Fatigue in Palliative Care - PowerPoint Presentation

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Fatigue in Palliative Care

Dr Anne Hounsell, Speciality Doctor(with special thanks to PT Lucy and OT Chrissie)

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Objectives

DefinitionWho gets fatigued and whyPathophysiologyAssessing fatigueWhat can be done to help – behavioural, psychological, medication

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Personal experience of fatigue

What does it feel like?What do you struggle with?

.

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Definition

“A distressing persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is

not proportional

to recent activity and interferes with usual functioning.”

2012 National Comprehensive Cancer Network

Intensity is the key between that in healthy patients and that in palliative care patients.

The definition is tricky.

Wording important.

Weakness is thought to paraphrase the physical dimension.

Tiredness thought to paraphrase the cognitive dimension.

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Our patients’ experiences of fatigue.

1)How do they describe it?2) How does it affect them?

Small groups

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Definition continued

Reduced capacity to maintain performance –reduced FS and AKPSOften co-exists with a number of other

symptoms

–

eg

anorexia, pain, SOB

Includes mental fatigue –decrease in concentration and memory, emotional lability. Reduced ability to make decisions.

Cancer related fatigue –vicious circle of decreased physical performance, inactivity, avoidance of effort, absence of regeneration, helplessness and depressed mood.

Affects QOL, functional status, mood and social interactions

(So you think you are tired? MS fatigue

youtube

)

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Background

Almost a universal experience in our patients: -60-90% prevalence in patients with advanced cancer. - 48-78% in palliative care setting.

Likelihood increases with recurrence/progression of disease.

One of the most distressing symptom.

(3) –most prevalence in colorectal and pancreatic cancers

-least prevalence in prostate cancers

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Causes of fatigue in our patient population?

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Fatigue induced by treatments

Not fully understood.DirectlyRT/chemotherapy SEs:Anaemia, diarrhoea, anorexia, weight loss, N/V

Medication SEs

:

Steroids and ciclosporin –myopathy

Opioids -effects on RAS

Others -midazolam,

cyclizine

, gabapentin, amitriptyline, levomepromazine, sertraline

Indirectly

Eg

the treatment can cause pain which in turn can contribute to fatigue

Eg

–immunosuppression –infection –catabolic state

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Psychological Issues

Anxiety, low mood, distress all contribute to fatigue though nature of this relationship is unclear. Needs further research-Adjustment reaction-Low mood –cognitive slowing-Loss of control/independence

-Unable to complete their planned ideal goals

-Social isolation

-Family/personal pressure of doing too much ….

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Pathophysiology of Fatigue

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Proposed Pathophysiology of CRF

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1) Inflammation and cytokines

Cytokines eg TNF alpha, IL1/6 –from tumour and cancer treatments. Excess inflammation Altered metabolism. Can contribute to cachexia, fever, anorexia.

Can affect the HPA (hypothalamic-pituitary-adrenal axis)

Also tumours secrete lipolytic and proteolytic factors

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2) Altered Metabolism and endocrine systems

CytokinesSerotonin –Increases in hypothalamus.

-Decreases motor drive and affects HPA.

Hypothalamic pituitary axis –

dysfunction includes reduced CRH.

- reduced cortisol ( also less cytokine inhibition).

- altered stress response and circadian rhythms.

Testosterone Deficiency

Anorexia Cachexia Syndrome

(See reference 9)

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Testosterone Deficiency

Loss of muscle mass, fatigue, reduced libido, anaemiaDue to :Hypothalamic –pituitary-adrenal axis dysfunction

Anorexia-Cachexia Syndrome

Treatment –hypogonadism due to : chemotherapy, RT

: anti-androgens (prostate cancer)

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3)Muscle abnormalities

Impaired muscle function is one of the main underlying mechanism of fatigueA)The cancer and the body’s response to the cancerIncrease in cytokines, lactate

Loss of muscle (ACS, atrophy, altered protein synthesis and breakdown)

