The cachexia syndrome is seen across a wide range of chronic diseases and is especially evident in the cancer patient. This weight loss causes difficulties for the patient and clinician as it reduces quality of life (QoL) and also reduces tolerance of treatment. Weight loss is significantly associated with cancer morbidity and mortality.1,2 It is believed that up to 20 % of cancer patients die as a direct consequence of cachexia and that up to 50 % of cancer patients die with some degree of cachexia.3,4 The incidence of cachexia varies with tumour type, being lowest in sarcoma and breast cancers, whereas 80–90 % of pancreatic and gastric cancer patients experience weight loss.5 In cachexia, weight loss is attributed to a loss of both adipose tissue and skeletal muscle. However, it is the skeletal muscle wasting that likely contributes to excess morbidity and mortality in cancer patients.6 An international consensus recently defined cancer cachexia as a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. The pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism.7 A combination of primary and secondary anorexia, hyper-metabolism, hyper-catabolism and hypo-anabolism act together to aggravate weight loss. It is now recognised that cachexia exists through a range of phases (precachexia, cachexia syndrome and refractory cachexia) and it may be that even within the cachexia syndrome itself the more severe stages are less amenable to treatment and reversal. Clearly once a patient is confined to bed and moribund, the chances of reversal in muscle mass by multimodal rehabilitation are virtually gone. The greatest potential for prevention, recognition and reversal therefore lies with the precachectic state and during early cachexia syndrome. According to international consensus, pre-cachexia may be recognised before any significant involuntary weight loss (i.e. >5 %) by clinical and metabolic signs such as anorexia and impaired glucose tolerance.8 Patients with >5 % loss of stable bodyweight over the past 6 months, or a body mass index (BMI) <20 kg/m2 and ongoing weight loss of more than 2 %, or sarcopenia and ongoing weight loss of more than 2 %, but have not entered the refractory stage, are classified as having cachexia.7 Refractory cachexia is characterised by a low performance status (World Health Organization [WHO] score 3 or 4) and a life expectancy of less than 3 months. This is an actively catabolic state where alleviation of symptoms is the mainstay of intervention. Treating cachexia posses a difficult challenge to the cancer multidisciplinary team. The heterogeneity in presentation of cachexia has, in part, delayed formal descriptive terminology. In addition, there is no validated classification of pre-cachexia. Moreover, although there are a range of biomarkers that might be used in this context (e.g. circulatory interleukin [IL]-6 or C-reactive protein [CRP] levels), the lack of longitudinal studies to integrate clinical classification with biological mechanism coupled with the complexity and duration of modern oncological management (chemotherapy, surgery, radiotherapy) makes this a difficult task. Risk Stratification Cancer cachexia is a continuum (pre-cachexia, cachexia syndrome, and refractory cachexia); however, not all patients traverse the entire spectrum. In fact it is plausible that some patients demonstrate protective mechanisms against progression. The risk of progression varies and depends on numerous clinical factors that should be taken into account when risk stratifying and counselling patients about weight loss in cancer and possible interventions. Tumour type, tumour stage, co-morbidities, systemic inflammation, low food intake and response to anti-cancer therapy all play roles in determining whether a patient will be at risk of cachexia progression. Depending upon the tumour type, weight loss occurs in 30 to 80 % of cancer patients. Patients with pancreatic or gastric cancer have the highest frequency of weight loss, while patients with non-Hodgkin’s lymphoma, breast cancer, acute non-lymphocytic leukaemia and sarcomas have the lowest frequency of weight loss.9 Cross-sectional imaging analysis of skeletal muscle depletion is a powerful prognostic indicator. Utilising staging computed tomography (CT) scans and routinely collected patient clinical information, analysis of images can demonstrate previously occult muscle depletion that carries with it a poorer overall prognosis and likelihood to progress in cachexia severity.10 Measurements of systemic inflammation (Glasgow Prognostic Scale) have been shown to be reliable predictors of survival, independent of tumour stage, performance status, treatment (active or palliative) and has been shown in a variety of advanced common solid tumours.11 Knowing that cachexia is a metabolic process driven by the systemic inflammatory response the utilisation of such scores to risk stratify progression of cachexia seems intuitive. Clearly the most pertinent of these factors in risk stratification will be response to oncological treatment and therefore disease progression, for if