sign in sign up
<<
Home , Anorexia (symptom), Cachexia, Fatigue, Wasting

CME Palliative care

Cancer and mechanisms (Fig 1). The cachectic Other cachectic factors patient is analogous to an accelerating Cachexia can occur in the absence of car running out of petrol. The anorexia, suggesting that catabolic component of cachexia reduces mediators produced by tumour or host fuel supply (by ca 300–500 kcal/day) cells are involved in the cancer cachexia whilst accelerated metabolic cycling Grant D Stewart BSc(Hons) MBChB MRCS(Ed), process.9 Experimental cachexia models drives (by ca Surgical Research Fellow suggest pro-inflammatory cytokines, 100–200 kcal/day). There are also the Richard JE Skipworth BSc(Hons) MBChB such as tumour necrosis factor- , inter- direct catabolic effects of muscle proteol- α MRCS(Ed), Surgical Research Fellow leukin (IL)-6, IL-1 and - , can ysis and lipolysis. These changes underlie γ Kenneth CH Fearon MBChB(Hons) MD all play a role. Activation of the neuro- a key paradox of cachexia: whilst meta- FRCS(Glas) FRCS(Ed) FRCS(Eng), Professor of endocrine response is also bolic rate may be increased, overall (or Surgical to be important. Potential mediators total) energy expenditure is decreased Department of Clinical and Surgical Sciences include increased adrenergic activity, ele- due to a fall in physical activity.7 (Surgery), University of Edinburgh, Royal vated cortisol, low and increased Infirmary, Edinburgh activity of the renin-angiotensin system.1 Anorexia With regard to tumour-specific Clin Med 2006;6:140–3 The anorexia component of cancer cachectic factors, proteolysis-inducing cachexia has both a neurohumoral mech- factor (PIF) is produced by tumours and anism due to disturbance of the central excreted in the urine of patients with Background physiological mechanisms controlling cancer cachexia. PIF is thought to Cachexia is a process that food intake8 and a broad raft of clinical contribute to increased muscle break- develops in numerous chronic, end-stage causes. Secondary contributory factors down and decreased muscle protein 10,11 disease processes (eg cancer, , include , , intestinal synthesis in such patients. Cachectic AIDS, renal failure). It has no agreed obstruction, nausea, , constipa- cancer patients can also excrete a definition but represents the complex tion, taste alterations and persistent . lipid-mobilising factor which may metabolic process that occurs in patients contribute to depleted adipose tissue and can be detected in their urine.12 with these conditions.1 Cachectic patients Cancer-related fatigue lose lean muscle mass as well as , unlike where only fat stores are The mechanisms of cancer-related fatigue Diagnosis initially depleted. In addition, the muscle are unclear. Physiological factors leading of cachexia cannot be reversed by to fatigue include anaemia, cancer treat- History and examination are the most increased food intake alone.2,3 Weight ments, tumour bulk and cytokine release. useful tools in making the diagnosis of loss is the symptom most commonly Psychological factors such as depression cachexia and for assessing response to associated with cachexia but there are and anxiety, difficulty sleeping and a therapy. , anorexia and numerous other features (Table 1),1 of low degree of physical functioning also fatigue are the commonest symptoms 4 which fatigue is an important one contribute. reported by advanced cancer patients. (70–100% of cancer patients).4 Cancer cachexia is common. Half of all patients with cancer lose some body Table 1. Features of Table 2. The commonest malignancies in which cachexia.1 cachexia develops as part of the clinical course.6 weight; one-third lose more than 5% of their original body weight and up to 20% Patients with Weight loss of all cancer deaths are caused directly by • Malignancy cachexia (%) cachexia (through immobility, cardiac/ • Anorexia Gastric cancer 85 respiratory failure).5 Cachexia is Fatigue • 83 particularly prominent in solid tumours Muscle wasting • Non-small cell lung cancer 61 of the upper gastrointestinal (GI) tract Aesthesia • Small cell lung cancer 57 and lung (Table 2). Weight loss is a prog- Anaemia nostic factor in the survival of cancer • Prostate cancer 56 Oedema patients and is associated with a reduced • Colon cancer 54 response to chemoradiotherapy.2 Unfavourable non-Hodgkin’s 48 Sarcoma 40 Pathogenesis Acute non-lymphocytic leukaemia 39 Breast cancer 36 Cancer cachexia is a complex metabolic Favourable non-Hodgkin’s lymphoma 31 disturbance involving numerous

