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2. Nutritional complications in cancer

3. 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

4. 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

5. 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%)

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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)

12. 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

13. 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

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

16. 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

17. 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.

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

25. 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

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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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)

34. 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

35. 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

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

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

38. 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

39. 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

40. 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.

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

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

50. 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

51. 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

52. 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.

53. 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

54. 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

55. 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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