Cancer Cachexia

Question 1

What are primary tumour and secondary tumours?

Answer 1

The first tumour identified, classified according to its size and invasion of surrounding tissues
Secondary tumours are other tumours of the same histological origin as the primary tumour, usually located nearby

Question 2

What is metastasis?

Answer 2

The invasion of distal tissues and organs causing malignant secondary development

Question 3

List the four main tumour imaging techniques used

Answer 3

MRI: magnetic resonance imaging (less invasive)
CT: computed tomography
PET: positron emission tomography
Chest X-ray, ultrasound, mammogram, bone scans

Question 4

What are the stages of cancer?

Answer 4

Stage 0: Carcinoma in situ (early form)
Stage I: Localized 
Stage II: early locally advanced 
Stage III: late locally advanced 
Stage IV: metastasized

Question 5

How are solid tumours based on using the TNM system?

Answer 5

Primary tumours: T - T1 to T4 , ranked based on tumour size (if TX then it is unknown where the primary tumour is
Lymph nodes: N - N0 to N3 , if no nodes contain malignant cells then it will be classified as N0
Metastasis: M - M0 or M1, presence of metastasis is M1 independent of where or how many

Question 6

What is the first choice of anti-cancer treatment for curative Tx?

Answer 6

Surgical removal, mostly for primary local tumours (stage I) and pre-cancerous lesions
May be palliative to alleviate pain

Question 7

How does radiotherapy work and who is it best suited for?

Answer 7

Ionizing radiation altering DNA to control growth or kill malignant cells
Targeted to tumours with relatively limited damage around surrounding tissues
For curative Tx or adjuvant (enhances body’s immune response to antigens or treatment regimens)

Question 8

List the side effects of radiotherapy

Answer 8

If tumour is located on head and neck: mucositis, dygeusia, xerostomia, dysphagia, odynophagia, severe esophagitis (may require tube feeding/enteral nutrition)
Abdomen and pelvis: severe diarrhea, malabsorption, radiation enterotitis

Question 9

What is chemotherapy?

Answer 9

Cytotoxic drugs that block DNA and RNA synthesis or cell division at different stages
Drugs may be taken orally, through IV infusion or intramuscular injections

Question 10

How do immunotherapy or biological response modifiers function?

Answer 10

It uses the body’s own immune system to eradicate cancer cells
Typically works on synthesized interferons, interleukins, cytokines

Question 11

What anticancer treatment is used for blood cancers?

Answer 11

Hematopoietic stem cell transplantation

Question 12

What does Cachexia mean?

Answer 12

It stems from Greek, “kakos” = bad and “hexis” = condition

Question 13

Define cancer cachexia

Answer 13

It is a complex metabolic syndrome associated with the underlying illness and characterized by loss of muscle with OR without loss of fat mass. The prominent clinical feature is weight loss

Question 14

How is muscle wasting a predictor for cancer associated outcomes?

Answer 14

Muscle wasting will increase fatigue and treatment induced toxicity (from chemotherapy drugs) and decrease host response to tumours, performance status and survival outcome (due to high loss of respiratory muscle causing issues with breathing)

Question 15

What is sarcopenic-obesity?

Answer 15

Obesity with depleted muscle mass, typically seen in 15% of patients with lung or gastro-intestinal tumours

Question 16

What is the prevalence of cachexia and what types of cancer has a higher frequency?

Answer 16

50 - 80% and is mostly seen at the end stages of the disease
Upper gastrointestinal cancer: ~80%
Lung cancer: ~60%

Question 17

What is the pathophysiology of cancer cachexia?

Answer 17

Metabolic change and reduced food intake will contribute to cachexia
Metabolic changes: hypercatabolism will increase systemic inflammation and catabolic factors and hypoanabolism are usually decreased with progression of cancer
Down regulation of anabolic pathways, IGF-1 and testosterone (hypogonadism) are lowered which will likely worsen muscle mass and function (increased fatigue)
Surgery, radiotherapy, chemotherapy, nutritional deficiencies will enhance catabolic response leading to unsustainable levels of fat and muscle mobilization and a significant decrease in muscle mass
Reduced food intake: may see patients with primary or secondary anorexia
Regulated by hypothalamic hormones
Cytokines closely mimic leptin signaling and suppress ghrelin and NPY secretion
Overall patient will have negative energy and protein balance

Question 18

What are some key definitions in cachexia?

Answer 18

Undernutrition: insufficient food intake
Malnutrition: insufficient intake in one or more nutrient
Starvation: food deprivation of all nutrients
Sarcopenia: decreased muscle mass in the absence of weight loss

Question 19

What are the different stages of cachexia?

Answer 19

Pre-cachexia : weight loss <5% , anorexia and metabolic change
Cachexia: weight loss >5% or BMI <20 and weight loss >2% or sarcopenia and weight loss >2%, reduced food intake/systemic inflammation
Refractory cachexia: end stage of the disease (usually survival is < 3 months), cancer disease both procatabolic and not responsive to anticancer treatment

Question 20

What can be said about BMI, weight loss and risk of reduced survival?

