Cancer-related fatigue: where next? Cambridge Pancreatic Cancer Symposium 2013 Anna Spathis, Consultant in Palliative Medicine

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1 Cancer-related fatigue: where next? Cambridge Pancreatic Cancer Symposium 2013 Anna Spathis, Consultant in Palliative Medicine

2 A distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness... that is not proportional to recent activity and interferes with usual functioning (NCCN 2011) It s a horrible feeling you don t belong anymore... Life goes on without me. I feel like someone let the plug out...just getting through each day... I did not have the physical or emotional energy to give to anyone else... a very humbling and isolating experience I am just not myself Why can t I be me again? Like wet cement

3 Outline Size of the problem Prevalence, impact Potential mechanisms Symptom clusters, pathogenesis Management Pharmacological, non-pharmacological

Prevalence Most common symptom 30%-50% at diagnosis 80-100% on treatment 20-70% survivors No differences between

4 Prevalence Most common symptom 30%-50% at diagnosis % on treatment 20-70% survivors No differences between cancer sites (Kirkova 2011) Prevalence moderate/severe symptoms in pancreatic cancer (Reyes-Gibby et al, JPSM 2007)

5 Impact Most negative impact QOL, functioning Psychological Socio-economic Reduced survival Baseline FACIT-F score strongly predicts prognosis in pancreatic cancer patients with cachexia (Robinson et al, J Support Oncol 2008)

6 Symptom clusters Yeo et al, patients pancreatic cancer post resection Exercise intervention 85% fatigue at baseline (VAS>5) Most prevalent symptom cluster (in 61 of 102 patients): Fatigue (97%) Anxiety (64%) Pain (72%) Insomnia (30%) Depression (69%) Dyspnoea (20%) Weakness (67%)

7 Symptom clusters Cancer Shared mechanism Concurrent mechanisms Fatigue Breathless Depression Insomnia Pain

8 Symptom interaction Inefficient breathing pattern Increased work of breathing Breathlessness Disturbed sleep Reduced activity Deconditioning Fatigue

9 Neurasthenia [nervous exhaustion] has been the central Africa of medicine an unexplored territory into which few may enter and those few have been compelled to bring back reports that have been neither credited or comprehended Beard, 1880

10 Potential mechanisms 1. Proinflammatory cytokines 2. HPA axis dysfunction 3. Circadian rhythm disruption 4. Serotonin dysregulation 5. Muscle metabolism dysregulation

11 1. Proinflammatory cytokines Fatigued breast cancer survivors have elevated markers of proinflammatory activity (Bower et al, Psychosomatic Medicine 2002) Evidence of T-cell mediated inflammatory process (Bower et al, Journal National Cancer Institute 2003)

12 1. Proinflammatory cytokines Schubert et al, Brain Behav Immun 2007 Review of 19 studies (1037 participants) Positive correlation fatigue and inflammatory markers (p<0.0001) IL-6 (p=0.004) IL-1 ra (p=0.0005) Neopterin (p=0.0001) [Not TNF- (p=0.34)] Monk et al, J Clin Oncol 2006 Etanercept blocks interaction TNF- α with its receptors Etancercept/docetaxel less fatigue than docetaxel alone (p<0.001)

13 2. HPA axis dysfunction (O Connor, QJ Med 2000)

14 2. HPA axis dysfunction Fatigued women had lower serum levels of cortisol during morning peak than non-fatigued controls (p=0.02) (Bower et al, Psychosomatic Medicine 2002) Fatigued breast cancer survivors have flatter cortisol slope Increased fatigue severity correlates with flatter slope (Bower et al, Psychoneuroendocrinology 2005)

15 2. HPA axis dysfunction Breast cancer survivors undertaking a Social Stress Test Fatigued women had blunted response to stressor (Bower et al, Psychosomatic Medicine 2005)

16 3. Circadian rhythm disruption Changes in many endocrine, metabolic, immune and restactivity rhythms in cancer More advanced disease, greater rhythm alterations Evidence for significant correlation with fatigue (Roscoe et al, Support Care Cancer 2002)

