CANCER CACHEXIA
PATHOPHYSIOLOGY AND NUTRITIONAL
TREATMENT
Gaga Irawan Nugraha, Siti Nur Fatimah
Cancer cahexia
• Prevalence • Found in more than 80% late stage of cancer.
• Related with more than 20% mortality.
• Definition (Cachexia Consensus Conference);
Multifactorial syndrome characterised by an ongoing loss of skeletal
muscle mass (with or without loss of fat mass) that cannot be fully
reversed by conventional nutritional support and leads to
progressive functional impairment.
Cachexia in advanced cancer has a negative effect on
outcomes such as quality of life (QoL), physical function,
and survival.
Mantovani et al, 2010, Suzuki et al, 2013
Blum et al, 2011, Crit Rev Oncology)
• Anorexia related with Weight Loss (WL)
• Patient with WL had more: Depresssion,
Abdominal fullness, Taste change, Vomiting,
Mouth dryness, Dysphagia, Loss of appetite
Calorie intake & Nutrition Impact
• WL related with high CRP
• WL related with low albumin
• TNFα, IL-10 and IL-12 related with WL
Catabolic drive & Increased Metabolism
• Fat Mass and Fat Free Mass↓
• ↓ Hand Grips strength
Muscle mass & Strenght
• Insulin resistance :↑ Insulin level, ↑ Glucose
uptake, ↑ Carbohydrate oxidation
• ↑ body protein catabolism:
• ↑ rate of fat oxidation
Metabolic alteration
With
involuntary
weight loss
Features of
Cancer
Cachexia
Fearon et al, 2013
The CNS integrates the regulation of food intake and of energy expenditure. CNS
outputs, neuroendocrine outputs, the sites of energy storage (adipose tissue and
skeletal muscle) and the site of integration and transformation of energy fuels (liver)
provide an energy fuel mixture for systemic use. An elevated level of mobilization of
energy stores is required to fuel immune responses during activation of the immune
system, and an energy appeal reaction for this purpose is mediated directly by
proinflammatory cytokines acting both in the CNS and periphery.
A simplified model of the hypothalamic neuropeptide circuitry in
response to starvation and cancer anorexia–cachexia
Suzuki et al, 2013
An abbreviated diagram of skeletal muscle in cancer cachexia.
Catabolic state
1. Protein metabolism:
• Derease of protein synthesis
• Decrease of hormon adn enzyme synthesis
• Increase of acute phase protein synthesis
• Energi sources
Increase amino acid uptake in liver but decrease
in muscle
Negative protein balance
Lowry, 2014; Smith, 2005
Myostatin:
• Myostatin, also known as growth/differentiation factor-8 (GDF-8) .
• Active myostatin mostly binds to the ActRIIB and engages the signalling
cascade leading to the inhibition of myoblast differentiation and proliferation.
• Normally it functions to regulate hypertrophy of muscles, but a role in the
induction of muscle loss was observed in muscle wasting diseases and
cachexia associated with severe illnesses
• Under normal conditions, IGF-1 signalling seems to be dominant and blocks
the myostatin pathway. However, an inhibition of IGF-1 was observed when
myostatin is overexpressed
Elkina et al, 2011, Lenk et al, 2010
• .
Tisdale et al, 2009; Lenk et al, 2010; Elkina et al, 2011;
Morissette et al, 2009; Evans et al, 2008
Catabolic state
Proteolysis inducing factor (PIF)
• Glycoprotein mediator produced by tumour tissue.
• Decrease of protein synthesis and increase muscle
degradation by ubiquitin proteasome system.
• High level in cancer cahexia patient.
Catabolic state
• TNFa-induced lipolysis acts through a TNFa receptor 1 (TNFR-1) dependent pathway, which inhibits perilipin allowing hormone-sensitive lipase (HSL) to access the surface of lipid droplets.
• ZAG-stimulated lipolysis may be mediated by b3- adrenoceptors (b3AR) and the activation of the intracellular cAMP pathway.
Lipid metabolism
Lipid metabolism
• Zinc-a2-glycoprotein (ZAG), which is overexpressed by
certain malignant tumours, has been identified as a novel
adipokine.
• ZAG transcripts and protein expression in adipose tissue
are up regulated in cancer cachexia.
• Studies in vitro demonstrate that recombinant ZAG
stimulates lipolysis.
• Further elucidation of ZAG function in adipose tissue may
lead to novel targets for preventing adipose atrophy in
malignancy.
