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Exercise for Fatigue Effective Treatment for Breast Cancer Survivors Lynn Gerber, MD College of Health and Human Services Center for Chronic Illness and.

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Presentation on theme: "Exercise for Fatigue Effective Treatment for Breast Cancer Survivors Lynn Gerber, MD College of Health and Human Services Center for Chronic Illness and."— Presentation transcript:

1 Exercise for Fatigue Effective Treatment for Breast Cancer Survivors Lynn Gerber, MD College of Health and Human Services Center for Chronic Illness and Disability

2 Fatigue lasting >2 weeks, each day Associated with distress and functional loss Clinical association with cancer diagnosis and/or chemotherapy Not explained by primary psychiatric diagnosis (eg depression) – guidelines/breast/index.html#/110/ guidelines/breast/index.html#/110/ CRF: Definition

3 Clinical expression of CRF is multidimensional Fatigue may be experienced and reported differently by each individual May occur as an isolated symptom or as one component within a cluster (pain, fatigue, depression, sleep disturbances) Qualitative studies of fatigue show: –CRF experience is unlike other fatigue –Unpredictability and refractoriness to self-management contributes to distress Personality and coping style may also influence the experience of CRF Features

4 A. Six (or more) of the following symptoms have been present every day or nearly every day during the same two-week period in the past month, and at least one of the symptoms is significant fatigue (A1). –A1. Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level –A2. Complaints of generalized weakness or limb heaviness –A3. Diminished concentration or attention –A4. Decreased motivation or interest to engage in usual activities –A5. Insomnia or hypersomnia –A6. Experience of sleep as unrefreshing or nonrestorative –A7. Perceived need to struggle to overcome inactivity –A8. Marked emotional reactivity (e.g., sadness, frustration, irritability) to feeling fatigued –A9. Difficulty completing daily tasks attributed to feeling fatigued –A10. Perceived problems with short-term memory –A11. Postexertional malaise lasting several hours 1. Cella, D., Davis, K., Bretibart, W., Curt, G. (2001). Cancer-related fatigue: Prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. Journal of Clinical Oncology; 19 (14), 3385-3391 ICD-10 Criteria for Cancer-Related Fatigue 1

5 ICD-10 Criteria for Cancer-Related Fatigue B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer therapy. D. The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium

6 Fatigue: Classification Peripheral Fatigue –Neuromuscular –Exercise induced Energy production is impaired Energy utilization is inefficient Central Fatigue –Mediated by the central nervous system –Exercise independent, independent of disease severity Dysregulation of the neuroendocrine system –Neuropeptides, catecholamines, cytokines, cortisol

7 Central features: loss of efficiency, mental fogginess, inertia, and sleep that is not restorative Peripheral features: excessive need to rest, an inability to recover promptly from exertion, muscle heaviness and weakness Challenging to distinguish CRF from depression, cognitive dysfunction, or asthenia –Overlapping symptoms? –Shared neurophysiologic mechanisms? Variability in Manifestations of CRF

8 Goldstein, D, BMC Cancer, 2006

9 Prevalence of fatigue in cancer survivors: –30% to 96% of survivors report persistent fatigue Fatigue has consequences for physical, vocational, cognitive and social functioning; mood; treatment adherence, psychological and spiritual distress, and possibly for long-term survival outcomes Stasi, R, 2003 Scope of the Problem

10 Fatigue – what happens over time  Increases in fatigue during adjuvant treatment  Inconsistent evidence relating to what happens beyond treatment 20-30% up to 2 years ptx 20% (5-34%) up to 5 years ptx It is a persistent problem

11 Single items that gauge fatigue severity Single items or subscales that measure relevant aspects of the fatigue experience that have been drawn from measures of quality of life (eg. FACIT-Fatigue), psychosocial adjustment, mood, or self-reported health status (eg. vigor, vitality) Instruments designed specifically to evaluate CRF from a multidimensional perspective (eg. Multidimensional Fatigue Inventory; Piper Fatigue Scale) Neurophysiologic and performance-based measurements of fatigue, including muscle force, endurance time, muscle reserve, neuromuscular-junction impulse propagation, and functional performance Minton & Stone (2009); Alexander, Minton & Stone (2009), Approaches to Measuring Cancer- Related Fatigue

12 Measurement Considerations Fatigue is a multidimensional construct: –sensory dimension (fatigue severity, persistence) –physiologic dimension (eg. leg weakness, diminished mental concentration) –affective dimension (sadness, depression, fear) – behavioral dimension (reduction in the performance of needed or valued activities) Multidimensional measures provide information about this full range of characteristics beyond fatigue presence and intensity Weakness, tiredness or the absence of vigor or vitality, may not necessarily be equated with fatigue