17 4. Serotonin dysregulation Increased central 5HT in exercise induced fatigue Up-regulation of 5HT receptors in cancer Proinflammatory cytokines may have a role SSRIs reduce capacity to perform exercise Conflicting evidence 5HT3 antagonists in chronic fatigue syndrome

5. Muscle metabolism dysregulation ATP Evidence depleted cellular ATP in cancer and chronic fatigue syndrome (CFS) Agterish 2000: ATP infusion in NSCLC improves muscle strength,

18 5. Muscle metabolism dysregulation ATP Evidence depleted cellular ATP in cancer and chronic fatigue syndrome (CFS) Agterish 2000: ATP infusion in NSCLC improves muscle strength, tiredness, energy, appetite Forsyth 1999: Oral NADH decreases fatigue in CFS Proteolysis TNF-α and tumour factor PIF increase protein degradation through ubiquitin proteasome pathway

19 Depression and fatigue 1) HPA axis: hypofunction in fatigue vs. hyperfunction in depression 2) 5HT regulation: SSRIs improve depression, but not fatigue (Morrow et al, JCO 2003)

20 Depression and fatigue 3) Inflammation Raison et al, Curr Psychiatry Rep 2011 Only a subset of depressed patients have systemic inflammation Bower et al, J Clin Oncol 2011 Role for TNF-α in chemotherapy induced fatigue Depression and sleep disturbance correlate with fatigue but not TNF-α Overall, depression and fatigue some distinct mechanisms

21 Fatigue management model Predisposing factors Precipitating factors Perpetuating factors Examples Pre-treatment fatigue, depression, pain, sleep disturbance, stress Treatments, anaemia, onset of symptoms, hospitalisation, distress Maladaptive behaviours relating to activity, sleep, nutrition. Cognitive misconceptions Actions Proactively identify and assess high risk patients Identify and treat potentially reversible causes Education Psychological approaches

22 Management: reversible precipitants De Raaf et al, J Clin Oncol fatigued patients advanced cancer Randomised to protocolized symptom control vs. usual care Significant improvements in fatigue at 2 months (p=0.005, effect size 0.35)

23 Management: pharmacological Minton et al, Cochrane Database Systematic Reviews 2010 Drug Std. mean difference 95% CI Psychostimulants , Erythropoetin , Antidepressants , 0.07 Progestational steroids , 0.75 Psychostimulants FACT-F WMD of 2.21, not clinically significant Erythropoetin No longer recommended because safety concerns

24 Antidepressants Publication bias 94% positive published studies 51% positive published and unpublished studies Modest effect size Only clinically significant in severe depression, limited long-term efficacy Decline in efficacy of placebo rather than increase in efficacy of drug Increase susceptibility to relapse Adverse effects Bleeding, hyponatraemia, neuronal damage etc (Turner 2008, Kirsch 2008, Andrews 2012)

25 Too much medicine?

26 Management: non-pharmacological Exercise Cramp et al, Cochrane Database Systematic Reviews studies, 2083 participants (1172 breast cancer) Exercise effective, SMD -0.23, 95% CI -0.33, Yeo et al, Journal American College of Surgeons patients with pancreatic cancer post resection Randomised to walking programme or usual care

27 (Yeo, J Am Coll Surgeons 2012)

28 Management: non-pharmacological Psychosocial interventions Geodendrop et al, Cochrane Database SR 2009 During treatment: education, activity management 4 of 5 fatigue focused studies positive 3 of 22 remaining studies positive Gielissen et al, J Clin Onc 2006, Br J Cancer 2007 CBT improves fatigue in cancer survivors Addresses misconceptions, maladaptive behaviours Benefits maintained long term

29 Management in practice Identify and assess high risk individuals Actively manage reversible causes, particularly concurrent symptoms Non-pharmacological approaches best: The three Es Education Exercise Energy conservation Components Balance of rest and activity Preventing deconditioning vicious cycle Goal setting, graded increments Diary Prioritising, pacing, delegating, relaxation techniques, sleep hygiene

