Download Effects of Exercise Training on Physiological and Psychological

University of Northern Colorado
Scholarship & Creative Works @ Digital UNC
Dissertations
Student Research
6-29-2016
Effects of Exercise Training on Physiological and
Psychological Measurements of Cancer-Related
Fatigue
Trista Manikowske
Follow this and additional works at: http://digscholarship.unco.edu/dissertations
Recommended Citation
Manikowske, Trista, "Effects of Exercise Training on Physiological and Psychological Measurements of Cancer-Related Fatigue"
(2016). Dissertations. 351.
http://digscholarship.unco.edu/dissertations/351
This Text is brought to you for free and open access by the Student Research at Scholarship & Creative Works @ Digital UNC. It has been accepted for
inclusion in Dissertations by an authorized administrator of Scholarship & Creative Works @ Digital UNC. For more information, please contact
[email protected].
© 2016
TRISTA LYNN MANIKOWSKE
ALL RIGHTS RESERVED
UNIVERSITY OF NORTHERN COLORADO
Greeley, Colorado
The Graduate School
EFFECTS OF EXERCISE TRAINING ON PHYSIOLOGICAL
AND PSYCHOLOGICAL MEASUREMENTS OF
CANCER-RELATED FATIGUE
A Dissertation Submitted in Partial Fulfillment
of the Requirements for the Degree of
Doctor of Philosophy
Trista Lynn Manikowske
College of Natural and Health Sciences
School of Sport and Exercise Science
Exercise Science
July, 2016
This Dissertation by: Trista Lynn Manikowske
Entitled: Effects of Exercise Training on Physiological and Psychological Measurement
of Cancer-Related Fatigue
has been approved as meeting the requirements for the Degree of Doctor of Philosophy in
College of Natural and Health Sciences in School of Sport and Exercise Science,
Program of Exercise Science
Accepted by the Doctoral Committee
______________________________________________________
Reid, Hayward, Ph.D., Research Advisor
_______________________________________________________
David Hydock, Ph.D., Committee Member
_______________________________________________________
Gary Heise, Ph.D., Committee Member
_______________________________________________________
Patrick Burns, Ph.D. Faculty Representative
Date of Dissertation Defense June 8th, 2016
Accepted by the Graduate School
________________________________________________________________________
Linda L. Black, Ed.D.
Associate Provost and Dean
Graduate School & International Admissions
ABSTRACT
Manikowske, Trista Lynn. Effects of Exercise Training on Physiological and
Psychological Measurement of Cancer-Related Fatigue. Published Doctor of
Philosophy dissertation, University of Northern Colorado, 2016.
While exploring the differences in psychological and physiological fatigue among
cancer survivors is not completely novel, the relationship between muscle function and
perceptions of fatigue in cancer survivors remains mechanistically unclear. Furthermore,
the effect of exercise on objectively measured muscular fatigue has yet to be studied in
cancer patients. PURPOSE: To evaluate the relationship between subjective selfreported psychological fatigue measures and objectively-measured muscular fatigue in
cancer survivors following a 24-week exercise intervention. METHODS: Cancer
survivors were asked to complete two measures of fatigue prior to and following 12 and
24 weeks of an exercise intervention. Participants completed the revised Piper Fatigue
Scale (PFS) which produces a total score (PFST) and four subscale scores. A handgrip
fatigue index (HFI) was determined for each participant by repetitively squeezing a
handgrip dynamometer maximally for 15 repetitions. Participants also completed 15
maximal force knee extensions at a joint velocity of 60 deg∙s-1 and a quadriceps fatigue
index (QFI) was computed. RESULTS: Significant positive relationships between the
HFI and PFST (r = .303; p < .001), PFSB (r = .287; p < .001), PFSA (r = .220; p < .001),
PFSS (r = .352; p < .001), and PFSC (r = .301; p < .001) were observed. In addition, peak
hand force (PHF) was significantly negatively correlated to PFST (r = -.177; p = .027),
PFSB (r = -.209; p = .009) and PFSS (r = -.194, p = .015). Following the exercise
iii
intervention, significant main effects were found for PFST and all four subscales (p <
.05). Results indicate significant decreases in PFST (p = .001), PFSB (p = .015), PFSA (p
= .001), PFSS (p = .001), and PFSC (p = .004) following 12 weeks of the exercise
intervention. Testing following 24 weeks of the intervention resulted in significant
decreases in PFST (p = .031), PFSA (p = .023), and PFSS (p = .016). CONCLUSION:
The lack of strong correlation between variables indicates self-reported fatigue measures
may not be good predictors of fatigue at the muscular level and should therefore not be a
primary determinant in exercise dose in cancer survivors. KEY WORDS: FATIGUE
INDEX, MUSCULAR FATIGUE ASSESSMENT, REVISED PIPER FATIGUE
SCALE, CANCER REHABILITATION
iv
DEDICATION
This dissertation is dedicated to all who have suffered from cancer; those who
have survived, those who did not, those who are still fighting, and family and of friends of
these brave individuals. I am forever grateful for the time I have spent working with the
wonderful individuals at the Rocky Mountain Cancer Rehabilitation Institute. You have
all taught me so much about what life is about and I appreciate all you have taught me.
To all the friends I have made and to those lost along the way, you will live in my heart
forever.
v
ACKNOWLEDGEMENTS
Many people have provided encouragement and assistance in the development
and completion of this dissertation, and I would like to take this opportunity to personally
acknowledge and thank them. First, I would first like to acknowledge Dr. Carole
Schneider for accepting me into this great program and providing me with so much
support before her passing. While you have been incredibly missed your spirit and legacy
still lives on through RMCRI.
