Fatigue in Palliative Care Dr Anne Hounsell, Speciality Doctor (with special thanks to PT Lucy and OT Chrissie) Objectives Definition Who gets fatigued and why Pathophysiology Assessing What fatigue
can be done to help behavioural, psychological, medication Personal experience of fatigue What does it feel like? What do you struggle with? . 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. Our patients experiences of fatigue. 1)How do they describe it? 2) How does it affect them? Small groups Like wading through treacle
Heavy legs Uncomfortabl e Restless No strength I tire very easily Washed out Worn out
No energy Exhausted Weak Wiped out Drained So tired I cant concentrate No desire to
do anything Sluggish Definition continued Reduced capacity to maintain performance reduced FS and AKPS Often 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) 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 Causes of fatigue in our patient population?
Symptoms Pain, SOB, N/V Psychologic al Adjustment reaction, depression, anxiety, family stress Cancer itself Treatment Chemotherapy RT
Medications surgery Inflammation Altered metabolism Muscle and CNS ACS, Anaemia Paraneoplastic Cancer Related Fatigue Nutrition Sleep Anorexia, N/V
endocrine, infection Fatigue induced by treatments Not fully understood. Directly RT/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 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 . Pathophysiology of
Fatigue Proposed Pathophysiology of CRF Inflammatio n Cytokines Others Muscle abnormalities 1. CNS abnormalities Cancer Induced Fatigue Altered Metabolism
5HT AnorexiaCachexia Syndrome Endocrine Changes HPA axis Testosterone 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
2) Altered Metabolism and endocrine systems Cytokines Serotonin 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) Testosterone Deficiency Loss of muscle mass, fatigue, reduced libido, anaemia Due to :
Hypothalamic pituitary-adrenal axis dysfunction Anorexia-Cachexia Syndrome Treatment hypogonadism due to : chemotherapy, RT : anti-androgens (prostate cancer) 3)Muscle abnormalities Impaired muscle function is one of the main underlying mechanism of fatigue A)The cancer and the bodys response to the cancer
Increase in cytokines, lactate Loss of muscle (ACS, atrophy, altered protein synthesis and breakdown) Abnormal enzyme activity and muscle metabolism Reduced testosterone
Paraneoplastic (eg polymyositis) 3)Muscle abnormalities continued B) Due to medications Steroids Cyclopsorin 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 4) Central Nervous System Abnormalities Perception or induction of fatigue by the CNS important but not well understood. General Experience 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 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 .. 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) Assessing Fatigue? 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
-Pace -Eliminate unnecessary activities -Ask for/accept help Energy Conservation continued Pacing Encourage patients to remain active balancing rest and activity Focus on enjoyable important activity
Break 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 2) Exercise
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. Other Practical Tips to Help Fatigue Sleep Use relaxation techniques to settle busy minds
Routine hours, limit the naps Sleep 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 Other Practical Tips to Help Fatigue Memory/cognition
Keep a diary/lists/pin boards/notes Take 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 Living Well Centre groups Living Better, Living Well.
8 weekly sessions (though can drop in and out of) Run by OT and PT Information on fatigue, stress, anxiety, relaxation, sleep, pain management Well 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. Possible Medications for Fatigue? 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 Dexamethasone 2-4mg OD (what is the best dose?) 2-4 week effect Mechanism of action unknown ? Inhibition of tumour induced substances Often 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 Methylphenidate Psychostimulant. Increase DA/A/NA in prefrontal cortex Main 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. 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. 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)
Modafenil For narcolepsy, obstructive sleep apnoea, sleepiness ? enhances DA and orexin levels in hypothalamus -heightened arousal Suggested 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. Etanercept Used for rheumatoid arthritis, ankylosing spondylosis, psoriatic arthritis Tumour necrosis factor inhibitor TNFi - a soluble inflammatory
cytokine Paper (5) : Given for psoriasis but significant and meaningful reduction in fatigue 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)
Summary -1 Definition Fatigue -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. Summary -2 Assessing fatigue Impact 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. Thankyou for listening References Breathless Intervention Service Cambridge University Hospitals. Factsheet 4 fatigue. Oxford Handbook of Palliative Medicine, PCF
Practical 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-Whats 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
Appendices More information on: -Definition -Pathogenesis -Relationship between cachexia and fatigue -Assessing fatigue (including tools) -Evidence for medications Whats in a name? Word descriptors of cancer related fatigue (3) 3 fatigue word descriptors : -easy fatigue, weakness, lack of energy
1000 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. Other Pathogenesis theories vEGF inhibition (vascular endothelial growth factor) angiogenesistumour growth. Inhibitors (eg sunitinib) hypothyroidism. Vagal afferent activation serotonin, cytokines, prostaglandins activate the vagal nerve reduced somatic output
ATP hyopthesisdecrease in regeneration, build up of by products. ATP is the energy source for muscles contraction. (See reference 9) Other Neurological Factors Contributing to Fatigue Autonomic dysfunction Common complication of advanced cancer Malnutrition/ 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 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 Cachexia Fatigue 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. Edmonton Functional Assessment Checklist*** For patients with advanced cancer
(ECOG/AKPS can be less helpful at lower numbers and dont 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 Multidimensional Scales Chalder Fatigue Scale - FACIT Questionnares Functional Assessment of chronic illness/ cancer therapy fatigue A number for different symptoms and conditions: eg -F fatigue, An anaemia/fatigue, Pal palliative care Often used in research Evidence for Dexamethasone Study (6)dexamethasone vs placebo Prospective randomised double blinded study -6
132 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. Evidence for Methylphenidate Evidence in HIV fatigue Weak 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. 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 4aminopyridine, expert opinion for modafinil. Evidence for Etanercept Paper (5) :
50mg twice a weak given for psoriasis, vs placebo 618 pts, with mild to moderate psoriasis Secondary endpoint FACIT F At 12 weeks significant and clinical meaningful reduction in fatigue (stat significant, p< 0.0001) and less joint problems
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