Answer 20

Cachexic patient with a higher BMI will have a higher survival time due to more fat reserves to aid a stressful condition and where there is reduced food intake
While there is more cancer prevalence in people with obesity, once they are diagnosed with cancer it has a more protective factor

Question 21

What is the acute phase response?

Answer 21

Coordinated adaptations of the body to limit and clear the tissue damage caused by hydrolases released from inflammatory, injured or malignant cells.
Inflammation is a hallmark of cachexia

Question 22

How is the acute phase response regulated?

Answer 22

Cytokines are produced by the tumour and/or the host - secreted from immunocompetent cells
Acting locally and systemically
Pro-inflammatory cytokines are usually found in some types of cancer: TNF-a, IL-1, Il-6, IFN-y, LIF

Question 23

What are some of the effects of cytokines?

Answer 23

Decrease appetite and food intake, direct action in hypothalamus
Decrease GI function: decrease gastric emptying which can lead to constipation and nausea, intestine mobility
Decrease blood flow
Inhibit LPL: necessary for storage of fat
Inhibit growth hormone and IGF-1 signaling
Induce insulin resistance

Question 24

How do host-tumour interactions affect cancer cachexia?

Answer 24

Systemic inflammation induced by the tumour will trigger cytokine production which will affect the liver, skeletal muscle and brain.
Liver will increase acute phase proteins and decrease urinary nitrogen loss
There will be direct catabolic effect on skeletal muscle, contributing to muscle wasting and increased substrate demand using more AA in liver for acute phase proteins
Cytokine effects on the brain will initiate anorexia thereby reducing substrate supply to skeletal muscles

Question 25

What is hypermetabolism and what is the indicator of it in cachexia?

Answer 25

Increased REE in cachexia patients is due to hypermetabolism while they are eating less, their REE accounts for almost 85-90% of TEE
Lipids
Mobilization of lipids and increased turnover of fatty acids: increase lipolysis FFA and VLDL leading to hypertriglyceridemia
Decreased LPL activity lowering storage of dietary fats
Glucose
Tumours use glucose as fuel
Tumours produce lactate which will enter Cori cycle to be recycled in liver - but will use ATP and produces less glucose than the oxidative pathway
Increase gluconeogenesis since tumours are constantly using glucose so the body must maintain a set point of glucose , this will increase proteolysis in muscles
Creating an insulin resistance in cells

Protein
Negative N balance
Increase protein turnover: tumours will use AA to grow
Muscle proteolysis to provide AA for gluconeogenesis, acute phase proteins and tumour growth
Increased hepatic protein synthesis

Question 26

Explain the pathophysiology of the ubiquitin-proteasome pathway and how it is related to cancer cachexia

Answer 26

Ubiquitin will undergo three ubiquitination process
The E3 ligase is an enzyme which will link ubiquitin to protein substrates which will be recognised by the proteasome system which is proteolytic
When ubiquitinated proteins are recognised by the system it will begin the process of degradation and ubiquitin will be recycled
Acute phase proteins can stimulate the expression of E3 ligases, triggering the proteolytic system to degrade more muscle proteins
The ubiquitin-proteasome pathway is ATP dependent

Question 27

Describe the integrated metabolic changes with cancer

Answer 27

Tumours require a lot of glucose, which is provided by the Ciri cycle from the the liver and it will recycle lactate.
Cytokines secreted from the tumour can trigger proteolysis which will signal AA to increase gluconeogenesis to be brought into the liver to provide the ATP and glucose for the tumour
LMF and TNF-a will also signal increased lipolysis in adipose tissue to release more FA for energy
All these mechanisms will lead to hypermetabolism and increasing energy expenditure

Question 28

What factors may decrease food intake in terms of cachexia and anorexia?

Answer 28

Obstruction of the GI, malabsorption, pain, depression, constipation, radio or chemotherapy, inflammation

Question 29

How is appetite and food intake regulated?

Answer 29

NPY - hypothalamic orexigenic signals will stimulate feeding
POMC - anorexigenic signals will inhibit feeding
In cachexia there is a dysregulation of homeostasis by persistent activation of POMC neurons - less feeding and increase energy expenditure

Question 30

Why do cancer patients feel early satiety?

Answer 30

Usually results from reduced GI motility and increased gastric emptying time
May be caused by autonomic dysfunction and opioid analgesics

Question 31

Nausea and chemosensory abnormalities are common in cachexia patients, why?

Answer 31

They are direct consequences of antineoplastic therapies
Nausea may occur as a side effect of drugs, GI stasis, abdominal disease, intracranial metastases, metabolic derangements
Taste aversions may be due to hypersensitivity to odors and flavours, persistent bad tastes, phantom smells which may stem from chronic nutritional deficiencies

Question 32

What are some therapeutic agents to increase appetite in cancer cachexia?

Answer 32

Progestational agents: increase appetite and weight gain but not lean mass
Corticosteroids: transient increase in appetite and well-being , should be used for restricted periods
Cannabicoids: may have potential but inconsistent evidence - it is a derivative of THC

Question 33

What therapeutic agents may be used for symptom management?

Answer 33

Antimetics, antidepressants, corticosteroids, anti GI motility agents, narcotics and other analgesics