To my current advisor and mentor, Dr. Reid Hayward, it is hard to describe how
grateful I am for all you have done for me. Through your mentoring I have gained skills
invaluable to my future research and writing efforts. I have been continually impressed
by your incredible knowledge, writing expertise, and willingness to give so generously of
your time. You have inspired me as an educator and a researcher and I can only hope to
someday achieve that type of excellence for myself and make you proud in my future
endeavors. Thank you so much for the support and the opportunity to work with the
incredible individuals at RMCRI. I will miss it immensely.
I had the fortunate opportunity to take a great majority of my graduate
coursework from the incredible Dr. David Hydock. For this reason, and many others, I
cannot begin to thank you for all I have learned from you. Your kindness, in addition to
your immense knowledge, made courses that seemed daunting a truly great experience.
You have continually provided incredible insight and clarity to both my studies and my
research and for this, and countless other things, I am eternally grateful.
vi
I would also like to express my sincere appreciation to the members of my
committee who were extremely helpful at focusing my efforts at the inception and
conclusion of this research. Dr. Gary Heise and Dr. Patrick Burns have provided valuable
insights both in and outside the domain of exercise physiology and have provided
incredible guidance throughout my time here at UNC.
Dr. Smith, thank you so much for your guidance while beginning my research and
the continued guidance throughout. Thank you for being so gracious to let me use the
biomechanics lab and equipment for more than a year and a half. Thank you for the
countless hours you spent writing MATLAB code and getting it to work for me. I also
appreciate your feedback and guidance on my research, writing, and your contributions to
my research endeavors. I appreciate the opportunity to collaborate with Biomechanics
and your students as it helped me learn about a different aspect of this discipline and
work with some amazing people.
Brent, there are no words to express my appreciation for all that you have done
for me. You have been an incredible friend and advisor to me and I am so happy I have
had you to guide me thorough this process. You have been my absolute number one
person in my corner from the very beginning and have done so with such grace and
professionalism. You have helped me grow both personally and professionally and have
always been there to answer any and all of my questions. You constantly put the interest
of others before yourself and are truly an amazing person. Your energy and enthusiasm
for this profession and life is unmatched and you’re an inspiration for myself and others. I
am so excited to see what you do and how you will impact the world. I want to thank you
for all your guidance in my writing, research, and life in general. Thank you for
vii
everything you have done for RMCRI and for me. I couldn’t have asked for a better
friend or mentor and hope our paths cross again professionally.
Kevin, again another person where words cannot express my gratitude. There are
likely days I have spent more time in your office than in mine. I so admire your
intelligence in addition to your immense research and mentoring skills. I have learned so
much from you that I honestly don’t know where to begin. Thanks for being my listening
ear and always giving me such great advice. Thank you also for all of the time you spent
helping me schedule, evaluate, and in general complete my research. You have been such
a wonderful friend these past few years I am going to miss you immensely. You’re
absolutely incredible and I am very jealous of your future colleagues.
Jessica I would like to thank you for your guidance and friendship during these
last four years. You have taught me, and many others, absolutely everything that I/we
know about cancer rehabilitation. You have been incredibly instrumental in making
RMCRI (UNCCRI) the most premier cancer rehab facility in the world. Your passion for
the field is unmatched by anyone that I have ever met. I know Dr. Schneider would be so
incredibly proud of the advances we have made to the Institute and the accomplishments
we have made since her passing. I want to thank you for all you have done and will
continue to do for me, cancer survivors, and the field of cancer rehabilitation.
To the other doctoral students that I have had the pleasure of crossing paths with.
Barb, thank you so much for helping me to schedule my data collection in addition to
many other things. Thank you so much for the early mornings and the evenings you
stayed to accommodate me to use the lab equipment. Thank you also for including me in
viii
your research it has been a pleasure to work with you. Dan, you have been a wonderful
colleague to work with. I appreciate your wisdom and all that you have done for RMCRI.
Doc T, thank you for your continued guidance throughout my college career and
as I start my professional one. I truly believe that I the reason I was so successful at UNC
is the high standards you set for me in addition to the opportunities and guidance you
provided during my undergraduate and graduate years at NDSU.
To my mom, you have taught me the importance of learning and instilled in me
the desire to further my education. You have always been there for me and I could not
ask for a better role model. You are my inspiration and have been an incredible support
through this process and my life. I can only hope that someday I will be as great of an
educator and mentor as you are. There are no words to express my gratitude and
appreciation for your unconditional support. I can never thank you enough.
