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Nutritional complications in cancer 2

Cancer is a major public health problem in developed and developing countries Currently, one in four deaths in the United States is due to cancer It isprojected that by the year 2020, cancer incidence willdouble worldwide 3

Malnutrition is observed in patients with cancer, and nutrition status is an important prognostic factor inpatients with cancerMalnutrition and weight loss Often contribute to the death of patients with cancer . Unfortunately , these issues persist despite decades of basic and clinical research 4

Attributable Risk of Nutrition in Cancer In 1981, Doll and Peto published a widely quoted estimatethat 35% of all cancer deaths may be avoided by changes in diet. Willett updated this estimate, narrowing theconfidence interval but still concluding that about 32% ofall cancer in the United States may be avoided by dietarymodifications (range, 20% to 42% ) 5

Prevalence and Significance: Undernutrition Anorexia and weight loss are frequent findings in patients with cancer. As many as 40% of patients with cancer present with weight loss , and the prevalence of the cancer cachexia syndrome (CCS)is as high as 80% in those with advanced malignanciesThe extent of weight loss at the time of diagnosis is of prognostic significance. For any given tumor type,survival is shorter in patients with significant pretreatment weight loss6

Early recognition of these consequences of weight loss may afford the best opportunity to prevent the debilitating consequences. These issues may be especially problematic in children and the elderly7

A study estimated a fivefold increase in mortality in underweight patients (body mass index [BMI] 18.5 kg/m2) undergoing major intra-abdominal cancer surgery. In fact, some patients may not be candidates for potentially curative cancer surgery because of the overwhelming risk of life-threatening complications as a result of malnutrition8

Causes of Malnutrition in Patients with Cancer Multiple metabolic and cytokine -induced changes, andclinical factors contribute to the development of malnutrition in patients with cancer 9

Anorexia is a prominent contributor to weight loss in many patients with cancer Anorexia is not usually the primary cause of weight loss; it is a secondary effect that contributes to the downward cycle often observed in patients with cancer who lose weightthe perceived anorexia is actually an adaptive decrease of food intake in response to weight loss . Therefore, merely telling patients to eat more is unlikely to reverse thepresence of CCS10

Other factors that contribute to weight loss in patients with cancer include mechanical factors, the side effects of cancer therapy, and psychosocial factors. The psychological factors associated with cancer that may alter food intake include pain, anxiety, depression, and social isolation.(behavior therapy) Mechanical causes may be a direct effect of tumor,or may relate to complications of therapy(surgery)11

Tumors may cause obstruction of the gastrointestinal (GI) tract. cancer surgery may be effects on nutrition status, nutrient absorption, and fluid and electrolyte balance . Symptoms that relate to these mechanical issues include alterations in taste, early satiety, pain, cramps, vomiting, diarrhea, and constipation ,all of which may exacerbate anorexia12

Cancer treatments may induce anorexia and weight loss The postoperative state is invariably accompanied by a temporary catabolic state and decreased nutrient intake Chemotherapyoften induces transient nausea and vomiting or injuryto GI mucosa with resultant stomatitis, mucositis , diarrhea, and/or typhlitis 13Signs and symptoms of typhlitis may include diarrhea, a distended abdomen, fever, chills, nausea, vomiting, and abdominal pain or tenderness

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Radiation therapy can cause acute GI injury It also may cause chronic radiation enteritis with malabsorption and stricture formation. 15

MODES OF NUTRIENT–CANCER INTERACTION In 1930, Warburg noted that cancer cells rely mostly on conversion of glucose into lactate rather than mitochondrial oxidation for energy production even in the presence of adequate oxygen supply conversion of glucose into lactate, combinedwith suppression of mitochondrial function, is the most fundamental metabolic change in malignant transformationSO16

Proliferation, Apoptosis, and Autophagy Dysregulated cell proliferation is a hallmark of cancer. Cancer cell proliferation is sensitive to the presence of required nutrients. This has raised concern that feeding patients with cancer may have the unwanted effect of stimulating tumor growth. 17

Carotenoids (e.g., lycopene), flavonoids (genistein), stilbenes (resveratrol), polyphenols (curcumin), and isothiocyanates all have beendemonstrated to induce apoptosis in cancer cells 18

vitamins A and D both have effects on suppress tumor growth Similarly, inorganic micronutrients such as selenium have been demonstrated to modulate cancer growth in vitro and in vivo19

Immunity Many nutrients have been postulated to influence cancer risk and progression through their effects on immune function So-called immune-enhancing EN formulas containingmixtures of GLN, arginine, and omega-3(n-3) fatty acids appear to improve surgical outcomes inpatients with cancer but do not play an obvious direct role in cancer therapy 20

GLN is the most extensively studied single nutrient. Analysis of GLN metabolism in the tumorbearing host suggests that in patients with cancer GLNmay be conditionally essential. Peripheral muscle storesof GLN are reduced in patients with cancer. It is hypothesized that GLN supplementation in patients with cancer may restore immunocompetence and gut barrier function by providing substrate to GLN-requiring tissues, such aslymphocytes involved in cancer control, that are madeconditionally deficient by the presence of a tumor 21

