Anorexia-Cachexia CBM and Oxford

Question 1

What is anorexia?

Answer 1

• Anorexia: Loss of appetite

Question 2

What the symptoms of anorexia/cachexia?

Answer 2

Symptoms:

• anorexia
• fatigue
• depression
• early satiety
• reduced function
• weight loss

Question 3

What are the “biological” features?

Answer 3

• increased resting energy expenditure
• High CRP
• High LDH
• low albumin (late finding)
• low testosterone

Question 4

What is the difference between primary and secondary cachexia?

Answer 4

Primary Cachexia

• host-tumour liason
• wasteful consumption of energy
• Resetting of metabolic processes in fat, muscle and organs
• muscle and fat loss

Secondary Cachexia

• potentially treatable causes from reduced nourishment
• muscle and fat loss

Question 5

List causes of secondary cachexia

Answer 5

Psychological

• anxiety
• depression
• family distress
• spiritual distress

Eating problems

• appetitie
• disturbed taste or smell

Oral problems

• dentures
• thrush
• mucositis/ulceration
• dry mouth

Swallowing problems

Stomach problems

• gastric reflux
• early satiety
• nausea and vomiting

Bowel problems

• Obstruction
• Constipation
• Diarrhea

Malabsorption

• Pancreas
• Fistulas
• short gut syndrome (ileostomy, etc)

Fatigue

• sleep disturbance
• physical limitations
• motivation
• cognitive fatigue

Function

Pain

Metabolic disorders

• diabetes
• adrenal insufficiency
• hypogonadism
• thyroid insufficiency

Question 6

Which cancers are more likely to cause anorexia-cachexia?

Answer 6

• upper GI
• pancreas
• lung

Unusual in :

• breast
• heme

Question 7

How does a chronic inflammatory state cause cachexia?

Answer 7

• Strong immune response
• unknown trigger
• Neutrophils, lymphocytes and macrophages invade tumour
• produce inflammatory chemokines and cytokines
• cytokines activate tumour oncogenes –> further stimulates inflammatory actions of immune cells
• Cytokines:
  
  • IL-1B, IL-6, IL-8 and MIC-1

Question 8

Muscle loss

Answer 8

• inflammatory activity activates genes that stimulate proteolytic system (normally balances muscle synthesis and breakdown)
  
  • ubiquitin-proteosome system
  • muscle tissue is catabolized
• Inflammtory cytokines blcok anabolic effects of growth hormone and insulin growth factor, induce insulin resistance.
  
  • reduced muscle synthesis
• Myostatin upregulatation
  
  • increased proteolysis
• Muscle synthesis decreases
  
  • reduced intake of protein, increased resting expenditure

Question 9

Anorexia pathophysiology

Answer 9

Appetite mediation

1. Hypothalamus

• cytokines activate POMC (pro-opiomelanocortin system)
• reduces appetite
• increases energy expenditure that cannot be met via:
• alpha-melanocyte-stimulating hormone binds to type 4 melanocortin recptor

2. Solitary tract nucleus (STN)

• brainstem
• appetite and gastric motility

Question 10

Fat Loss

Answer 10

• Lipolysis increases
• fat synthesis decreases
• increased catecholamine activity
• upregulated zinc alpha 2 glycoprotein (ZAG)

Question 11

Assessemnt of anorexia-cachexia

Answer 11

• Initial weight and height (BMI) kg/m2
  
  • BMI < 18.5 underweight
• Patient recorded information
  
  • ESAS
  • PG SGA
• Test of function
  
  • 6 minute walk test
  • sit to stand time
  • gait speed
  • steps measured
  • imaging (DEXA or CT scans)

Question 12

What lab tests are helpful for anorexia-cachexia?

Answer 12

• CRP ( > 10 mg/L)
  
  • acute phase protein
  • produced by liver
  • powerful prognosticator
• Albumin
  
  • not a reliable early marker
  • advanced cachexia only

Question 13

What is a framework for treating anorexia-cachexia?

Answer 13

1. Decide if at significant risk (grade 3-4 weight loss, BMI < 18.5, reduced appetite, evidence of muscle mass)
2. Decide if primary vs secondary
3. Treat secondary causes
4. Use interdisciplinary team
5. Address family concerns
6. Emply specific tools and protocols for assessment and treatment
7. Consider exercise program (resistance ideal)
   
   1. strong antiinflammatory effects
   2. single best therapy for fatigue
8. Relevant anti-inflammatory medications
   
   1. NSAIDS (ibuprofren 400 mg po tid)
   2. EPA/DHA (1.5-2.0 g/day)

Question 14

What dietary advice would you give?