And finally, thank you to my beautiful wife Stephanie. Thank you for putting the
faith in me and in us to come to Colorado with me, after only knowing me for a short
time. I can honestly say that I couldn’t have done it without you. You have been by my
side throughout this journey and I couldn’t have asked for a better companion. I love you
so much and after so many years of grad school I am so excited to finally start the
beginning of what is sure to be a long, wonderful life together.
ix
TABLE OF CONTENTS
CHAPTER I. INTRODUCTION ........................................................................................ 1
Statement of Purpose .............................................................................................. 6
Research Hypotheses .............................................................................................. 6
Significance of Study .............................................................................................. 7
CHAPTER II. REVIEW OF LITERATURE ..................................................................... 8
Effects of Cancer and its Treatments on Skeletal Muscle Structure and Function..8
Cancer ..................................................................................................................... 8
Chemotherapy ....................................................................................................... 12
Radiation ............................................................................................................... 14
Surgery .................................................................................................................. 16
Fatigue Overview .................................................................................................. 16
Definitions and Measurement of Fatigue .................................................. 16
Physiological Causes of Fatigue during Activity...................................... 18
Cancer-Related Fatigue ............................................................................. 19
Objective Measurement of Muscular Fatigue ........................................... 21
Causes of Cancer Related Fatigue ............................................................ 24
Effect of Exercise on Cancer-Related Fatigue ...................................................... 26
x
Aerobic Exercise …………………………………………………......................................................26
Resistance Training …………………………………………………………………………………27
Physical Activity and its Effects on Skeletal Muscle Structure and Function ...... 29
Aerobic Exercise ....................................................................................... 30
Resistance Training ................................................................................... 31
Cancer Survivors ....................................................................................... 33
CHAPTER III. METHODS .............................................................................................. 38
Participants ............................................................................................................ 38
Procedures ............................................................................................................. 38
Intervention ........................................................................................................... 41
Statistical Analysis ................................................................................................ 43
CHAPTER IV. MANUSCRIPT I: RELATIONSHIPS BETWEEN MUSCULAR
AND PSYCHOLOGICAL ASSESSMENT OF CANCER-RELATED FATIGUE ........ 45
Abstract ................................................................................................................. 45
Introduction ........................................................................................................... 47
Methods................................................................................................................. 51
Results ................................................................................................................... 54
Discussion ............................................................................................................. 58
References ............................................................................................................. 63
xi
CHAPTER V. MANUSCRIPT II: EFFECTS OF EXERCISE TRAINING ON
PHYSIOLOGICAL AND PSYCHOLOGICAL MEASUREMENTS OF CANCERREALTED FATIGUE ...................................................................................................... 71
Abstract ................................................................................................................. 71
Introduction ........................................................................................................... 73
Methods................................................................................................................. 77
Procedures ............................................................................................................. 78
Intervention ........................................................................................................... 80
Results ................................................................................................................... 82
Discussion ............................................................................................................. 87
References ............................................................................................................. 93
CHAPTER VI. GENERAL CONCLUSIONS ............................................................... 105
REFERENCES ............................................................................................................... 106
APPENDIX A. INSTITUTIONAL REVIEW BOARD DOCUMENTS ....................... 144
APPENDIX B. UNIVERSITY OF NORTHERN COLORADO CANCER
REHABILITATION INSTITUE INFORMED CONSENT ........................................... 149
APPENDIX C. STUDY INFORMED CONSENT ........................................................ 152
APPENDIX D. REVISED PIPER FATIGUE SCALE .................................................. 155
xii
TABLE OF TABLES
Table 1. Subject Characteristics ........................................................................................ 54
Table 2. Treatment History and Clinical Characteristics .................................................. 55
Table 3. Muscle Mass, Strength, and Fatigue ................................................................... 55
Table 4. Piper Fatigue Scale Classifications ..................................................................... 56
Table 5. Pearson Correlation Matrix for Main Study Variables ....................................... 57
Table 6. Subject Characteristics ........................................................................................ 83
Table 7. Treatment History ............................................................................................... 83
Table 8. Cancer Stage ....................................................................................................... 83
Table 9. Cancer Type ........................................................................................................ 84
Table 10. Means ± SD for Each Dependent Measure by Testing Session ....................... 85
Table 11. Contrast Analysis ............................................................................................. 86
xiii
TABLE OF FIGURES
Figure 1. Scatterplot of hand fatigue index versus total Piper Fatigue Scale scores…….57
Figure 2. Scatterplot of quadriceps fatigue index versus total Piper Fatigue Scale
scores................................................................................................................................. 58
Figure 3. Changes in total Piper Fatigue Scale scores and PFS subscale scores
following 12 and 24 weeks of exercise.. ........................................................................... 86
Figure 4. Changes in muscular fatigue following 12 and 24 weeks of exercise. .............. 87
xiv
1
CHAPTER I
INTRODUCTION
An estimated 1.6 million new cases of cancer will have been diagnosed in the
United States in 2015. This equates to more than 4,600 diagnoses each day (Siegel,
Miller, & Jemal, 2015). Prostate, lung, and colorectal cancers are the most prevalent
cancers among males, with prostate cancer accounting for one in five diagnoses. Breast,
lung, and colorectal cancers are the most prevalent cancers among females, with breast
cancer making up approximately one-third of all cancer diagnoses. It is estimated that
nearly 600,000 Americans will die from cancer this year with the most common causes of
death being from lung and bronchus cancer. The lifetime probability of being diagnosed
with an invasive form of cancer is higher for males at approximately 42% than for
females whose risk is slightly less at 38%. For adults under the age of 50, cancer risk is
actually higher for females (5.4%) than for males (3.4%) due to the high amount of
breast, thyroid, and genital cancers diagnosed in younger women (Siegel et al., 2015).