Abnormal enzyme activity and muscle metabolism

Reduced testosterone

Paraneoplastic (

eg

polymyositis)

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3)Muscle abnormalities continued

B) Due to medicationsSteroidsCyclopsorin –mitochondrial myopathies

C) Due to deconditioning

Prolonged best rest and inactivity –reduced muscle mass and reduced cardiac output –causes reduction in endurance

D) Due to over-exertion

Esp

in younger pts with aggressive treatment trying to maintain job/social life etc

E) Non malignant neurological conditions

Eg

MS, MND

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4) Central Nervous System Abnormalities

Perception or induction of fatigue by the CNS –important but not well understood.GeneralExperience of fatigue controlled by the reticular activating system?

Disturbed cognitive functioning can contribute to fatigue

Paraneoplastic

Cancer specific

Brain tumours/metastases.

Esp

if invades pituitary gland

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5)Anorexia Cachexia Syndrome

Involuntary weight loss + 3 of the following: -reduced muscle strength -reduced muscle mass -fatigue

-anorexia

-biochemical abnormalities (

eg

raised CPR, lowered Hb/albumin)

Increase in cytokines

Occurs in other long term conditions not just cancer –

eg

HF/lung disease

A catabolic state

Malnutrition can worsen.

NB

however often no obvious link between weight loss/fatigue/malnutrition …..

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6) Anaemia

Anaemia is common in cancer patients :Bone marrow infiltration /failure (myeloma, bone metastases, leukaemia) chemotherapy)Bleeding (eg GI cancer)

Haemolysis

Anaemia occurs in our non cancer patients also

eg

:

Renal failure –lack of

erythropoetin

Anaemia of chronic disease

Malabsorption –

eg

Fe, B 12 or folate deficiency

Bleeding (

eg

peptic ulcer)

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Assessing Fatigue?

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Assessing fatigue

Firstly a comprehensive general assessment (often multiple causes).Severity, onset, duration, level of interference with life, associated cognitive psychological or social problems. No gold standard tools for formally assessing fatigue. Complex as multidimensional and subjective.

Functional capacity

eg

treadmill, driving

Performance Status

AKPS, ECOG, Edmonton functional assessment tool

Subjective Assessment tools

Unidimensional - NRS/VRS,

Mulidimensional

–MANY!! Chalder, Fatigue Severity Scale, FACTIT, Brief Fatigue Inventory , Piper Fatigue Scale.

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Subjective Assessment Tools

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Visual Analogue Scale

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Managing Fatigue?

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1)Energy Conservation

Principles:-Plan-Prioritise

-Pace

-Eliminate unnecessary activities

-Ask for/accept help

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Energy Conservation continued

PacingEncourage patients to remain active – balancing rest and activityFocus on enjoyable important activityBreak into manageable chunks

Set achievable goals. Completion psychologically important

Activity /fatigue diary might be helpful

Even phone calls can be tiring

Emotional energy used up

eg

with staff talking too long.

Discussions with relatives present so they understand also

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2) Exercise

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Rest vs Exercise

Increased rest may exacerbate the problem.Leading to loss of muscle strength and lower energy levels.Alongside energy conservation, exercise is important:

(the balance depending on the patients situation)

Reduces tiredness, boosts mood, stimulates appetite, aids sleep and improves self esteem.

It can also help build muscle strength, improve heart and bone health, and help with managing constipation.

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Other Practical Tips to Help Fatigue

SleepUse relaxation techniques to settle busy mindsRoutine hours, limit the napsSleep in a cool room

Short term course of sleeping tablets –reset cycle?

Diet

Digestion uses up a lot of energy (postprandial nap)

Eat little and often

Depends a little on prognosis (balanced diet/forget the rules)

Drink plenty of fluids

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Other Practical Tips to Help Fatigue

Memory/cognitionKeep a diary/lists/pin boards/notesTake someone with you to appointments

Emotions/Stress

Focus on the positives and what

can

be done.