THE CANCER CACHEXIA SYNDROME CCS refers to a complicated clinical syndrome characterized by host tissue wasting, anorexia, fatigue, anemia, insulin resistance, and hypoalbuminemia It occurs as a result of a complex cascade of physiologic and metabolic derangements 22

23 The presence of a chronic inflammatory state seems to account for seemingly disparate aberrations, including changes in the hypothalamic–pituitary axis, dysautonomia , hypermetabolism, oxidativestress, decreased muscle protein synthesis, and muscle protein degradation, together with other metabolic changes such as insulin resistance ω3

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The muscle wasting observed in cachexia differs from the wasting observed in starvation or aging. The weight loss associated with CCS cannot be reversed through increased nutrient intake alone and usually continues despite increased administration of nutrients Studies indicate no benefit of isolated increased caloric intake on weight25

The clinical signs and symptoms of CCS include host tissue wasting, anorexia, skeletal muscle atrophy, fatigue, anemia, and hypoalbuminemia 26

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GI malignancy is associated with the largest decreases ( 50%) in muscle mass and protein content as well as a 30% to 40% loss of body fat Patients with solid tumors can lose as much as 1.34 kg ofFFM in 4 weeks These changes affect surgical outcomes Patients with cancer with GImalignancies undergoing surgery experience increasedrates of severe complications that correlate with decreases in lean body mass 28

Metabolic Sequelae The metabolic changes seen in CCS are multiple and variable The most striking feature of the energetics of the metabolic response to cancer is its variability In comparison with control groups, patients with cancer mayhave reduced, normal, or increased energy expenditure29

The variability is in part caused by the heterogeneity of “cancer,” but is also likely owing to differences inhost responses to tumor and to the presence of comorbid conditions such as infection. Estimation of energy needs in patients with cancer is problematic because of this heterogeneity in energy expenditure30

Decreased skeletal muscle mass is a hallmark of CCS Cachexia is often seen in end-stage cancer An apparent failure exists in patients with cancer of the normal mechanism of protein metabolismadaptation seen during simple starvation This appears to result from a combination of decreased synthesis and increased proteolysis 31

Proteolysis-inducing factor (PIF), detected in the urine of patients with cancer with cachexia, is associated with decreased plasma amino acid levels and decreased protein synthesis PIF activates an RNA-dependent proteinkinase, which in turn activates nuclear factor- B (NF- B). NF- B in turn activates the ubiquitin proteasome proteolytic pathway. This NF- B pathway is proposed as theprimary proteolytic pathway in CCS32

Depletion of fat stores is a characteristic feature of CCS Glucose infusion fails to suppress lipolysis in patients with cancer Adipose cells from cachectic patients demonstrate increased lipolytic activity TNF- may playa role in lipolysis by inhibiting lipoprotein lipase, therebypreventing the ability of adipocytes to extract fatty acidsfrom circulating lipoproteins (i.e., low-density lipoprotein ) 33

Lipid-mobilizing factor (LMF) also has been linked with increased lipolysis, increased free fatty acid turnover, and increased serum glycerolLMF appears to increase lipolysis via increases in hormone sensitive lipaseIncreased lipid levels in the blood seen in patientswith cancer may help the host by fueling the generalized Unfortunately, the same lipids also may be used by thetumor to meet essential requirements 34

Alterations in carbohydrate metabolism are also commonly seen in cancer cachexia. Weight loss in CCS isoften associated with glucose intolerance and diminished insulin sensitivity This may be a result of insulin resistance or decreased leptin levels or both 35

Gluconeogenesis may be increased as a resultof up-regulated Cori cycle activity in response to tumor production of lactic acid 36

37 Cytokine mediators of CCS increase glucose demand, which induces gluconeogenic enzymes in the liver, further driving glucose synthesis

Mediators and Mechanisms of Cancer Cachexia Syndrome A myriad of chemical, metabolic, and clinical factors are implicated in the pathogenesis of CCS. This complexity goes a long way in explaining the historic intractability of CCS to clinical interventions 38

Proinflammatory Cytokines and Other Molecular Mediators Proinflammatory cytokines such as tumor necrosis factor(TNF- ), interferon- (IFN- ), and interleukins 1 and 6 (IL-1 and IL-6) are considered important mediators of CCS A strong correlation exists between high levelsof these factors and the presence of cachexia Thetumor appears to be the primary source of these cytokines 39

IL-6 levels are usually elevated in CCS. IL-6 induces increased hepatic gluconeogenesis and protein synthesis Increased serum levels of TNF - have been associated with increases in lipolysis and proteolysis . IFN- also is associated with increased lipolysis and increased hepatic protein synthesis. IL-1 induces anorexia Allof these cytokines may act both peripherally to alter host metabolism and centrally to affect appetite and the host neuroendocrine axis . 40