For many of the most prevalent cancers, overall incidence and mortality rates
have been steadily declining since 1990. In addition, all-cause mortality rates have
decreased by 23% since 1991. Despite the observed reductions in incidence and mortality
rates, cancer is now the leading cause of death in nearly half of the states in the U.S. The
number of people living following cancer diagnosis is expected to grow from 14.5
million to 19 million by 2024 (Kohler et al., 2015). The 5-year relative survival rates for
all cancers have increased by 20% among Caucasians and 23% among African
2
Americans over the past 30 years (Siegel et al., 2015). Increased survival rates may be
attributable to current progressive methods of prevention, detection, education, improved
treatment methods, and/or increased implementation of individualized cancer
rehabilitation programs. These increased survival rates contribute to greater numbers of
cancer survivors that may be living with the side effects of cancer treatments (Dittus et
al., 2015).
Treating cancer is often challenging and involves techniques that may include
surgery, radiation, chemotherapy, immunotherapy, hormone therapy, or various
combinations of treatments. Type of treatment is dependent on a wide variety of factors
including cancer type, stage, and location. Cancer treatments are generally known to
negatively affect many dimensions of an individual’s life and have been associated with
decreased endurance, decreased muscular strength, and increased fatigue. In addition,
side effects may include decreased bone density, cardiotoxicities, cognitive defects, and
pulmonary dysfunction (J. C. Brown, Winters‐Stone, Lee, & Schmitz, 2012). The
majority of cancer patients experience one or more side effects or symptoms during and
following treatment with the most common being pain, emotional distress, and fatigue.
The management of side effects from cancer treatment is an important aspect of patient
care, and can positively influence quality of life, as well as psychological and physical
functioning (Siegel et al., 2012).
The most common symptom cancer survivors report is cancer-related fatigue
(CRF). It is estimated that 60-96% of cancer survivors report CRF as a side effect of
cancer treatment (Mock et al., 2000; Morrow, Andrews, Hickok, Roscoe, & Matteson,
2002). Cancer-related fatigue has been reported to be characterized by extreme fatigue
3
and exhaustion and has a considerable negative effect on quality of life (QOL) (Mock et
al., 2000; Wagner & Cella, 2004). The impact of CRF on a patient’s functional capacity
can be significant, and is therefore one of the most distressing of reported symptoms
(Hofman, Ryan, Figueroa-Moseley, Jean-Pierre, & Morrow, 2007). Critical components
of CRF are different from what is normally understood as fatigue. It is unrelieved by rest,
and is not a result of activity. The aforementioned phenomena suggest that other
mechanisms may be responsible for the observed differences in CRF versus exerciseinduced fatigue (Morrow et al., 2002). Additionally, CRF has been reported among wide
ranges of cancer types, stages and treatment protocols. Therefore, CRF does not appear to
be initiated by a specific cancer type or treatment, which suggests that unknown
physiological mechanisms may be responsible for the physical manifestations observed
among patients with CRF (Hofman et al., 2007).
The extent to which CRF is negatively affected by the cancer itself, cancer
therapies, or a combination of factors is currently unclear (Saligan et al., 2015). Several
mechanisms have been suggested to underlie the development of CRF; however, the
pathophysiology is still largely misunderstood as both psychological and physiological
factors appear to play a role (Ahlberg, Ekman, Gaston-Johansson, & Mock, 2003; Ryan
et al., 2007; Saligan et al., 2015; X. S. Wang, 2008). Other factors such as tumor necrosis
factor-α (TNF-α), physical inactivity, and weight loss may contribute to CRF by
decreasing muscle mass, resulting in inhibited muscle contractile force, and impairing
activities of daily living (Kasper & Sarna, 2000). In light of this, accurate assessment of
CRF is often times a significant challenge for clinicians. Fatigue in healthy individuals is
often described in both subjective (psychological) and objective (physiological) ways and
4
explaining the pathophysiology should account for both dimensions (Morrow et al.,
2002).
There is currently no universally accepted standard for CRF measurement. Selfreport measures in the form of surveys are the most widely used and accepted forms of
CRF assessment. However, these methods are only measuring one dimension in
subjective fatigue (Ahlberg et al., 2003). Subjective fatigue is a complex construct but
likely has links to reductions in physiological capacity (M. S. Miller, Callahan, & Toth,
2014). Self-report measures are clearly missing a critical component, which is that the
biological or physiological mechanisms might explain the physical manifestations of
CRF. When assessing CRF, both subjective and objective data should be considered;
however, at this time there is no validated objective CRF measurement (Ahlberg et al.,
2003). Therefore, accurate measures of both psychological and physiological fatigue are
necessary to determine the most appropriate treatment methods for patients experiencing
CRF. In addition, this will also allow researchers to evaluate the effectiveness of fatigue
intervention strategies (P. C. Stone & Minton, 2008).
Functional capacity is a broad term used to describe capacity of an individual to
perform activities considering a person’s body function, environmental factors, personal
factors, and/or health status (Arena et al., 2007). In addition to CRF, a common side
effect of cancer and its treatment is loss of functional capacity. This reduction in capacity
makes physical activity and normal activities of daily living increasingly demanding
(Der-Torossian, Couch, Dittus, & Toth, 2013). Since fatigue seems to be associated with
a physical and/or physiological component, a growing number of studies are investigating
5
physical activity as a treatment option for CRF to improve functional capacity (van Weert
et al., 2006).
Physical activity can attenuate multiple side effects of treatment, potentially
reverse functional losses that occurred during treatment, aid in the prevention of longterm effects, reduce the rate of recurrence, and increase survival (J. C. Brown, Winters‐
Stone, et al., 2012; Siegel et al., 2012). Both aerobic and resistance exercise training have
been reported to be beneficial in cancer survivors both during and after treatment and
have been shown to reduce CRF (Adamsen et al., 2009; Arnold & Taylor, 2011; J. C.