140 Clinical Medicine Vol 6 No 2 March/April 2006 CME Palliative care

Homeostatic delay gastric emptying and worsen Cytokine response anorexia). Formal nutritional counselling network should be sought from a .8 Provision of energy and protein-dense Neuroendocrine HOST oral feeds (1.5 kcal/ml) can be useful, but TUMOUR response METABOLIC ABNORMALITIES these must not replace normal food. One way of optimising nutritional Tumour- input is for the patient to take a fixed specific dose of supplements at regular times (as product(s) Treatment with a prescription ). Patients should aim to take 200–400 ml of Fig 1. Mediator pathways implicated in cancer cachexia. Different pathways supplements daily (300–600 kcal), contribute to a variable extent, depending in part on both host and tumour. accepting that this will suppress some normal food intake but providing an overall gain of 200–400 kcal/day. Symptoms associated with declining will provide the ideal background for food intake are key warning signals optimisation of , function of the Artificial nutritional support (eg loss of appetite, early satiety, GI tract and treatment of the metabolic nausea/vomiting and taste/smell alter- disorder:1 It is sometimes justified to provide artifi- ations). Weight and height should be • nausea/vomiting can be controlled cial nutritional support (either enteral or recorded. Weight loss greater than 5% with regular anti-emetics (or surgery parenteral) in advanced cancer patients suggests developing cachexia, while for mechanical obstruction) when the main cause of cachexia is above 15% suggests the patient is well • early satiety is eased by gastric reduced food intake and where limited advanced into the cachectic state. Body tumour burden and good performance mass index (BMI) should be calculated is treated with status justify such invasive forms of sup- (BMI <18 indicates significant under- • pancreatic enzyme supplements portive therapy. It is at all times impor- nutrition). Oedema and ascites are tant to balance the benefits to a patient’s constipation is relieved with laxatives common, and this fluid retention may • quality of life with the problems of mask the severity of underlying weight • pain should be controlled with the artificial nutritional support (eg time in loss. Plasma albumin concentration may minimum of sedation hospital, complications of central venous be low and, if accompanied by an • depression may be treated with access for total ). elevated C-reactive protein or erythro- and counselling. cyte sedimentation rate, reflects an Severe anorexia underlying systemic inflammatory Diet response that occurs in many malig- In patients complaining of severe nancies and which contributes to the Food intake can be improved by pro- anorexia or early satiety an appetite weight-losing process.13 viding small, frequent energy-dense meals may provide symptomatic that are easy to eat (eg dairy products, improvement. Moderate alcohol con- Management ice cream). Patients should eat in pleasant sumption before and during a meal can surroundings and be given to help. Early satiety will respond The management of cachexia requires a the presentation of food. Extremes of temporarily to the use of prokinetic dedicated multidisciplinary team taste/smell should be avoided, as should agents (eg metoclopramide). High doses approach: physician, surgeon, general meals with very high fat contents (which of progesterones (eg or practitioner, nurse specialist and dietitian. Cachexia is a chronic problem requiring repeated re-evaluation as the Initiating Compensatory clinical condition of the patient changes factors changes (Fig 2). Intervention is not usually bene- Normal Mild Moderate Severe Death ficial for a patient who has become cachexia cachexia cachexia severely wasted, is bedridden and within ▲ weeks of dying, but such patients may be helped by a course of steroids to improve mood and appetite. Early recognition Weight Below Muscle Reduced loss ideal body wasting survival and prophylactic measures are better weight obvious than trying to reverse an advanced situa- tion. Control of the following symptoms Fig 2. The cancer cachexia journey.