Answer 14

• enquire about specific atypical diets
• Broad balanced diet
• Total protein intake 1.5 g/kg/day
  
  • meats, eggs, dairy, protein supplements
• Improve taste
  
  • spices
  • flavouring with lemon, orange, juices, pickles
  • sugar
  • marinate meats
  • meat aversion common
  • sparkling water
• Improve food presentation
• Eat aware from odours
• Small portions, more frequently
• Social meals with atmosphere

Question 15

What about dietary supplements?

Answer 15

• Can complement regular food intake
• Omega 3 fatty acids (oily fish)
  
  • suppress IL-6 production, stop lipolysis
  • EPA 2-2.5 g/ day
  • DHA (inflammatory reducing)
    
    • may prevent platelet aggregation , incr bleeding risk?
  • 2007 cochrane review and 2021 systematic review : insufficient data.
  • Maybe more beneficial for pancreatic cancer
• Vit D.
  
  • muscle function and synthesis
  • 1000 IU daily
  • NOT IN HYPERCALCEMIA
• Vit C / multivitamin
  
  • if malnourished
  • check with oncology if chemotherapy

Question 16

Medications for anorexia and cachexia:

STEROIDS

Answer 16

• short term use, shorter life expectancy
• proximal myopathy
• could be used long term for patients in whom appetite > need to maintain mobility
• Increases appetite and wellbeing, but not necessarily weight gain
• tachyphlaxis to appetite stimulation
• Dexamethasone 4mg / day
  
  • fluorinated corticoids ++ muscle catabolism
  • Prednisone + cogeners safer, but + electrolye imbalance

Question 17

Medications for anorexia-cachexia:

CANNABINOIDS

Answer 17

• orexigenic (appetite stimulant) effects
• enhance taste and smell
• unclear evidence in Yavuzsen systemic review 2005
  
  • Dronabinol vs MA vs combo
  • Appetite increased with MA vs dronabinol.
• Multicentre trial 243 patients, double blind
  
  • cannabis extract vs dronabinol vs placebo
  • terminated due to lack of benefit
• 2 centre proof of principle study 46 cancer patients
  
  • RCT, double blind
  • dronabinol vs placebo for 18 days
  • dronabinol ++ improvements in appetite and protein intake, chemosensory enhancement

Question 18

Medications for anorexia-cachexia:

PROGESTATIONAL AGENTS

Answer 18

• Megestrol Acetate
• increases appetite
• weight gain - fat accumulation, not muscle synthesis
• catabolic muscle destruction (< steroids)
• Short term use in advanced cancer patients
• Antiinflammotry MOA
• Risks :
  
  • Thromboembolism, edema and HP-adrenal suppression
• Liquid form (more bioavailable, lower expense)
• Dose : 400 mg/day and titrate prn

-Systematic review (Yavuzsen 2005).

• 23 trials 3400 patients with varying doses of megestrol acetate
• Appetite and weight gain MA > placebo
• MA on quality of life was minimal
• 5 trials suggested optimal dose 480-800 mg per day.
• 5 trials compared MA to other drugs
• MA = steroids
• MA> dronabinol and fluoxymesterone
• MA + ibuprofen > placebo

-2013 Cochrane review

• MA vs placebo
• MA significantly improves appetite, weight, QOL
• no benefit compared to other drugs
• increased mortality (RR 1.42%), greater risk > 800 mg / day.

Question 19

Medications for anorexia-cachexia:

ANABOLIC STEROIDS

Answer 19

• hypogonadism (elderly, opioids)
• low levels of testosterone –> decreased muscle synthesis
• poor evidence:
  
  • 3 arm trial 475 patients. Megace vs dex vs fluoxymesterone (steroid)
  • megace most beneficial
  • early trial 37 patients NSCLC and chemo. Got nandrolone sc injections vs chemo alone. No stat sig difference

Question 20

Medications for anorexia-cachexia:

GASTRIC STIMULANTS and LAXATIVES

Answer 20

• Constipation
  
  • decreases appetite
  • GI dysmotility
• No evidence
• Bowel routine +
• Gastric stimulant if early satiety and bloating

Question 21

Enteral - Parenteral Nutrition

Answer 21

• Role if malnourishment result of aggressive therapy, surgery, expected to improve
• indolent malignancy causing multifocal bowel obstruction
• Benefits less clear in advanced cancer patients with primary anorexia-cachexia