the disease picture progresses the patient will almost certainly definitely succumb to weight loss. Moreover, as the clinical picture evolves through the treatment phase, the necessity to continually risk stratify and treat is heightened (see Figure 1) A Complex Multidimensional Problem The tumour’s role in the aetiology of cachexia includes the local secretion of pro-inflammatory cytokines (tumourkines) that initiate the host systemic inflammatory response/acute phase protein response (APPR),12 and the production of pro-cachectic factors that have direct catabolic effects on host tissues.13,14 Host mechanisms involve an aberrant response to the tumour’s presence, and include activation of both the APPR12 and the neuroendocrine stress response.15,16 The net result of such host–tumour interaction is an alteration in body composition, a major feature of which is a severe and specific loss of skeletal muscle mass.17 Besides the primary role of fat in storing excess lipids, adipose tissue is a major endocrine organ secreting hormones and cytokines (adipokines) that modulate appetite and nutrient metabolism. Therefore, alterations in adipose tissue mass can have significant effects on whole-body energy homeostasis.18 In the setting of cancer cachexia, there is emerging evidence that inflammatory signals from tumours intersect with the normal crosstalk between adipose tissue and other organs, leading to impaired energy balance and catabolism of fat and muscle.19
Prevention of Cachexia in Cancer
European Oncology & Haematology 2013;9(1):46–50
Abstract:The cachexia syndrome is seen across a wide range of chronic diseases and is especially evident in the cancer patient. Weight loss causes difficulties for the patient and clinician alike as it reduces quality of life and also reduces tolerance of anti-cancer therapy. It is now recognised that cachexia exists through a range of phases (pre-cachexia, cachexia syndrome and refractory cachexia); however, not all patients traverse the entire spectrum. The risk of progression varies and depends on numerous clinical factors that should be taken into account when risk stratifying and counselling patients about weight loss and possible interventions. Tumour type, tumour stage, co-morbidities, systemic inflammation, low food intake and response to anti-cancer therapy all play roles in determining whether a patient will be at risk of cachexia progression. The acknowledgement that multiple components are responsible for the development of cachexia has led to the view that any cachexia intervention strategy should target all components i.e. multimodal therapy for a multimodal problem. There is growing acceptance that anti-cachexia therapy must form a major component of supportive oncology and be given along with anti-cancer therapy. The critical concern remains when to start such treatment and in which individuals?
Keywords: Cachexia, cancer, weight loss, inflammation
Disclosure: The authors have no conflicts of interest to declare.
Received: December 28, 2012 Accepted April 03, 2013 Citation European Oncology & Haematology 2013;9(1):46–50
Correspondence: Ross W Stewart, Clinical Research Fellow Department of Clinical Surgery, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK. E: Ross.email@example.com
- R ennie MJ, Anabolic resistance in critically ill patients, Crit Care Med, 2009;37(Suppl. 10):S398–9.
- Brandt C, Pedersen BK, The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases, J Biomed Biotechnol, 2010;2010:520258.
- von Haehling S, Anker SD, Cachexia as a major underestimated and unmet medical need: facts and numbers, J Cachexia Sarcopenia Muscle, 2010;1(1):1–5.
- Inagaki J, Rodriguez V, Bodey GP, Proceedings: Causes of death in cancer patients, Cancer, 1974;33(2):568–73.
- Dewys WD, et al., Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group, Am J Med, 1980;69(4):491–7.
- T sai, S, Importance of lean body mass in the oncologic patient, Nutr Clin Pract, 2012;27(5):593–8.
- Fearon K, et al., Definition and classification of cancer cachexia: an international consensus, Lancet Oncol, 2011;12(5):489–95.
- Honors MA, Kinzig KP, The role of insulin resistance in the development of muscle wasting during cancer cachexia, J Cachexia Sarcopenia Muscle, 2012;3(1):5–11.
- DeWys WD, Weight loss and nutritional abnormalities in cancer patients: Incidence. In: Fearon KC (editor), Clinics in Oncology. 2. Vol. 5, London: Saunders, 1986;251–61.
- M artin L, et al., Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index, J Clin Oncol, 2013;31(12):1539–47.
- M cMillan DC, An inflammation-based prognostic score and its role in the nutrition-based management of patients with cancer, Proc Nutr Soc, 2008;67(3):257–62.
- Deans, DA, et al., Elevated tumour interleukin-1beta is associated with systemic inflammation: A marker of reduced survival in gastro-oesophageal cancer, Br J Cancer, 2006;95(11):1568–75.
- T odorov P, et al., Characterization of a cancer cachectic factor, Nature, 1996;379(6567):739–42.
- Hirai K, et al., Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients, Cancer Res, 1998;58(11):2359–65.
