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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
Disability
CRF: Definition
•
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/cancerguidelines/breast/index.html#/110/
Features
• 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
ICD-10 Criteria for Cancer-Related Fatigue1
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
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
Variability in Manifestations of CRF
• 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?
Goldstein, D, BMC Cancer, 2006
Scope of the Problem
• 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
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
Approaches to Measuring CancerRelated Fatigue
• 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)
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
EORTCfatigue
subscale


Functional

Assessment of
Cancer
Therapy
Fatigue scale
(FACT-F)


Fatigue

Questionnaire
(FQ)


Domain(s)
Measured
Evaluation Comments
Time Frame
3-item uni-dimensional Physical
scale converted to a
fatigue
score/100
Minimal time for
completion
Fatigue over 
past week

13 item uniPhysical
dimensional scale: 5- fatigue
point Likert Scale
Fatigue scale part of a
20-item anemia scale
Higher scores = less
fatigue
5-10 minutes
Fatigue over 
past week

11-item multiPhysical
dimensional scale
and mental
Subscales: 7-item
fatigue
physical fatigue and 4
item mental fatigue
5-10 minutes
Fatigue over 
the last
month vs.

when patient
felt well





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
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
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)
Etiology and Risk Factors
• 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
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) Cancerrelated 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 metaanalyses 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
Interventions for Cancer Related Fatigue—
General Principles
• More than 170 empiric studies of pharmacologic and nonpharmacologic 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
Research & Reviews: Exercise
# of
Overall
studies
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 = During and
0.54
Post(-.90 to -0.19) treatment
Velthuis,
2010
N=12
SMD = 0.29 Home-based Favour supervised
(0.06 to 0.52) vs. supervised aerobic
Brown,
2011
N=25
WMD = 0.39 Predictors
(0.30 to 0.47)
Favour exercise
(post, but not during
treatment)
> 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) (GastonJohansson 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