Catabolic state
Klement & Kammerer, 2011
Development of the cachectic state via
sustained inflammatory signaling
Glucose metabolism in peripheral tissues is impaired
already at early stages, while hepatic gluconeogenesis increases during tumor progression at later
stages
Catabolic state
Carbohydrate metabolism
CHOs can have direct and indirect effects on tumor cell proliferation:
1. Contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction.
2. High insulin and IGF-1 levels, can directly promote tumor cell proliferation.
3. Ketone bodies elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands.
Nutritional
consequences
of radical resection
in alimentary tract
Nutritional complication of radiotherapy
Energy Intake Activity
CACHEXIA
INFLAMMATION
Tumour-associated and
treatment-associated factors
TUMOUR
Fearon et al, 2013
Diagnosis criteria
Another diagnosis consideration
Fearon:
1. Weight loss >10%,
2. Low food intake <1,500 kcal/day
3. Systemic inflammation, CRP >10 mg/l.
had prognostic and functional implications and generated potential
evidence for the significance of a classification system based on
different phenotypes.
Bozetti and the SCRINIO Working Group:
Defined a four different stages of severity based on weight loss of
more than 10% or less than 10% and on the presence of the three
symptoms: anorexia, early satiety, or fatigue.
The stages range from asymptomatic pre-cachectic (or patients “at
risk for cachexia”) to symptomatic cachectic.
Another diagnosis consideration
Principle of nutritional therapy
Combination of nutritional support with treatment targeted against the inflammatory response and/or metabolic abnormalities, focussing also on energy expenditure.
Therapeutic strategies aimed at modulating the mediators of the catabolic response, such as cytokines and eicosanoids, or metabolic
regulation, such as with anabolic and anti-catabolic agents, may thus offer more promise in the future.
Early detection and intervention more effective.
Strategies to counteract both hypermetabolism and reduced dietary intake may be important for the survival, function and quality of life of cancer patients and should be further explored.
Bossaeus, 2008
Principle of nutritional therapy
Principle of nutritional support
Metaanalisis:
Nutritional support increase energy intake to 430 kcal/dari body weigh 1,9 kg
Another research:
Pancreatic cancer with defisit energy intake 200 kcal/day, and protein 0,7-1 g/kgBW/d increase calorie intake 300 – 400 kcal/day and protein 1-1,5 g/kgBW/day.
Trendelenburg et al, 2009, Fearon et al, 2013
Principle of nutritional support
Recommendations:
1. Minimum energy and protein needs in adult non-surgical patients
are 30–35 kcal/kg/d and 1.2–1.5 g protein/kg/d
2. The average protein intake of bedrest patients is about 0.7–1.0
g/kg per day, if such a patient is to start some minimal daily
exercise and reach a protein intake that might combat anabolic
resistance (recommended intake 1.0–1.5 g/kg per day), it is
evident that food energy intake needs to increase by 300–400
kcal per day and protein intake increase by up to 50%.
3. The average daily energy expenditure of a patient with
advanced-stage cancer is 1,600–1,800 kcal
Trendelenburg et al, 2009, Fearon et al, 2013
• Before starting the re-feeding process, electrolyte disorders should be
corrected and circulatory volume should be carefully restored.
• Caloric repletion should be at a slow rate of approximately 20 kcal/kg
per day (or 1000 kcal per day) initially.
• Hypophosphatemia has to be treated if the serum level is less than
0.30 mmol/l or the patient is symptomatic.
• Supplementation of phosphate should be given intravenously at 40–
80 mmol/day, together with magnesium (8–16 mmol/day) and
potassium (80–120 mmol per day). These dosages should be
adjusted according to monitored serum levels
Principle of nutritional support
Current Understanding and Areas for Future Research GLUCOSE
Hyperglycemia has two other important negative effects for the host:
1. Even modest blood glucose elevations as they typically occur after a Western diet meal competitively impair the transport of ascorbic acid into immune cells. Ascorbic acid is needed for effective phagocytosis and mitosis, so that the immune response to malignant cells is diminished.
2. It has been shown in vitro and in vivo that hyperglycemia activates monocytes and macrophages to produce inflammatory cytokines that play an important role also for the progression of .
3. High plasma glucose concentrations elevate the levels of circulating insulin and free IGF1, two potent anti-apoptotic and growth factors for most cancer cahexia
LIPID
Many systematic review about ketogenic diet in cancer patient
Implementing a KD with additional calorie restriction in a female patient with glioblastoma multiforme clearly demonstrated that this intervention was able to stop tumor growth
Comprehensive
therapy
in cancer cahexia
1. Inhibitors of production/release of
cytokines and other factors
2. Gastroprokinetic agents with or
without antinausea effect
3. Blockers of the Cori cycle ,
4. Blockers of fat and muscle tissue
wasting
5. Blockers of fat and muscle tissue
wasting
6. Appetite stimulants with or without
antinausea effect
7. Antianxiety/depressant drugs.
• Fearon et al, 2013
Physical activity
Physical exercise may be beneficial in the treatment of
cancer cachexia, as it increases insulin sensitivity, protein
synthesis rate, and anti-oxidative enzyme activity .
It also may lead to a suppression of the inflammatory
response and an enhancement of immune function
Schematic drawing of factors involved in regulating muscle mass (a) and
the impact of exercise training on these factors (b). Factors influenced
by exercise training are shaded in
Lenk et al, 2010