Clinical Medicine Vol 6 No 2 March/April 2006 141 CME Palliative care

medroxyprogesterone) improve appetite known both to downregulate pro- psychosocial support.4 If fatigue proves a in about 70% of patients and can result inflammatory cytokines and to block the problem or occurs in tandem with in increased food intake and weight gain effects of tumour-specific cachectic anaemia, there is evidence to suggest that in approximately 20%.14 However, this factors (eg PIF). EPA can be provided recombinant erythropoietin (EPO) may weight gain is often due to oedema or either as fish oil capsules or as a combina- be beneficial.16 However, recent evidence increased fat deposition rather than tion therapy by being incorporated in a has also raised the issue of of . Together with progesta- high protein and calorie oral feed tumour progression with EPO in gens, induce a temporary (eg Prosure®). This combination has been patients with head and neck cancer.17 effect on appetite, performance status shown to arrest nutritional decline and Finally, it is important to recognise and the patient’s feeling of physical improve physical activity levels but not to that, although some patients with well-being. These changes are limited to cause weight gain.7,15 cachexia can be improved, the goals of a few weeks. Due to the greater toxic Drugs with a direct anabolic effect intervention are often to stabilise the side effects associated with corticos- (eg testosterone) have been suggested for situation or attenuate decline. Patients teroids, progestagens are the current the treatment of cachexia, and anabolic should be encouraged to keep active to front-line agents used to treat anorexia in steroids have been shown to improve prevent muscle wasting due to immobil- patients with cancer. patients’ weight without any apparent isation. Patients with limited energy adverse effect.1 reserves/physical activity capacity should Metabolic management be advised to make most efficient use of Fatigue the energy they have (focusing on meal The metabolic management of patients times and social interaction). Advice with cachexia should focus on down- Management of cachexia as outlined from occupational therapy and provision regulating the systemic inflammatory above can improve fatigue.4 Decreased of physical aids in the home may enhance response to malignancy. Non-steroidal activity in order to conserve energy may quality of life. anti-inflammatory drugs together with lead to deconditioning and decreased Unfortunately, no single therapy is peptic ulcer prophylaxis have been shown tolerance. Exercise regimens, effective in all patients. Even with to prolong survival of cancer patients, such as walking programmes, can reduce optimal management only a proportion reduce systemic and the level of fatigue experienced by of patients will respond to therapy with preserve body fat.13 Eicosapentaenoic acid patients.4 Fatigue can also be lessened by weight stabilisation and possible transla- (EPA), a natural component of fish oil, is attempting to reduce stress and increase tion into stable or improved physical

Key Points Table 3. Possible future therapies for cancer cachexia. Therapy Details

Cancer cachexia has no agreed (eg ) Affect cytokine production definition but represents a wasting Stops weight loss in unresectable pancreatic cancer by syndrome involving loss of muscle downregulating pro-inflammatory cytokines and fat caused directly by tumour factors and/or indirectly by Suramin Inhibits cachexia by inhibition of TNF-α and IL-6 abnormal host response to tumour ATP infusion Modestly increases strength and slows decline in quality presence of life Cytokine traps Block cytokines (no clinical data yet) Patients with cancer cachexia develop chronic negative energy and which increases food intake and stops protein balance driven by a weight loss in animal models combination of reduced food intake Branched chain amino acids Improve energy levels (secondary to anorexia) and Increases food intake and mood metabolic change Melatonin In combination with fish oils stabilises weight The management of cachexia requires Nitric oxide and Reduce tumour growth and improve anorexia a dedicated multidisciplinary team β-blockers Reduce resting energy expenditure and potentially reduce and is best commenced earlier weight loss rather than later ACEIs Angiotensin II can stimulate muscle breakdown; hence No single or combined treatment ACEIs can potentially attenuate this weight loss strategy will be successful in all β-hydroxy-β-methylbutyrate Increases lean body mass patients plus arginine and

