CME Palliative care Cancer cachexia 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 anorexia, suggesting that catabolic fatigue component of cancer 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 hypermetabolism (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 interferon- , 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 stress response is also thought bolic rate may be increased, overall (or Surgical Oncology 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 insulin 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 disease 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, heart failure, include anxiety, depression, intestinal synthesis in such patients. Cachectic AIDS, renal failure). It has no agreed obstruction, nausea, vomiting, constipa- cancer patients can also excrete a definition but represents the complex tion, taste alterations and persistent pain. 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 fat, unlike starvation where only fat stores are The mechanisms of cancer-related fatigue Diagnosis initially depleted. In addition, the muscle are unclear. Physiological factors leading wasting 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. Weight loss, 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 • Pancreatic cancer 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 lymphoma 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 dietitian.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 medication). 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 appetite, 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 stimulants tumour burden and good performance mass index (BMI) should be calculated malabsorption 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 parenteral nutrition). elevated C-reactive protein or erythro- antidepressants 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 stimulant 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 attention 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 megestrol acetate 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