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Nutritional complications in cancer

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 is projected that by the year 2020, cancer incidence will double worldwide

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

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

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 malignancies The 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 loss

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 elderly

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 malnutrition

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

patients to eat more is unlikely to reverse the 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 weight the 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 the presence of CCS

or may relate to complications of therapy(surgery) 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)

all of which may exacerbate anorexia 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 anorexia

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

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

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, combined with suppression of mitochondrial function, is the most fundamental metabolic change in malignant transformation SO

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.

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

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 vivo

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

GLN is the most extensively studied single nutrient. Analysis of GLN metabolism in the tumorbearing host suggests that in patients with cancer GLN may be conditionally essential. Peripheral muscle stores of 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 as lymphocytes involved in cancer control, that are made conditionally deficient by the presence of a tumor

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

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

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 weight

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

Patients with solid tumors can lose as much as 1.34 kg of 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 of FFM in 4 weeks These changes affect surgical outcomes Patients with cancer with GI malignancies undergoing surgery experience increased rates of severe complications that correlate with decreases in lean body mass

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 may have reduced, normal, or increased energy expenditure

The variability is in part caused by the heterogeneity of “cancer,” but is also likely owing to differences in host 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 expenditure

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 metabolism adaptation seen during simple starvation This appears to result from a combination of decreased synthesis and increased proteolysis

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 protein kinase, 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 the primary proteolytic pathway in CCS

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 play a role in lipolysis by inhibiting lipoprotein lipase, thereby preventing the ability of adipocytes to extract fatty acids from circulating lipoproteins (i.e., low-density lipoprotein)

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

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

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

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

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 levels of these factors and the presence of cachexia The tumor appears to be the primary source of these cytokines

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 All of these cytokines may act both peripherally to alter host metabolism and centrally to affect appetite and the host neuroendocrine axis.

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

target in cachexia remain to be elucidated 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 to the orexigenic effects of hypoleptinemia . The exact impact of hypoleptinemia and its potential as a therapeutic target in cachexia remain to be elucidated

Alteration of control loop (Leptin & NPY) 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

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

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

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

For example, malabsorption can occur after GI, 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 procedure

Symptoms can occur immediately or in Chemotherapy for cancer can affect food intake and absorption by inducing GI symptoms such as nausea, vomiting, anorexia, abdominal pain, 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 also negatively affect nutrition intake

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

large intestine, and as many as 50% can go on to develop 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 and cramping . These can lead to pain, dehydration, and food aversion. Fatigue also may be a prominent side effect of radiation therapy, and can contribute to impaired food intake through a lack of desire to prepare or consume food

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 hypogeusia

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 effect of anticancer therapy. The experience of pain anywhere in the body can lead to nutritional deterioration Therefore, pain control is a significant element of optimal nutrition care.

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 of malignant obstruction of the esophagus, stomach, small intestine, colon, or biliary tract, or secondary to tumor induced changes in gastric wall compliance

satiety, pain, cramps, vomiting, diarrhea, and constipation 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 patients

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 treatment Malnutrition is differ from CCS To treatment cancer we must work as a team work

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