Brown et al., 2011; J. C. Brown, Huedo-Medina, et al., 2012; Dimeo, 2001; Haas, 2011;
Keogh & MacLeod, 2012; Kuchinski, Reading, & Lash, 2009; Litterini & Jette, 2011;
Puetz & Herring, 2012; M. E. Schmidt et al., 2012; Schneider, Hsieh, Sprod, Carter, &
Hayward, 2007a, 2007b; van Waart et al., 2015; Velthuis, Agasi-Idenburg,
Aufdemkampe, & Wittink, 2010; Wyrick & Davis, 2009), improve functional capacity
(L. W. Jones et al., 2012; Macvicar, Winningham, & Nickel, 1989; Vardar Yagli et al.,
2015), and increase muscular strength (Courneya et al., 2007; Fong et al., 2012; A. L.
Schwartz & Winters-Stone, 2009; Segal et al., 2003; R. L. Siegel, J. Ma, Z. Zou, & A.
Jemal, 2014; Speck, Courneya, Masse, Duval, & Schmitz, 2010; van Waart et al., 2015;
van Weert et al., 2006).
Several studies have indicated that a commonly observed reduction in muscle
mass among cancer survivors and decreased functional capacity may be due to cancer
and its treatments (Christensen et al., 2014; Kilgour et al., 2010; Weber et al., 2009).
While exploring the differences in psychological and physiological fatigue among cancer
survivors is not completely novel, the relationship between muscle function and
6
perceptions of fatigue in cancer survivors remains mechanistically unclear (Kilgour et al.,
2010). Furthermore, the effect of exercise on objectively measured muscular fatigue has
yet to be studied in cancer patients.
Statement of Purpose
The purpose of this study was to evaluate the relationship between
physiologically measured muscular fatigue and psychological fatigue in cancer survivors
following a supervised combined aerobic and resistance exercise intervention.
Research Hypotheses
H1
It was hypothesized that muscular fatigue would have a positive linear
relationship to subjective fatigue survey scores.
H1 was tested by examining Pearson correlations between upper and
lower body fatigue indexes and total CRF scores as assessed though the
revised Piper Fatigue Scale (PFS). Correlations between fatigue indexes
and each of the four subscales of the PFS including sensory, affective,
behavior, cognitive and mood were also made. Similarly, correlations
were also examined between peak torque and total PFS as well as between
peak torque and each of the PFS subscales.
H2
It was hypothesized that following exercise training there would be a
reduction in both psychological and physiological fatigue.
H2 was tested using a repeated measures multivariate analysis of variance
(RMANOVA) examining differences between total PFS, PFS subscales,
upper and lower body fatigue index, and peak torque following a 12 and
24 week supervised exercise intervention.
7
Significance of Study
Direct assessment of fatigue provided further understanding into how cancer
survivors experience fatigue beyond solely administering questionnaire-based
assessments. The potential relationship between the two fatigue dimensions provided
insight into methods for improving CRF in cancer rehabilitation programming and
targeting fatigue. Evaluating how exercise modulates psychological and physiological
fatigue dimensions aided in our understanding of how exercise reduces fatigue in cancer
patients.
8
CHAPTER II
REVIEW OF LITERATURE
Effects of Cancer and its Treatments on Skeletal
Muscle Structure and Function
Cancer and its side effects on skeletal muscle have been a topic of recent study.
Overall, cancer and its treatments are known to cause skeletal muscle atrophy and
weakness. Because of the prevalence of atrophy and impaired functioning in the cancer
population, it is difficult to discern whether impairment is due to damage to contractility
or loss of contractile components themselves (M. S. Miller et al., 2014). Skeletal muscle
atrophy is a significant side effect of cancer that greatly depends on the tumor type and
stage of cancer. Cachexia is the term used to describe muscle and fat loss that occurs due
to various chronic disease states. Cachexia that occurs in conjunction with cancer and/or
its treatment is termed cancer-related cachexia, and unlike muscle wasting due to
starvation it, cannot be remedied by nutritional interventions (Fearon, Glass, & Guttridge,
2012; Fearon et al., 2011; Skipworth, Stewart, Dejong, Preston, & Fearon, 2007). Despite
the prevalence of cachexia in the cancer population, cancer patients without cachectic
symptoms have also shown significant impairments in muscle function and strength
(Christensen et al., 2014; Toth et al., 2013)
Cancer
Typically, malignant solid tumors of the head and neck, gastrointestinal tract,
pancreas and lungs result in the greatest amount of muscle loss. Advanced cancer stages
9
are also associated with greater amounts of muscle loss which can affect prognosis,
survival, and quality of life (Der-Torossian et al., 2013). Decreases in skeletal muscle
mass have been shown to reduce contractile function, increase muscle weakness, and
decrease aerobic capacity (Bogdanis, 2012). Because of the debilitating effects of cancerrelated cachexia and its relation to poor outcomes, interventions to combat muscle loss in
cancer patients has become a priority for oncologists (Der-Torossian et al., 2013).