13 ScaleFeaturesDomain(s) Measured Evaluation Time Frame Comments EORTC- fatigue subscale  3-item uni-dimensional scale converted to a score/100  Minimal time for completion Physical fatigue Fatigue over past week  Benefit in clinical setting: brief and simple to administer  Ceiling effect: questionable for use in palliative setting  Cut point score of 40/100 for clinically significant CRF suggested Functional Assessment of Cancer Therapy- Fatigue scale (FACT-F)  13 item uni- dimensional scale: 5- point Likert Scale  Fatigue scale part of a 20-item anemia scale  Higher scores = less fatigue  5-10 minutes Physical fatigue Fatigue over past week  Recommended for use with intervention studies in research setting  Can be used independently or administered with the FACT-General scale  Score of 34/ 52 cut-point for clinically significant CRF  MCID : 3.0 points for fatigue subscale Fatigue Questionnaire (FQ)  11-item multi- dimensional scale  Subscales: 7-item physical fatigue and 4 item mental fatigue  5-10 minutes Physical and mental fatigue Fatigue over the last month vs. when patient felt well  Measures both subjective physical and mental fatigue  Originally developed for use with chronic fatigue syndrome  Useful for screening for CRF  Cut-point for fatigue: >4.0 (McNeely and Courneya, 2009)

14 Advanced/metastatic disease or cancer recurrence Cancer treatment (chemotherapy, radiation, surgery, biologic agents, hormonal agents, molecularly targeted agents) Anemia Neutropenia Hypothyroidism Adrenal Insufficiency Hypogonadism Infection Malnutrition Depletion of vitamins B1, B 6 and B12 Electrolyte disturbances (calcium, magnesium, phosphorus) Cardiopulmonary, hepatic or renal dysfunction Sarcopenia, asthenia, deconditioning Etiology and Risk Factors

15 Proinflammatory cytokine expression/generalized inflammation Medications with sedating side effects (eg. narcotics, anxiolytics, antiemetics, antidepressants), or medications with fatigue as part of the side effects profile (e.g. beta-blockers) of medications Concurrent symptoms (eg. pain, dyspnea, nausea, diarrhea) Impaired sleep quality Psychological distress (depression, anxiety) Accumulating evidence also suggests a role for gene polymorphisms, altered circadian rhythmicity, immune dysregulation, abnormal cortisol secretion, elevated body mass index, and metabolic syndrome In any one individual, the etiology of CRF likely involves the interaction of several physiologic and psychobehavioral mechanisms Etiology and Risk Factors

16 Comparison Between Fatigued and Non-Fatigued: Immune Status Markers Collado-Hidalgo A, et al

17 Treatment with Chemotherapy Raises Fat Mass and Lowers Lean Mass in BrCA Demark-Wahnefried, W et al, J Clin Oncol, 19:2381, 2001

18 Organizing Framework for Understanding Cancer-Related Fatigue ©Berger & Mitchell (In Press) Cancer- related fatigue and sleep-wake disturbances. In J Lester and P. Schmitt (Eds), Personalized Approach to Cancer Survivorship. Pittsburgh: Oncology Nursing Society Press, 2011.

19 What we know about exercise for CRF Numerous recent systematic reviews and meta- analyses have evaluated the efficacy of interventions to reduce CRF in adults with mixed types of cancer. –Breast cancer patients have participated in most studies. –These interventions have been categorized in 2 major, clinically applicable domains: –physical activity enhancement and psychosocial therapies Since fatigue may respond to one/another or combined treatment, both were searched

20 More than 170 empiric studies of pharmacologic and non- pharmacologic interventions to reduce or manage CRF, and several recent meta-analyses or systematic reviews (Cramp & Daniel, 2008; Goedendorp, Gielissen, Verhagen, & Bleijenberg, 2009; Jacobsen, Donovan, Vadaparampil, & Small, 2007; Kangas, Bovbjerg, & Montgomery, 2008; Minton, Richardson, Sharpe, Hotopf, & Stone, 2008; Mitchell, Beck, Hood et al, 2007; Mitchell, in press). For some interventions, there is strong and consistent evidence to support effectiveness, while for other interventions only preliminary data are available Many of the interventions for fatigue have not been studied in HSCT recipients or long-term survivors of HSCT Interventions for Cancer Related Fatigue— General Principles


22 Research & Reviews: Exercise # of studies OverallOther?Finding Kangas, 2008 N=17ES = -.42 (-0.60 to - 0.23) Psychosocial vs. exercise No diff. in psychosocial vs. exercise Cramp & Daniel, 2008 N=16SMD = -0.36 (-0.49 to - 0.23) Mediators?Associated with change in fitness Speck, 2009 N= 14WMES = - 0.54 (-.90 to -0.19) During and Post- treatment Favour exercise (post, but not during treatment) Velthuis, 2010 N=12SMD = 0.29 (0.06 to 0.52) Home-based vs. supervised Favour supervised aerobic Brown, 2011 N=25WMD = 0.39 (0.30 to 0.47) Predictors> Intensity (resistance), older, theoretically driven.