Realistic goals

Distraction (

eg

craft supplies), relaxation techniques, mindfulness

Talking therapies

Complementary therapies –Acupuncture, Aromatherapy, Reflexology, Massage etc

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Living Well Centre groups

Living Better, Living Well. 8 weekly sessions (though can drop in and out of) Run by OT and PTInformation on fatigue, stress, anxiety, relaxation, sleep, pain managementWell Being Exercise Group

Pace according to the individual. Referral from PT needed

Chair Based Exercise Group

Referral from PT needed

Living with Breathlessness

Includes information on fatigue.

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Possible Medications for Fatigue?

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Possible Medication for fatigue

Dexamethasone Methylphenidate

Megestrol acetate

Amantadine

Modafenil

(Etanercept)

Studies are heterogenous, with variable definitions and outcome parameters

Limited evidence such that a particular medication for CRF cannot be recommended

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Dexamethasone

2-4mg OD (what is the best dose?) 2-4 week effectMechanism of action unknown ? Inhibition of tumour induced substancesOften used but minimal evidence

Study (6) –dexamethasone vs placebo –

-4mg BD dexamethasone for 14 days. Physical aspects of the scale improved but not the emotional or psychological aspects.

Most studies have used 40mg prednisolone

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Methylphenidate

Psychostimulant.Increase DA/A/NA in prefrontal cortexMain use in ADHD Off licence for patients with advanced cancers with fatigue/depression/opioid induced sedation start 2.5-5mg BD. Usual maximum dose 20mg BD

Conflicting evidence

Suggested by NCCN guidelines for those active cancer

- at end of life and no other reversible factors.

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Progestogens

Eg Megestrol acetate (MEGACE) or cyproterone acetate

Modulates cytokine production and effects.

MEGACE -80-800mg OD

Rapid improvement in about 10 days

Efficacy in cachexia is debatable

Can help with anorexia.

Expensive, side effects

Better for long term than steroids

.

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Amantadine

Licensed for use in Parkinsons disease and some viral infections Side effects –insomnia and vivid dreams.Use in Multiple Sclerosis-Fatigue is a common and disabling feature-Mechanism unclear -?effect on the immune system, ?amphetamine like action

-100mg OD PO

-

Generally the studies are inconclusive but promising.

-

NICE recommends

offer amantadine (may be small benefit)

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Modafenil

For narcolepsy, obstructive sleep apnoea, sleepiness? enhances DA and orexin levels in hypothalamus -heightened arousalSuggested for MS patients (not in NICE), but weak to inconclusive evidence (1). Only consider if MS and narcolepsy if benefits > risks (4)

Can have significant SEs –psychiatric, cardiovascular, skin.

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Etanercept

Used for rheumatoid arthritis, ankylosing spondylosis, psoriatic arthritisTumour necrosis factor inhibitor –TNFi - a soluble inflammatory cytokine Paper (5) :Given for psoriasis but significant and meaningful reduction in fatigue

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However …..In the final stages of life, fatigue can provide protection and shielding from suffering.

Therefore treatment might be detrimental. Its important to identify when treatment is no longer indicated to alleviate distress –’giving permission’ (2)

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Summary -1

DefinitionFatigue -distressing, persistent, subjective sensation of physical/emotional/cognitive tiredness/exhaustion. Interferes with usual functioning and profound effect on QOL.

Who gets fatigued and why?

Common symptom in many palliative care patients –cancer, COPD, HF, MND, MS.

Related to the condition itself, medications, treatments, nutrition, sleep, psychological and other symptoms.

Pathophysiology

Inflammation and cytokines.

Altered metabolism and endocrine systems (including 5HT, testosterone, HPA, ACS)

Muscle and CNS abnormalities.

Anaemia.

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Summary -2

Assessing fatigueImpact on function, QOL. Ask about associated symptoms.Multidimensional. Scales and tools

eg

NRS, AKPS, Fatigue severity scale.

What can be done to help?

Treat reversible components if appropriate.

Education (+ family), energy conservation (plan, prioritise, pacing), exercise, psychological support.

