Exercise for Fatigue

Effective Treatment for Breast Cancer Survivors

Lynn Gerber, MDCollege of Health and Human

ServicesCenter for Chronic Illness and

Disability

• 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)

– http://www.nccn.com/files/cancer-gui

delines/breast/index.html#/110/

CRF: Definition

• 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

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 Fatigue1

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

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

• 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

Goldstein, D, BMC Cancer, 2006

• 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

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

• 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

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

Scale Features Domain(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)

• 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

• 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

Comparison Between Fatigued and Non-Fatigued:

Immune Status Markers

Collado-Hidalgo A, et al

Treatment with Chemotherapy Raises Fat Mass and Lowers

Lean Mass in BrCA

Demark-Wahnefried, W et al, J Clin Oncol, 19:2381, 2001

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.

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

• 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

Research & Reviews: Exercise# of studies

Overall Other? Finding

Kangas, 2008

N=17 ES = -.42(-0.60 to -0.23)

Psychosocial vs. exercise

No diff. in psychosocial vs. exercise

Cramp & Daniel, 2008

N=16 SMD = -0.36 (-0.49 to -0.23)

Mediators? Associated with change in fitness

Speck, 2009

N= 14 WMES = -0.54 (-.90 to -0.19)

During and Post-treatment

Favour exercise (post, but not during treatment)

Velthuis, 2010

N=12 SMD = 0.29 (0.06 to 0.52)

Home-based vs. supervised

Favour supervised aerobic

Brown, 2011

N=25 WMD = 0.39 (0.30 to 0.47)

Predictors > Intensity (resistance), older, theoretically driven.

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

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

Summary for Exercise

• Benefits favored programs with multiple exercise components, at least partially home-based, individualized, and >8 weeks long

– Therefore: aerobics and weights,

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)

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

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

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

Guidelines

• Rock et al 2012: Physical Activity Guidelines

• NCCN 2010: Exercise guidelines

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)

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

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

Acknowledgements

Collaborators:

Ali Weinstein Nicole Stout

Ancha Baranova Cindy Pfalzer

Aybike Birendinc Charles McGarvey

Kathryn Doyle Ellen Levy

Support: PNC Foundation, Dominion Guild

Thanks to Sandy Mitchell, Kristen Campbell for slides borrowed for this presentation