30 Sleep hygiene Improve the sleep environment Quiet, dark, 18ºC bedroom Avoid using bedroom for other activities Improve sleep-wake patterns Avoid naps (unless short and after lunch) Daylight and exercise in afternoon Hot bath ideally one hour before sleep Regular, relaxing pre-sleep routine Light snack or milky drink Relatively fixed bedtime and waking time Optimise bladder and bowel function Optimise drug intake Avoid caffeine, alcohol, steroids Change diuretic timing Sleep hygiene alone can improve sleep in cancer patients (Epstein 2007)

31 What next...? Develop targeted approaches that relate to mechanisms Melatonin to promote circadian function Anti-cytokines eg anti IL-6R antibody, tocilizumab Oral NAD to increase ATP Proactively anticipate fatigue and educate patients and carers Keeping active, preventing deconditioning vicious cycle Prioritisation, pacing, sleep hygiene Multidisciplinary approach Allied Health Professionals, Fatigue Group

32 References Agteresch J et al. Randomised clinical trial of adenosine 5-triphosphate in patients with advanced non small cell lung cancer. Journal of the National Cancer Institute 2000;92(4): Andrews P et al. Primum non nocere: an evolutionary analysis of whether antidepressants do more harm than good. Frontiers in Psychology 2012;3 article 117 Bower JE et al. Inflammation and behavioural symptoms after breast cancer treatment: do fatigue depression and sleep disturbance share a common underlying mechanism? J Clin Oncol 2011;29(26): Bower JE et al. Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinology 2005;30(1): Bower JE et al. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosomatic Medicine 2002;64: Cramp F et al. Exercise for the mangement of cancer-related fatigue in adults. Cochrane Database of Systematic Reviews 2010;Issue 2:Art No: CD Robinson D et al. The prognostic significance of patient-reported outcomes in pancreatic cancer cachexia. J Support Oncol 2008;6: De Raaf et al. Systematic monitoring and treatment of physical symptoms to alleviate fatigue in patients with advanced cancer: a randomized controlled trial. J Clin Oncol 2013;31(6):716 Gielissen M et al. Effects of CBT in severely fatigued disease-free cancer patients compared with patients waiting for CBT: a randomised controlled trial. J Clin Oncol 2006;24(30: Gielissen M et al. Cognitive behavioural therapy for fatigued cancer survivors: long-term follow up. Br J Cancer 2007;97(5): Goedendrop M et al. Psychological interventions for reducing fatigue during cancer treatment in adults. Cochrane Database of Systematic Reviews 2009;Issue 1:Art No: CD006953

33 References Kirkova J et al. The relationship between symptom prevalence and severity and cancer primary site in 796 patients with advanced cancer. Am J Hosp Palliat Care 2001;28(5): Kirsch I et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PloSMed. 2008;5, e45.doi: /journal.pmed Minton O et al. Drug therapy for the management of cancer-related fatigue. Cochrane Database of Systematic Reviews 2010;Issue 7:Art No: CD Monk JP et al. Assessment of Tumor Necrosis Factor Alpha blockage as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J Clin Oncol 2006;24(12): Morrow G et al. Differential effects of paroxetine on fatigue and depression: a randomized, doubleblind trial from the University of Rochester. J Clin Oncol 2003;21(24): Reyes-Gibby C et al. Patterns of self-reported symptoms in pancreatic cancer patients receiving chemoradiation. J Pain Sy Manage2007;34(3): Riason C et al. Interferon-α effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry 2010;15(5): Roscoe J et al. Temporal interrelationships among fatigue, circadian rhythm and depression in breast cancer patients undergoing chemotherapy treatment. Support Care Cancer 2002;10: Schubert C et al. The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain Behav Immun 2007;21(4): Turner E et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358: Yeo T et al. A progressive postresection walking program significantly improves fatigue and healthrelated quality of life in pancreas and periampullary cancer patients. J Am Coll Surg 2012;214:

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