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.stewart@ed.ac.uk

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
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Keywords: Cachexia, cancer, weight loss, inflammation