- Barber MD, et al., The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer, Br J Cancer, 2004;90(6):1129–32.
- Costelli P, et al., IGF-1 is downregulated in experimental cancer cachexia. Am J Physiol Regul Integr Comp Physiol, 2006;291(3):R674–83.
- Fearon KC, Preston T, Body composition in cancer cachexia, Infusionstherapie, 1990;17 Suppl. 3:63–6.
- G alic S, Oakhill JS, Steinberg GR, Adipose tissue as an endocrine organ, Mol Cell Endocrinol, 2010;316(2):129–39.
- Johns N, Greig C, Fearon KC, Is tissue cross-talk important in cancer cachexia?, Crit Rev Oncog, 2012;17(3):263–76.
- Smith KL, Tisdale MJ, Mechanism of muscle protein degradation in cancer cachexia, Br J Cancer, 1993;68(2):314–18.
- Bodine, SC, et al., Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo, Nat Cell Biol, 2001;3(11):1014–19.
- Blum D, et al., Cancer cachexia: a systematic literature review of items and domains associated with involuntary weight loss in cancer. Crit Rev Oncol Hematol, 2011;80(1):114–44.
- T isdale MJ, Mechanisms of cancer cachexia, Physiol Rev, 2009;89(2):381–410.
- Wigmore SJ, et al., Cytokine regulation of constitutive production of interleukin-8 and -6 by human pancreatic cancer cell lines and serum cytokine concentrations in patients with pancreatic cancer, Int J Oncol, 2002;21(4):881–6.
- Wigmore SJ, et al., Endogenous production of IL-8 by human colorectal cancer cells and its regulation by cytokines, Int J Oncol, 2001;18(3):467–73.
- O liff A, et al., Tumors secreting human TNF/cachectin induce cachexia in mice, Cell, 1987;50(4):555–63.
- A rgiles JM, et al., Catabolic mediators as targets for cancer cachexia, Drug Discov Today, 2003;8(18):838–44.
- A charyya S, et al., Cancer cachexia is regulated by selective targeting of skeletal muscle gene products, J Clin Invest, 2004;114(3):370–78.
- G uttridge DC, et al., NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science, 2000;289(5488):2363–6.
- R uan H, et al., Tumor necrosis factor-alpha suppresses adipocytespecific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory, Diabetes, 2002;51(5):1319–36.
- Hotamisligil GS, Mechanisms of TNF-alpha-induced insulin resistance, Exp Clin Endocrinol Diabetes, 1999;107(2):119–25.
- A rgiles JM, Lopez-Soriano FJ, The role of cytokines in cancer cachexia, Med Res Rev, 1999;19(3):223–48.
- Barreiro E, et al., Both oxidative and nitrosative stress are associated with muscle wasting in tumour-bearing rats, FEBS Lett, 2005;579(7):1646–52.
- Carbo N, et al., Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats, Br J Cancer, 2000;83(4):526–31.
- T an BH, Fearon KC, Cytokine gene polymorphisms and susceptibility to cachexia, Curr Opin Support Palliat Care, 2010;4(4):243–8.
- G lass DJ, Signalling pathways perturbing muscle mass, Curr Opin Clin Nutr Metab Care, 2010;13(3):225–9.
- Bodine SC, et al., Identification of ubiquitin ligases required for skeletal muscle atrophy, Science, 2001;294(5547):1704–8.
- G omes MD, et al., Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy, Proc Natl Acad Sci U S A, 2001;98(25):14440–45.
- T rendelenburg AU , et al., TA K-1/p38/nNFkappaB signalling inhibits myoblast differentiation by increasing levels of Activin A, Skelet Muscle, 2012;2(1):3.
- Zimmers TA , et al., Induction of cachexia in mice by systemically administered myostatin, Science, 2002;296(5572):1486–8.
- A versa Z, et al., Changes in myostatin signalling in non-weightlosing cancer patients, Ann Surg Oncol, 2012;19(4):1350–56.
- T isdale MJ, Cachexia in cancer patients, Nat Rev Cancer, 2002;2(11):862–71.
- Inui A, Cancer anorexia-cachexia syndrome: are neuropeptides the key?, Cancer Res, 1999;59(18):4493–501.
- P lata-Salaman CR, Central nervous system mechanisms contributing to the cachexia-anorexia syndrome, Nutrition, 2000;16(10):1009–12.
- O para EI, et al., Correlation between food intake and CSF IL-1 alpha in anorectic tumor bearing rats, Neuroreport, 1995;6(5):750–52.