Several neuropeptides have been implicated in the pathogenesis of cachexia. Neuropeptide Y (NPY) is orexigenic (appetite stimulating) in the normal state; withdecreased production, it causes anorexia. NPY receptors appear resistant to NPY and production of NPY appears to be decreased in cancer cachexiaMelanocyte stimulating hormone ( -MSH) and corticotropin-releasingfactor (CRF) are anorexigenic in the normal state. -MSH and CRF production are stimulated by IL-1, IL-6, andTNF- , and may be mediators of the effects of these proinflammatory cytokines. Melanocortin signaling also appears to be increased in CCS 41

Leptin , an adipocytokine crucial for body weight regulation and a modulator of inflammatory and immune Responses Leptin has been observed to be down-regulated in patients with cancer cachectic patients This hypoleptinemia may play a role in the increased insulin resistance seen in patients with cancer However, unlike in healthy individuals,cachectic patients with cancer appear to be resistant tothe orexigenic effects of hypoleptinemia . The exact impact of hypoleptinemia and its potential as a therapeutic target in cachexia remain to be elucidated 42

Cachexia Alteration of control loop ( Leptin & NPY)tumor-derived factors(PIF &LMF) proinflammatory cytokines β-hydroxy β-methylbutyrate (HMB), regular resistance exercise, high-protein diet, Omega-3 fatty acids and Non steroidal anti-inflammatory drugs 43

Impaired Caloric Intake Although CCS is fundamentally a metabolic syndrome, reduced caloric intake exacerbates the consequences ofthe underlying metabolic abnormality Impaired caloric intake is the most significant cause of malnutrition among patients with cancer44

Changes in taste and appetite, learned food aversions, depression, and disturbances of the GI tract frequently impair adequate calorie intake by patients with cancerSome of the most common and distressing symptoms in patients with advanced cancers relate to the GI tractThese symptoms may include Early satiety, changes in taste, and loss of appetite45

Side Effects of Therapy Unwanted side effects of cancer treatment are an important cause of decreased food intake and malnutrition in some patients with cancer Surgery induces a stress response characterized by hypermetabolism, tissue wasting, anorexia, and catabolism, all of which contribute to weight loss 46

Major surgical resections for cancer may necessitate en bloc removal of adjacent normal tissue with resultant loss of function. For example, malabsorption can occur after GI, pancreas, and liver resections It is intuitively evident that the incidence of complications, length of hospitalization,duration of postoperative anorexia, and degree of malnutrition all increase with increasing complexity of the surgical procedure47

Chemotherapy for cancer can affect food intake and absorption by inducing GI symptoms such as nausea, vomiting, anorexia, abdominalpain, diarrhea, fever, stomatitis, mucositis, and food aversions Symptoms can occur immediately or in a delayed fashion and may last from several hours to days Fatigue and pain induced by chemotherapy alsonegatively affect nutrition intake48

Radiation therapy , especially to the head and neck, abdomen, and pelvis, has the potential to interfere with dietary intake.49

More than 70% of patients receiving pelvic radiation develop acute inflammatory changes in the small and large intestine, and as many as 50% can go on to develop chronic symptoms Acute, radiation induced injury to GI epithelium is manifested as diarrhea andcramping . These can lead to pain, dehydration, andfood aversion. Fatigue also may be a prominent side effectof radiation therapy, and can contribute to impaired foodintake through a lack of desire to prepare or consume food50

Changes in Taste and Mood distorted taste, can be a distressing accompaniment of cancer and cancer therapy that interferes with eating In some cases, taste acuity returns in 2 to 3 months after cessation of treatment; however, in the case of radiation induced dysgeusia , patients may develop permanent hypogeusia51

Pain and Other Adverse Consequences of Eating Pain is a common cause of anorexia and/or food aversion . The pain may be a result of the tumor itself or a side effectof anticancer therapy. The experience of pain anywhere in the body can lead to nutritional deterioration Therefore, pain control is a significant element of optimalnutrition care. 52

Obstruction, Fistula, and Malabsorption Mechanical factors related to tumor or complications of therapy may compromise GI tract continuity and normal motility This effect occurs most commonly as a result ofmalignant obstruction of the esophagus, stomach, small intestine, colon, or biliary tract, or secondary to tumor induced changes in gastric wall compliance53

Symptoms related to mechanical factors may include alterations in taste sensation, early satiety, pain, cramps, vomiting, diarrhea, and constipation Surgery or endoscopic stenting are often the best approaches to dealing with these complications in acceptable risk patients54

Comments Cachexia (The formal definition of cachexia is the loss of body mass that cannot be reversed nutritionally: Even if the affected patient eats more calories, lean body mass will be lost, indicating a primary pathology is in place ) is remain as a powerful challenge and refractory to treatmentMalnutrition is differ from CCS To treatment cancer we must work as a team work55

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