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