Mechanisms of skeletal muscle atrophy from cancer lie largely in the imbalance
of protein synthesis and breakdown. In animal models, the magnitude of this imbalance
depends largely on the tumor type and stage (Lorite, Cariuk, & Tisdale, 1997; K. Smith
& Tisdale, 1993; Strelkov, Fields, & Baracos, 1989). Data retrieved from studies utilizing
human cancer patients are limited, however, some point to similar protein
synthesis/degradation mechanisms which lead to muscle atrophy (Gallagher et al., 2012;
J. P. Williams et al., 2012). Evidence suggests that decreases in skeletal muscle protein
synthesis may be related to increases in serum level of proteolysis-inducing factor (PIF)
which is released from some cachexia-inducing tumors (Al-Majid & Waters, 2008). In a
reported study by Wigmore, Barber, Ross, Tisdale, and Fearon (2000), patients with
higher levels of PIF had significantly greater weight loss than those without PIF detected.
Additional studies have shown PIF to induce significant loss of lean mass in tumor
bearing mice (Eley, Russell, Baxter, Mukerji, & Tisdale, 2007; Lorite et al., 1997; Lorite
et al., 2001; Lorite, Thompson, Drake, Carling, & Tisdale, 1998; H. J. Smith, Lorite, &
Tisdale, 1999). Insulin may also play a role in cancer-induced muscle loss. Insulin is an
important anabolic hormone that promotes regulation of protein synthesis and balance.
Insulin resistance has been reported in studies examining a number of different cancer
10
types and may contribute to impaired protein synthesis (Copeland, Leinster, Davis, &
Hipkin, 1987; Lundholm, Holm, & Scherstén, 1978; Makino, Noguchi, Yoshikawa, &
Nomura, 1998; Yoshikawa, Noguchi, Doi, Makino, & Nomura, 2001).
Investigations into skeletal muscle contractile dysfunction in human cancer
patients have been minimal, due to the difficulty in discerning whether the contribution of
dysfunction is due to loss of muscle mass or another mechanism. A study by Weber et al.
(2009), investigated isometric and isokinetic quadriceps strength in cachectic cancer
patients compared with apparently healthy controls. After controlling for muscle mass
there were no significant differences observed in dynamic or static strength between the
groups. In contrast, a study by Stephens et al. (2012) found lower torque production in
both cachectic men and women compared to a control group after adjusting for crosssectional area. Similarly, Toth et al. (2013) found cancer patients produced 25% lower
torque after controlling for muscle mass compared to control subjects. An association
was also found in this study between muscular strength and 6-minute walk performance,
suggesting that any link between skeletal muscle dysfunction and reduced functional
ability in cancer patients may be independent of muscle mass (Toth et al., 2013).
In addition to whole muscle contractile dysfunction, investigations into cellular
and molecular mechanisms suggest intrinsic skeletal muscle dysfunction at the level of
the myofilament (Der-Torossian et al., 2013). A study by Weber et al. (2007) showed
significant decreases in Type IIx muscle fibers in advanced cancer patients. A study by
Toth et al. (2013) investigated single muscle fiber size and contractile function in
cachectic versus non-cachectic cancer patients. Results from this study observed nonsignificant reductions in Type I (-19%) and II (-16%) fiber cross-sectional area in cancer
11
patients compared to controls. In regards to contractile function, single fiber tension was
significantly lower (14%) in Type IIa fibers in patients with cancer compared to controls,
however, no difference was found in Type I fibers. Additionally, when cachectic and
non-cachectic patients were compared, there was no significant difference in contractile
function between the groups indicating that decreased tension was not a result of
cachexia. In the same study, an increase in myosin attachment time was reported in
cancer patients compared with controls; however, no difference was found again between
cachectic and non-cachectic patients. This increase in attachment time decreases
contractile velocity and as a result decreases power output. Lastly, a 50% decrease in
mitochondrial fractional area was found in cancer patients compared to controls as a
result in decreased size of mitochondria rather than number. Results from this study
support evidence of an increase in skeletal muscle dysfunction in cancer patients
independent of muscle mass (Toth et al., 2013).
Mechanisms of tumor-induced muscle dysfunction are still relatively unclear. The
majority of evidence in animal and human models points to tumor-induced inflammation
and activation of oxidative stress (Christensen et al., 2014; Sakuma & Yamaguchi, 2012).
Pro-inflammatory cytokines TNF-α, Interleukin-6 (IL-6), Interleukin 1 beta (IL1-β), and
Interferon gamma (INF-γ) are all derived from cancerous tumors and with chronic
exposure result in systemic inflammation. These cytokines can activate NF-κβ in muscles
which signals transcription of E3 ubiquitin ligases that result in myosin heavy chain
specific protein degradation (Acharyya et al., 2004; Guttridge, Mayo, Madrid, Wang, &
Baldwin Jr, 2000; Moldawer, Rogy, & Lowry, 1992; Saligan et al., 2015; Skipworth et
al., 2007; Tisdale, 1997; X. S. Wang, 2008; Zoico & Roubenoff, 2002). In animal
12
models, elevated levels of pro-inflammatory cytokines have been associated with
significant weight loss in tumor bearing mice (Cannon et al., 2007). Interestingly, studies
blocking inflammatory cytokines showed attenuation of cachexia in tumor bearing
animals (Costelli et al., 1993; Enomoto et al., 2004). Studies conducted using human
cancer subjects have shown elevated levels of TNF-α and IL-6 among cachectic
individuals with cancer (Dillon et al., 2007; Karayiannakis et al., 2001; KrzystekKorpacka et al., 2007). Evidence of activation of these pathways exists before onset of
cancer treatment and before muscle wasting is detected. This indicates that these
pathways are likely responsible for initiating the early phases of muscle degradation
(Bossola et al., 2003; Zampieri et al., 2010).
