Feature CaChexia

Cancer induced cachexia (CIC) is a syndrome of muscle wasting accompanied by anorexia with or without loss of adipose tissue. Underlying CIC is a complex interaction of proinflammatory cytokines that act centrally on the hypothalamus and peripherally to increase catabolism and resting energy expenditure, while decreasing protein synthesis. The presence of CIC is an important prognostic indicator in cancer patients. Nutritional strategies utilized by naturopathic doctors have been proven to slow down this condition, induce weight gain, and improve cancer related outcomes. Such therapies include high EPA fish oil, melatonin, L-carnitine, and branched chain amino acids and/ or whey protein. Cancer induced cachexia (CIC) is a multifactorial syndrome characterized by loss of skeletal muscle, accompanied by anorexia and (sometimes) loss of adipose tissue (Fearon 2011). A number of underlying metabolic derangements are implicated in CIC, and associated symptoms may include malnutrition, anemia, fatigue, and decreased muscle strength & impaired physical function. Cachexia, defined as a loss of body weight greater than 5%, leads to poor performance, poor quality of life, increased complications, and higher mortality rate among cancer patients (Burckart 2010, Fearon 2011). Targeted nutritional interventions are an important part of cachexia prevention and management. This paper reviews several key agents that can improve outcomes in cachexia, among them fish derived omega-3 fatty acids (EPA and DHA), melatonin, branched chain amino acids (BCAAs), l-carnitine, and whey protein. Cachexia is a therapeutic target of high importance in cancer patients due to its strong prognostic significance (Burckhart 2010). It is widely recognized that cachexia leads to poorer cancer outcomes, and is reported as the direct cause of death in up to 20-40% of cancer patients (Fox 2009). Recently, Yang et al found that, among a large cohort of lung cancer patients (n=14,751), those who showed weight loss (15.8% average) at time of diagnosis had significantly shorter survival time compared to those who did 071-076.IHP_Rouchotas.indd 65 12-08-15 10:22 AM 66 | IHP September 2012 } ihpmagazine.com Feature CaChexia not, 6.4 versus 9.2 mo, P < 0.001 (2011). Similar results have been found for other cancers as well, including colorectal cancer and pancreatic cancer, with up to two fold greater increase in risk of death (HR = 2.26; CI 1.18-4.32; P = 0.014) reported (Bachmann 2008, Thoreson 2012). Some teams have used serum albumin as a marker of malnutrition and cachexia, and low levels have been associated with decreased survival in ovarian, breast, and other cancers (Asher 2011, Lis 2003, Polterauer 2010). Cancer related weight loss is associated with decreased tolerance to anticancer therapy, and significantly predicts toxicity from cancer treatment (Fearon 2011, Ross 2004). Naito found that cachexia is associated with altered oxycodone pharmacokinetics due to decreased albumin levels (an important drug binding and transporting protein), resulting in increased levels of free drug and increased incidence of central adverse reactions (2012). Despite this, cachexia remains under-recognized in patients, and under-treated as a clinical entity (Churm 2009, Spiro 2006). The molecular mechanisms underlying CIC are still being elucidated, however, pro-inflammatory cytokines such as IL-1, IL-2, IL-6, interferon gamma and TNF α have a key role in mediating cancer cachexia (Macdonald 2003). IL-6 is a key cytokine in iniating multiple proinflammatory pathways including the acute phase response, and is known to be produced by the tumor microenvironment (Oshima 2012, Zamarron 2011). The inflammatory basis of CIC distinguishes it from age related sarcopenia or frank starvation (Pepersack 2011), and presents the therapeutic rationale for intervention with agents such as EPA, NSAIDS, and celecoxib, a COX-2 inhibitor. Ultimately, these pro-inflammatory cytokines initiate a cascade of events in the hypothalamus and peripherally that results in detrimental metabolic changes, including increased catabolism (proteolysis and lipolysis) and resting energy expenditure, reduced muscle protein synthesis, and anorexia (Burckart 2010). According to a more simple summation by Fearon, “The pathophysiology [of cachexia] is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism” (2011). Various definitions of CIC have been used. Two recent sets of diagnostic criteria are outlined in Table 1. These criteria by Fearon are recently proposed in a consensus statement published in Lancet Oncology (2011), while those by Evans are older and incorporate biochemical parameters (2008). Recently, work has been done to establish staging of cachexia. Precachexia is defined as “weight loss ≤5%, with anorexia and metabolic changes” (Fearon 2011). Cachexia is as defined below (Fearon 2011). Refractory cachexia is variable in terms of severity, with the presence of procatabolic state; cancer not responsive to anticancer treatment; low performance score; and <3 months expected survival (Fearon 2011). A proposed algorithm in terms of assessment and management is adapted in Figure 1. Fearon 2011 Evans 2008 1) Weight loss of at least 5% over the past 6 months; OR 2) BMI <20 kg/m2 and weight loss of at least 2%; OR 3) Loss of appendicular skeletal muscle mass consistent with sarcopenia as determined by DEXA or CT scan or BIA assessment 1) Weight loss of at least 5% in 12 months or less, (or BMI <20kg/ m2); AND 2) 3 of 5 from: i) Decreased muscle strength ii) Fatigue iii) Anorexia iv) Low fat-free mass index v) Abnormal biochemistry: Increased inflammatory markers (CRP, IL-6), Anemia (Hb < 12 g/dL), Low serum albumin (< 3.2 g/dL) Table 1: Diagnostic Criteria for Cancer Induced Cachexia Note: For Evans, the criteria from both 1) and 2) must be met.