Cancer Cachexia Flashcards by Karen Lam

What are primary tumour and secondary tumours?

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

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What is metastasis?

The invasion of distal tissues and organs causing malignant secondary development

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List the four main tumour imaging techniques used

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

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What are the stages of cancer?

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

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How are solid tumours based on using the TNM system?

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

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

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

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

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)

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List the side effects of radiotherapy

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

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What is chemotherapy?

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

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How do immunotherapy or biological response modifiers function?

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

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What anticancer treatment is used for blood cancers?

Hematopoietic stem cell transplantation

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What does Cachexia mean?

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

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Define cancer cachexia

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

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How is muscle wasting a predictor for cancer associated outcomes?

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)

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What is sarcopenic-obesity?

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

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

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

What is the pathophysiology of cancer cachexia?

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

What are some key definitions in cachexia?

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

What are the different stages of cachexia?

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

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

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

What is the acute phase response?

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

How is the acute phase response regulated?

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

What are some of the effects of cytokines?

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

How do host-tumour interactions affect cancer cachexia?

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

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

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

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

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

Describe the integrated metabolic changes with cancer

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

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

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

How is appetite and food intake regulated?

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

Why do cancer patients feel early satiety?

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

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

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

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

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

What therapeutic agents may be used for symptom management?

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