Limited evidence for particular medications. Examples are dexamethasone, methylphenidate, progestogens, amantadine,

modafenil

.

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Thankyou for listening

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References

Breathless Intervention Service –Cambridge University Hospitals. Factsheet 4 –fatigue.Oxford Handbook of Palliative Medicine, PCFPractical Approaches to Cancer Related Fatigue, Chrissie Carden-Noad

1-Pharmacological Treatments for Fatigue Associated with Palliative care, Google scholar,

Mucke

et al, May 15

2-Fatigue in Palliative Care Patients –European Association of Palliative Medicine Approach. Palliative Medicine (journal).

L.Radbruch

et al. Jan 2008

3-What’s in a name? Word Descriptors of Cancer Related Fatigue. Journal of Palliative Medicine. 2010,

K.Hauser

et al

4-Modafenil in MS, 2013

5-Etanercept and clinical outcomes, fatigue and depression in Psoriasis. A double blinded placebo CR phase 3 trial. The Lancet 2005,

Tyring

at al

6-HaemOnc today –Dexamethasone can provide short term care relief from cancer related fatigue. K Lisa, Jan 14

7-Effect of

methyphenidate

in patients With CRF: a systematic review and meta-analysis. NCBI –US national library of medicine,

Plos

one, 2014,

S.Gong

8-Effect of Amantadine for the treatment of fatigue in people with MS. Cochrane, 2007, Pucci et al

9-Pathophysiology on cancer related fatigue, Clinical Journal of Oncology

Nursing.Oct

08,

X.S.Wang

Fatigue and fatiguability in neurological diseases. Neurology, Jan 2013,

B.Kluger

at al

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Appendices

More information on:-Definition-Pathogenesis-Relationship between cachexia and fatigue

-Assessing fatigue (including tools)

-Evidence for medications

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What’s in a name? Word descriptors of cancer related fatigue (3)

3 fatigue word descriptors : -easy fatigue, weakness, lack of energy1000 palliative patients completed symptom checklist.Fatigue -69%

-associated with depression, diarrhoea and SOB

-not associated with anxiety or PS.

Weakness -66%

-associated with PS, anorexia, nausea and sedation

-not associated anxiety or depression or pain. (opioids as possible cause/contributor?)

-shorter survival

Lack of energy -61%

-associated with anxiety, depression, diarrhoea and SOB

-not associated with PS

Evaluation of fatigue should use multiple descriptors.

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Other Pathogenesis theories

vEGF inhibition (vascular endothelial growth factor) –angiogenesis-tumour growth. Inhibitors (

eg

sunitinib) –hypothyroidism.

Vagal afferent activation

–

serotonin, cytokines, prostaglandins –activate the vagal nerve –reduced somatic output

ATP

hyopthesis

–decrease in regeneration, build up of by products. ATP is the energy source for muscles contraction.

(See reference 9)

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Other Neurological Factors Contributing to Fatigue

Autonomic dysfunctionCommon complication of advanced cancerMalnutrition/ delayed gastric emptying/chronic nausea/ anorexia/ postural hypotension and poor PS.

Link with fatigue not established-more work needed

Paraneoplastic syndromes

May even precede the diagnosis of the cancer

Myasthenia gravis –thymoma, lymphoma

Eaton Lambert syndrome –strong

assoc

with SCLC

Dermatomyositis, polymyositis – 50% have cancer

Guillian

Barre syndrome (ascending acute polyneuropathy) –lymphoma

Subacute necrotic myelopathy –lung cancer

Paraneoplastic encephalomyelitis –lung cancers

Progressive multifocal

leucencephalopathy

– leukaemia and lymphoma

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Relationship between Cachexia and Fatigue

Not everyone who is cachectic has fatigue.Cachexia alone

–

eg

anorexia nervosa, some cancer patients

Fatigue alone

–

eg

early breast cancer, lymphoma, over exertion, infection, non palliative conditions –

eg

CFS, Fibromyalgia

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Assessing fatigue

Firstly a comprehensive general assessment is needed as there are often multiple causes.Need to ask about severity, onset, duration, level of interference with life, associated psychological or social problems. There are no gold standard tools for formally assessing fatigue. Complex as multidimensional and subjective.