ACEI = angiotensin-converting enzyme inhibitor; ATP = adenosine 5’-triphosphate; IL = interleukin; KEY WORDS: anorexia, cachexia, TNF = tumour necrosis factor. cytokines, fatigue

142 Clinical Medicine Vol 6 No 2 March/April 2006 CME Palliative care function/quality of life. However, the and proteolytic factors by a murine limited benefits of active management tumor-producing cachexia in the host. are no justification to ignore or fail to Cancer Res 1987;47:5919–23. 10 Lorite MJ, Cariuk P, Tisdale MJ. Induction treat reversible factors associated with of muscle protein degradation by a tumour cachexia. factor. Br J Cancer 1997;76:1035–40. 11 Wigmore SJ, Todorov PT, Barber MD, Ross JA et al. Characteristics of patients with The future pancreatic cancer expressing a novel cancer cachectic factor. Br J Surg 2000;87:53–8. Over the last decade there has been an 12 Hirai K, Hussey HJ, Barber MD, Price SA, explosion of research into the mecha- Tisdale MJ. Biological evaluation of a nisms of cancer cachexia and potential lipid-mobilizing factor isolated from the targets for treatment. Table 3 outlines urine of cancer patients. Cancer Res possible future therapies currently being 1998;58:2359–65. 13 Deans C, Wigmore SJ. Systemic inflamma- evaluated. Clinical trials evaluating tion, cachexia and prognosis in patients therapies for cancer cachexia patients are with cancer. Review. Curr Opin Clin Nutr hampered by patient heterogeneity, Metab Care 2005;8:265–9. difficulty in defining end-points, mild to 14 Maltoni M, Nanni O, Scarpi E, Rossi D et al. moderate activity of combination High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a regimens, patient attrition and cost. Such systematic review of randomised clinical problems need to be addressed actively trials. Ann Oncol 2001;12:289–300. by major research initiatives if there is to 15 Fearon KC, Von Meyenfeldt MF, Moses AG, be progress in management of this Van Geenen R et al. Effect of a protein and distressing syndrome. energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double Conflicts of interest blind trial. Gut 2003;52:1479–86. 16 Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld None. J et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of References Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002; 1MacDonald N, Easson AM, Mazurak VC, 20:4083–107. Dunn GP, Baracos VE. and 17 Henke M, Laszig R, Rube C, Schafer U et al. managing cancer cachexia. Review. J Am Erythropoietin to treat head and neck Coll Surg 2003;197:143–61. cancer patients with anaemia undergoing 2Tisdale MJ. Cachexia in cancer patients. radiotherapy: randomised, double-blind, Review. Nat Rev Cancer 2002;2:862–71. placebo-controlled trial. Lancet 2003;362: 3Body JJ. The syndrome of anorexia- 1255–60. cachexia. Curr Opin Oncol 1999;11:255–60. 4Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancer-related fatigue in adults. Review. Lancet 2003;362:640–50. 5Tisdale MJ. Biology of cachexia. Review. JNatl Cancer Inst 1997;89:1763–73. 6DeWys WD, Begg C, Lavin PT, Band PR et al. Prognostic effect of weight loss prior to in cancer patients. Eastern Cooperative Oncology Group. Am J Med 1980;69:491–7. 7Moses AW, Slater C, Preston T, Barber MD, Fearon KC. Reduced total energy expendi- ture and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. Br J Cancer 2004;90:996–1002. 8Laviano A, Meguid MM, Rossi-Fanelli F. Cancer anorexia: clinical implications, pathogenesis, and therapeutic strategies. Review. Lancet Oncol 2003;4:686–94. 9Beck SA, Tisdale MJ. Production of lipolytic

Clinical Medicine Vol 6 No 2 March/April 2006 143