- L aviano A, et al., Effects of intra-VMN mianserin and IL-1ra on meal number in anorectic tumor-bearing rats, J Investig Med, 2000;48(1):40–48.
- Bado A, et al., The stomach is a source of leptin, Nature, 1998;394(6695):790–93.
- . M oses AG, et al., Leptin and its relation to weight loss, ob gene expression and the acute-phase response in surgical patients., Br J Surg, 2001;88(4):588–93.
- Cowley MA, et al., Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus, Nature, 2001;411(6836):480–84.
- T oshinai K, et al., Ghrelin-induced food intake is mediated via the orexin pathway, Endocrinology, 2003;144(4):1506–12.
- M atsumura K, et al., Central ghrelin modulates sympathetic activity in conscious rabbits, Hypertension, 2002;40(5):694–9.
- Shimizu Y, et al., Increased plasma ghrelin level in lung cancer cachexia, Clin Cancer Res, 2003;9(2):774–8.
- T an BH, et al., Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer, Clin Cancer Res, 2009;15(22):6973–9.
- Baracos VE, et al., Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis, Am J Clin Nutr, 2010;91(4):1133S–1137S.
- Skipworth RJ, et al., Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer, Support Care Cancer, 2011;19(3):391–401.
- M oses AW, et al., Reduced total energy expenditure 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(5):996–1002.
- Wolfe RR, The underappreciated role of muscle in health and disease, Am J Clin Nutr, 2006;84(3):475–82.
- Baldwin C, et al., Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis, J Natl Cancer Inst, 2012;104(5):371–85.
- M cCarthy HD, et al., Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations, Eur J Pharmacol, 1994;265 (1–2):99–102.
- M antovani G, et al., Medroxyprogesterone acetate reduces the in vitro production of cytokines and serotonin involved in anorexia/ cachexia and emesis by peripheral blood mononuclear cells of cancer patients, Eur J Cancer, 1997;33(4):602–7.
- Berenstein EG, Ortiz Z, Megestrol acetate for the treatment of anorexia-cachexia syndrome, Cochrane Database Syst Rev, 2005(2):CD004310.
- Y avuzsen, T, et al., Systematic review of the treatment of cancer-associated anorexia and weight loss, J Clin Oncol, 2005;23(33):8500–11.
- Wigmore SJ, et al., The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer, Nutrition, 1996;12(1 Suppl.):S27–30.
- van der Meij BS, et al., Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT, Eur J Clin Nutr, 2012;66(3):399–404.
- van der Meij BS, et al., Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment, J Nutr, 2010;140(10):1774–80.
- G ordon JN, et al., Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial, Gut, 2005;54(4):540–45.
- . Fanelli M, et al., Thalidomide: a new anticancer drug?, Expert Opin Investig Drugs, 2003;12(7):1211–25.
- R eid J, et al., Thalidomide for managing cancer cachexia. Cochrane Database Syst Rev, 2012;4:CD008664.
- Bayliss TJ, et al., A humanized anti-IL-6 antibody (ALD518) in nonsmall cell lung cancer, Expert Opin Biol Ther, 2011;11(12):1663–8.
- P rado CM, et al., Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma, Br J Cancer, 2012;106(10):1583–6.
- Wu C, et al., Disrupting Cytokine Signalling in Pancreatic Cancer: A Phase I/II Study of Etanercept in Combination With Gemcitabine in Patients With Advanced Disease, Pancreas, 2013;42(5):813–18.
- Wiedenmann B, et al., A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia, J Support Oncol, 2008;6(1):18–25.
- G arcia, JM, Polvino WJ, Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers, Oncologist, 2007;12(5):594–600.
- G arcia JM, Friend J, Allen S, Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study, Support Care Cancer, 2013;21(1):129–37.
- Dalton JT, et al., The selective androgen receptor modulator GTx- 024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial, J Cachexia Sarcopenia Muscle, 2011;2(3):153–61.
- M cPherron AC, Lawler AM, Lee SJ, Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member, Nature, 1997;387(6628):83–90.
- Zhou X, et al., Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival, Cell, 2010;142(4):531–43.
- Fearon KC, Cancer cachexia: developing multimodal therapy for a multidimensional problem, Eur J Cancer, 2008;44(8):1124–32.
- M accio A, 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(3):417–25.
- M adeddu C, 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(2):176–82.
- A wad S, et al., Marked changes in body composition following neoadjuvant chemotherapy for oesophagogastric cancer, Clin Nutr, 2012;31(1):74–7.
Keywords: Cachexia, cancer, weight loss, inflammation