Functional capacity

eg

treadmill (speed and duration), number of errors (

eg

driving), 6 minute walk.

Task related fatigue

VAS/NRS.

Pearsons

and

Byars

fatigue feeling checklist

Performance Status

AKPS, ECOG (European co-operative oncology group), Edmonton functional assessment tool

Subjective Assessment tools

Unidimensional - NRS/VRS,

Mulidimensional

–MANY!! Chalder, Fatigue Severity Scale, FACTIT, Brief Fatigue Inventory , Piper Fatigue Scale.

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Edmonton Functional Assessment Checklist***

For patients with advanced cancer (ECOG/AKPS can be less helpful at lower numbers and don’t help advise about rehab potential)Physio led. To determine functional status in addition to identifying obstacles to clinical performance. 0 –normal, 4 unable perform at all

Communication, mental status, pain, dyspnoea, balance (sitting, standing), mobility (around bed for example), locomotion (walking, wheelchair etc), fatigue, motivation, ADLs, PS

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Multidimensional Scales

Chalder Fatigue Scale -

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FACIT Questionnares

Functional Assessment of chronic illness/ cancer therapy fatigueA number for different symptoms and conditions:

eg

-F –fatigue, An –anaemia/fatigue, Pal –palliative care

Often used in research

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Evidence for Dexamethasone

Study –(6)–dexamethasone vs placeboProspective randomised double blinded study -6132 pts with advanced cancer. Baseline -90% moderate/severe CRF

4mg BD dexamethasone for 14 days. FACIT F scale used on day 8 and 15.

Mean score –placebo 3.1, dexamethasone 9.

Physical aspects of the scale improved but not the emotional or psychological aspects.

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Evidence for Methylphenidate

Evidence in HIV fatigueWeak evidence in CRF (extrapolation, small samples, short follow up):1 study –superior effect in CRF (0.49 standard mean difference on function Ax

) –(1)

Systematic review –therapeutic effect and efficacy increased with time in some, not in others. On CRF not on depression or cognition. Large placebo effect. Subgroup analysis –better with long term use and in patients with more severe fatigue. Cannot recommend but is promising. -(7)

1 PAPER –(7) –Meta -analysis. 498 pts with CRF. -5X RCTS Primary outcome fatigue (FACIT-F and BFI). Secondary outcome depression, cognition, side effects. Therapeutic effect on CRF but not on depression or cognition. More vertigo, anxiety and nausea.

1 study –evidence for improvement at 6 weeks –weak

1 study –max 50mg. Significant improvement at 8 weeks

1 study –up to 15mg BD. No significant difference compared with placebo.

1 study –up to 54mg by 4 weeks –no statistically significant improvement

1 study –at 8 days. Improvement in both groups.

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Evidence for amantadine

Evidence in MS

-Cochrane review –heterogeneous studies (5)-:

1 study – no improvement

1 study –more efficacy, ,poor tolerability

-RCTs x 5- 3 vs placebo, 2 vs other medications. Use varied from 1 week to 3 months. Little information on tolerability. No clear recommendations can be made.

-CT – aspirin vs amantadine –no difference

-CT -1month amantadine –significant improvement

-1m a L -

acetycarnitine

–significant improvement

-1m modafinil -no change

-1 study- moderate improvement in subjective fatigue, concentration, memory and problem solving. Fairly well tolerated. Strong evidence for amantadine. Moderate for L-

acetylcaritine

and 4-aminopyridine, expert opinion for modafinil.

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Evidence for Etanercept

Paper (5) :50mg twice a weak given for psoriasis, vs placebo618 pts, with mild to moderate psoriasis Secondary endpoint –FACIT FAt 12 weeks –significant and clinical meaningful reduction in fatigue (stat significant, p< 0.0001) and less joint problems