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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 is
projected that by the year 2020, cancer incidence will
double worldwide
3
Malnutrition
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
4
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%)
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 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
6
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
7
A study estimated a fivefold
increase in mortality in underweight patients (body
mass index [BMI] 18.5 kg/m2) undergoing major intraabdominal 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
8
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
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 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
10
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 anorexia
12
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
13
14
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, combined
with suppression of mitochondrial function,
is the most fundamental metabolic change
in malignant transformation
SO
16
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 been
demonstrated 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 vivo
19
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
20
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
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
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
23
24
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
25
The clinical signs and symptoms of
CCS include host
tissue wasting, anorexia, skeletal
muscle atrophy, fatigue, anemia, and
hypoalbuminemia
26
27
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
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 may
have reduced, normal, or increased energy expenditure
29
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
30
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
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 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
32
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)
33
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
34
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
35
Gluconeogenesis
may be increased
as a result
of up-regulated
Cori cycle activity
in response to
tumor production
of lactic acid
36
Cytokine mediators of CCS
increase glucose demand, which induces
gluconeogenic enzymes in the liver, further driving
glucose synthesis
37
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 levels
of these factors and the presence of cachexia
The
tumor 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 . IFNalso 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.
40
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
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 to
the 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, highprotein 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 of
the underlying metabolic abnormality
Impaired caloric intake is the most significant
cause of malnutrition among patients with cancer
44
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
45
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
procedure
47
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
48
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 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
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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
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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.
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 of
malignant obstruction of the esophagus, stomach, small
intestine, colon, or biliary tract, or secondary to tumor
induced changes in gastric wall compliance
53
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
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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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