Consider if:

• Cachectic patients with normal CRP (look for secondary causes)
• Well maintained muscle strength
• Life expectancy > 6 months
• Bowel obstruction
• Malabsoprtion syndrome

Question 22

Future research in anorexia-cachexia

Answer 22

• Anti-inflammation
  
  • Cytokine inhibitors (IL-1B, IL-6)
  • NSAIDS
  • Thalidomide (no benefit)
• Autonomic modulation
  
  • beta-2 antagonists and agonists
  • block sympathetic drive and stimulate muscle synthesis
• Muscle synthesis
  
  • myostatin inhibitors
  • Selective androgen-recptor modifiers (SARMS). Anabolic agents with reduced androgen effects.
  • Grehlin
    
    • hormone secreted by stomach induces growth hormone activity.
• Hypothalamic modulation
  
  • selective inhibitors of melanocortin receptor 4 (MCA4) may reduce cachexia

Question 23

Other factors that influence cachexia (comorbidities)

Answer 23

• comorbid conditions (CHF, CRF, COPD)
• old age (age related sarcopenia)
• physical deconditioning
• hypogonadism
• insulin resistance
• nutritional deficiency
• drugs
• medical interventions

Question 24

What are the health risks of cachexia?

Answer 24

• functional loss
• decreased immune fuction
• increased morbidity (falls, infections)
• increased health service utilization
• increased mortality

Question 25

Patient Generated Subjective Global Assessment (PG-SGA)

Answer 25

• validated screening tool for malnutrition
• Grade 0 (< 1.9% loss)
• Grade 1 (2-5.9% loss)
• Grade 2 (6-9.9% loss)
• Grade 3 (10-19.9% loss)
• Grade 4 (>20% loss)

STORES (muscle mass)

• height, weight, loss amount
• Grade 3/4 and/or BMI < 18.5 = HIGH RISK

INTAKE

• amount, type, frequency, satiety, sx impeding intake

PSYCHOLOGICAL IMPACT and PERFORMANCE

• impact on patient and family
• functional status (PPS, ECOG)

CATABOLIC DRIVERS (potential for reversible causes)

• stable disease, prognosis > 2 months –> nutritional intervention
• prognosis < 2 months, symptomatic management (steroids, etc)

Question 26

Measurement of tissue wasting in anorexia-cachexia

Answer 26

• sarcopenia < 5th percentile
• Whole body muscle mass CT or MRI
  
  • can determine kg skeletal muscle/m2 (often lumbar skeletal muscle index)
  • men < 55 cm2/m2, women < 39 cm2/m2
• Xray absortiometry
  
  • for arms and legs only
  • men < 7.26 kg/m2, women < 5.45 kg/m2
• Anthropometrics
  
  • mid arm circumference
  • interobserver variation, low precision
  • men < 32cm2, women <18cm2

Question 27

Definition of cachexia

Answer 27

Cachexia:

• multifactorial syndrome defined by ongoing loss of skeletal muscle mass (with or without loss of fat) that cannot be reversed by conventional nutritional support.
• Leads to progressive functional impairment
• negative protein and energy balance
• driven by reduced food intake and abnormal metabolism
• inflammation MOA

Classification :

• WEIGHT LOSS > 10%
• REDUCED FOOD INTAKE < 15oo kcal/day
• SYSTEMIC INFLAMMATION CRP > 10mg/L
• FUNCTIONAL IMPAIRMENT
• PSYCHOSOCIAL IMPAIRMENT
• ANOREXIA

Question 28

Significant literature for anorexia-cachexia

Answer 28

Yavuzsen et al 2005.

• Systematic review of pharmacological therapies for cancer associated anorexia and weight loss in adult patients with non-hematological malignancies.
• 55 randomized controlled trial
• Only progestins and corticosteroids had sufficient evidence for use in cancer patients
• Heterogeneity of trials ++

Question 29

Olanzapine for anorexia-cachexia

Answer 29

• Olanzapine
  
  • 5mg/day trial
  • useful if also n/v
  • insufficicent evidence, small RCT 30 patients with n/v no chemo. Olanzapine - sig appetite improvement

Question 30

HIV and anorexia-cachexia

Answer 30

• Anabolic steroids
• Recombinant human growth hormone (rhGH)
• Dronabinol
• Megace
• Thalidomide
• Amino acids
• Multiple agents combined

Question 31

COPD and anorexia-cachexia

Answer 31

• Anabolic steroids
• Megace
• Growth hormone
• Polyunsaturated fatty acids
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