In addition to inflammation, the tumor itself can be metabolically active and
consume large amounts of glucose (Vaupel, Kallinowski, & Okunieff, 1989). Most
tumors use glycolysis as their primary energy source and compete directly with other
organs and tissues for energy. This increased use of anaerobic metabolism results in
increased reliance on the Cori cycle and gluconeogenesis to increase the availability of
glucose for the body from non-carbohydrate precursors, resulting in excessive protein
degradation (Koppenol, Bounds, & Dang, 2011; Warburg, Wind, & Negelein, 1927).
While the research is limited, a few investigations suggest cancer-induced skeletal muscle
contractile dysfunction is independent of muscle atrophy (Christensen et al., 2014; Toth
et al., 2013).
Chemotherapy
Few studies have examined the direct effects of cancer therapies on muscle
function. Chemotherapy agents have been known to cause decreases in muscular strength
13
as well as increased muscular fatigability. Chemotherapeutic treatment may indirectly
lead to increased fatigue though cancer-related cachexia and muscular atrophy. Other
factors such as inflammatory cytokines, reduced physical activity, and weight loss may
contribute to decreased skeletal muscle contractile function (Al-Majid & Waters, 2008;
Kasper & Sarna, 2000). Researchers who conducted performance assessments on cancer
survivors undergoing chemotherapy have documented muscle weakness, reduced
muscular strength, and reduced endurance (Gilliam & St. Clair, 2011; Kasper & Sarna,
2000; Toth et al., 2013). Underlying mechanisms of skeletal muscle dysfunction may be
due to increased reactive oxygen species (ROS) and chronic inflammation. In skeletal
muscle, exposure to high amounts ROS and circulating cytokines are known to produce
muscle weakness and accelerate CRF (Gilliam & St. Clair, 2011; Reid & Moylan, 2011).
Anthracycline-based chemotherapy regimens have been shown to produce a wide
range of negative side effects, but its most severe side effect is cardiotoxicity (Von Hoff
et al., 1979; S. Zhang et al., 2012; Y.-W. Zhang, Shi, Li, & Wei, 2009). The dosedependent cardiotoxicities observed in studies using these types of chemotherapy drugs
appear to be independent of the type of cancer treated (J. C. Brown, Winters‐Stone, et al.,
2012). More recent investigations, however have begun to uncover the effects of
doxorubicin on skeletal muscle dysfunction (Gilliam & St. Clair, 2011; Hayward et al.,
2013; Hydock, Lien, Jensen, Schneider, & Hayward, 2011). Several studies conducted in
animals have shown that doxorubicin exposure negatively affects contractile function in
skeletal muscle and that this dysfunction is dose dependent as with cardiotoxicity
(Falkenberg, Iaizzo, & McLoon, 2002; Gilliam, Moylan, Ferreira, & Reid, 2011; Gilliam
et al., 2012; Gilliam & St. Clair, 2011; Hardin et al., 2008; Hydock et al., 2011).
14
Mechanisms by which atrophy and dysfunction occur are not entirely understood,
however, Gilliam et al. (2012) proposed that atrophy and dysfunction occur similarly to
the TNF-α activated pathway induced by tumor dysfunction. One proposed mechanism
contributing to muscle weakness in chemotherapy patients includes disruption in control
of redox signaling and a state of oxidative stress. Chemotherapy agents directly and
indirectly produce a state of oxidative stress due to overproduction of reactive oxygen
species. Chemotherapy drugs directly produce ROS by interacting with molecular oxygen
and undergoing redox cycling. They may also indirectly contribute to increases in ROS
by decreasing anti-oxidant levels and reducing the body’s ability to guard against
elevated oxidants. Evidence supports that elevated reactive oxygen species can increase
protein degradation and subsequently decreases contractile force (Gilliam et al., 2012;
Gilliam & St. Clair, 2011). In addition to doxorubicin, other anthracycline
chemotherapeutic agents have been shown to induce contractile dysfunction, such as
cyclophosphamide (Friedman et al., 1990), bevacizumab (Poterucha, Burnette, & Jatoi,
2012) melphalan (Bonifati et al., 2000), and epirubicin (Gilliam & St. Clair, 2011).
Radiation
Radiation therapy is used as a treatment modality in approximately 50% of cancer
patients. While advances in technology have minimized exposure to non-cancerous
tissues, surrounding healthy tissues are often times exposed (J. C. Brown, Winters‐Stone,
et al., 2012). CRF is a common side effect of radiation and is reported in up to 80% of
cancer patients. The prevalence of radiation-induced fatigue and its effects on skeletal
muscle structure and function are difficult to quantify since chemotherapy is frequently
administered in addition to radiation. As with other treatments this fatigue can result in
15
decreased functional capacity, decreased quality of life, and persist for months to years
following radiation (Segal et al., 2003). While radiation-induced cardiovascular toxicities
have been reduced with more precise radiation delivery, increasing evidence shows
neuromuscular and skeletal muscular complications from radiotherapy. Radiation
exposure to muscle tissues may result in pain, weakness, fatigue, and focal myopathies.
Muscular damage may result in impaired blood flow and hypoxia. This condition may
upregulate the aforementioned pro-inflammatory cytokines, which can lead to decreased
muscular strength, increased atrophy, and decreased protein synthesis. Other clinical
evidence suggests damage to nerves, tendons, ligaments, and bone structure from
radiation treatment (J. C. Brown, Winters‐Stone, et al., 2012). The addition of
chemotherapy to radiation treatment has also been shown to significantly increase
fatigue, which may suggest an additive effect. Despite the prevalence of CRF in cancer
patients following radiotherapy, little is known about its etiology (Jereczek-Fossa,
Marsiglia, & Orecchia, 2002).
