWER trials). Curr Oncol Rep. 2016;18:37.
37. Garber K. No longer going to waste. Nat Biotechnol. 2016;34:458-61.
38. Loprinzi CL, Kugler JW, Sloan JA, et al. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol. 1999;17:3299-306.
39. Lundholm K, Gunnebo L, Körner U, et al. Effects by daily long term provision of ghrelin to unselected weight-losing cancer patients: a randomized double-blind study. Cancer. 2010;116:2044-52.
40. Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomized, double-blind, phase 3 trials. Lancet Oncol. 2016;17:519-31.
41. Lai V, George J, Richey L, et al. Results of a pilot study of the effects of celecoxib on cancer cachexia in patients with cancer of the head, neck, and gastrointestinal tract. Head Neck. 2008;30:67-74.
42. Reid J, Hughes CM, Murray LJ, et al. Non-steroidal anti-inflammatory drugs for the treatment of cancer cachexia: a systematic review. Palliat Med. 2013;27:295-303.
43. Riechelmann RP, Burman D, Tannock IF, et al. Phase II trial of mirtazapine for cancer-related cachexia and anorexia. Am J Hosp Palliat Care. 2010;27:106-10.
44. Naing A, Dalal S, Abdelrahim M, et al. Olanzapine for cachexia in patients with advanced cancer: an exploratory study of effects on weight and metabolic cytokines. Support Care Cancer. 2015;23:2649-54.
45. Navari RM, Brenner MC. Treatment of cancer-related anorexia with olanzapine and megestrol acetate: a randomized trial. Support Care Cancer. 2010;18:951-6.
46. Reid J, Mills M, Cantwell M, et al. Thalidomide for managing cancer cachexia. Cochrane Database Syst Rev. 2012;4:CD008664.
47. Grande AJ, Silva V, Riera R, et al. Exercise for cancer cachexia in adults. Cochrane Database Syst Rev. 2014;11:CD010804.
48. McMillan DC, Wigmore SJ, Fearon KC, et al. A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss. Br J Cancer. 1999;79:495-500.
49. Madeddu C, Dessi M, Panzone F, et al. Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib +/− megestrol acetate for patients with cancer-related anorexia/cachexia syndrome. Clin Nutr. 2012;31:176-82.
50. Mantovani G, Maccio A, Madeddu C, et al. Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist. 2010;15:200-11.
51. Maccio A, Madeddu C, Gamignanao G, et al. A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecol Oncol. 2012;124:417-25.
52. Del Fabbro E. Current and future care of patients with the cancer anorexia-cachexia syndrome. Am Soc Clin Oncol Educ Book. 2015. e229-37.