23 Minto & Stone, BCRT, 2008 9 cross-sectional studies –8 with comparisons to normal population –N=49-1957 –Mean time since tx – 4 months – 10 years 9 longitudinal studies –4 months – 10 years –N = 88-863

24 Fatigue – comparison with norms Comparisons up to 29 months post-tx Variety of methods used Lack of a priori clinical importance defined Consistently demonstrated statistical differences in fatigue in BC group Minton, Stone; BCRT, 2008, 112:5

25 Summary for Exercise Benefits favored programs with multiple exercise components, at least partially home-based, individualized, and >8 weeks long –Therefore: aerobics and weights,

26 Interventions With Demonstrated Effectiveness in Improving Fatigue Outcomes in Cancer Survivors Exercise (Shelton et al., 2009; Wiskeman et al., 2008; Coleman et al., 2003;Carlson et al. 2006; Dimeo et al., 1999; Wilson et al., 2005) Physical exercise combined with relaxation breathing (Kim and Kim, 2005) Physical rehabilitation (Dimeo et al., 1997) Exercise, relaxation and psychoeducation (Jarden et al. 2009) Coping skills training (preparatory information, cognitive restructuring, and relaxation with guided imagery) (Gaston- Johansson et al. 2000) Massage/healing touch for family caregivers (Rexilius et al., 2002) Massage therapy (Ahles et al., 1999)

27 Data from Individual Trials Courneya et al. 2013: CARE –25-30 minutes/session/3x/week (standard aerobic) –50-60 minutes/session 3x/week (high intensity) –Standard aerobic + resistance (2 sets 10-12 reps/3x/week) High intensity or combined were superior in improving muscles strength, pain and endocrine symptoms

28 Data from Individual trials Eyigor 2010: Pilates effective in reducing fatigue Sprod 2012;and Janelsins 2011: Tai Chi effective in reducing cytokines, insulin resistance and fatigue

29 Summary of Cochrane reviews McNeely et al.2006: Meta-analysis demonstrated that exercise had a positive effect on fatigue in breast cancer patients Markes et al. 2006:aerobic and resistive exercise had a positive effect on fitness, insignificant effect on fatigue Cramp et al 2012:aerobic exercise has a positive effect on fatigue Mishra et al 2012: aerobic exercise has a positive effect on cardiorespiratory fitness, strength

30 Guidelines Rock et al 2012: Physical Activity Guidelines NCCN 2010: Exercise guidelines

31 Exercise Exercise is effective in managing fatigue during and following cancer treatment in patients with undergoing hematopoietic stem cell transplantation, HSCT survivors, and patients with breast cancer or solid tumors Possible mechanisms: Improves aerobic capacity, and ameliorates muscle loss and deconditioning Favorable effects on sleep, mood, self-efficacy, body composition, and the immune system and cytokine Exercise modalities differ in: content (walking, cycling, swimming, resistive exercise, or combined exercise) frequency (ranging from two times per week to two times daily) intensity degree of supervision (fully supervised group versus self-directed exercise) duration (from two weeks up to one year)

32 Implications for Practice Ongoing periodic screening is an essential component of care quality 10 point scale for screening is efficient and sensitive; moderate to severe fatigue 4-10 (on 10 point scale) warrants further evaluation and treatment Use national guidelines (NCCN and ONS-PEP) to: –Examine your practice and expand the repertoire of interventions recommended for a specific patient based on efficacy

33 Implications for Practice Screen for correctable contributing factors: anemia, thyroid dysfunction, hypogonadism, cardiomyopathy, adrenal insufficiency, pulmonary dysfunction, sleep disturbance, fluid and electrolyte imbalances Provide patients with anticipatory information about fatigue prior to initiation of treatment, and as they transition to survivorship phase Develop plan to prevent/manage fatigue Systematic evaluation of fatigue at baseline and prospectively, to evaluate outcome of intervention

34 Acknowledgements Collaborators: Ali WeinsteinNicole Stout Ancha BaranovaCindy Pfalzer Aybike BirendincCharles McGarvey Kathryn DoyleEllen Levy Support: PNC Foundation, Dominion Guild Thanks to Sandy Mitchell, Kristen Campbell for slides borrowed for this presentation

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