Radiation therapy can affect skeletal muscle by physically disrupting its structural
integrity. Investigations in animal models have shown muscle injury following radiation
to result in cell death, increased protein breakdown, muscle atrophy, and fibrosis
(Gillette, Mahler, Powers, Gillette, & Vujaskovic, 1995). An early study by Rubin and
Casarett (1968), found muscle injury and atrophy in back and neck muscles of cancer
patients following treatment. Late complications have been reported from radiotherapy
and carry risk of injury to muscle and soft tissue (Gillette et al., 1995). Radiotherapy to
the thoracic region of the body has been shown to induce pulmonary damage and reduce
myocardial perfusion resulting in decreased oxygen delivery and a decrease in
16
cardiovascular fitness (L. W. Jones, Eves, Haykowsky, Freedland, & Mackey, 2009).
One important consideration is that progression of muscle injury may continue for as
long as 10 years following treatment and short-term follow-up could underestimate the
severity of radiation injury (Gillette et al., 1995).
Surgery
Surgery is the most common form of cancer therapy and is often accompanied by
other therapies. A number of symptoms and side effects can occur as a result of surgery
(J. C. Brown, Winters‐Stone, et al., 2012). For these reasons, as with radiotherapy, it is
difficult to discern modifications to muscular function from surgical treatment alone.
Fatigue is often a symptom reported by cancer patients. Following surgery, CRF has been
related to decreased muscle strength and cardiovascular fitness (Dimeo, Thomas, RaabeMenssen, Pröpper, & Mathias, 2004). Surgical treatments in patients with lung cancer
frequently result in decreases in pulmonary capacity and oxygen uptake which can induce
pulmonary and cardiac dysfunction, thereby reducing functional capacity. In other
cancers, surgical treatment has been associated with adverse outcomes such as
lymphedema, reduced range of motion, prolonged periods of inactivity and bedrest,
deconditioning, pain, functional limitations, muscle atrophy, and fatigue (J. C. Brown,
Winters‐Stone, et al., 2012; L. W. Jones et al., 2011).
Fatigue Overview
Definitions and Measurement of Fatigue
Muscle fatigue is a common symptom during exercise and sport but is also
observed in many disease states and health conditions (Bogdanis, 2012). In the literature,
fatigue has been defined in many ways; however, there are generally two commonly
17
accepted definitions (C. A. Williams & Ratel, 2009). Bigland-Ritchie and Woods (1984)
defined fatigue as an exercise-induced reduction in the ability of muscle to produce
power or force, irrespective of task completion. In this definition, fatigue can be
measured and can also be used with different exercise modalities or intensities
(Vollestad, 1997). Additionally, Edwards (1981) defined fatigue as the inability to
maintain a required or expected force or power output under maximal or submaximal
sustained contraction conditions. When applying a fatigue definition to that of dynamic
contractions, a ‘loss of power output’ may also be included in the definition (Vollestad,
1997). Other common terms that tend to be used interchangeably with fatigue include
weakness and exhaustion. It is important, however, to distinguish between weakness and
fatigue as weakness is generally used to describe low amounts of force and is
independent of exercise (Vollestad, 1997). Although these are commonly accepted
definitions surrounding an exercise activity, fatigue commonly occurs in other settings
and/or clinical conditions and is defined differently (C. A. Williams & Ratel, 2009).
In clinical conditions, fatigue is generally understood as a more subjective state
and is characterized by an individual’s perception of weakness, lack of energy, decreased
capacity for physical or mental work, or becoming easily tired. Evidence points to at least
two dimensions of fatigue, one of subjective nature and one of objective nature (P. C.
Stone, Richards, & Hardy, 1998). While perceived fatigue is useful clinically, it is
difficult to discriminate between perceived and physiological fatigue (Gilliam & St.
Clair, 2011). As with the varying definitions of fatigue there is also a variation in
measurement techniques. Muscular fatigue is generally objectively measured though
decrements in measurement of force, velocity of shortening, power, electromyography
18
(EMG) activity, and contractile function (C. A. Williams & Ratel, 2009), whereas the
subjective dimension of fatigue cannot be directly measured but is assessed though selfreport instruments such as a survey (P. C. Stone et al., 1998).
Physiological Causes of Fatigue during Activity
Causes of muscular fatigue involve many processes and can be specific to the
task, psychological state, training status, and environmental factors. Fatigue during
exercise is often due to declines in ability of the active musculature which is referred to
as peripheral fatigue. In general, fatigue in the musculature or peripheral fatigue is
understood to be a consequence of depletion of energy bearing metabolites and
accumulation of others which impair the contractile ability of the musculature (Baldwin,
Brooks, Fahey, & White, 2005). Fatigue may also be central which is understood as a
loss of voluntary activated muscle due to neural mechanisms surrounding the
neuromuscular junction (Yavuzsen et al., 2009).
Physiological mechanisms of fatigue involve both energy metabolism and
metabolic factors within the muscle including decreased phosphocreatine levels in the
muscle, muscle glycogen depletion, and blood glucose depletion. Depletion of energy
yielding metabolites limit the amount available for activity. Accumulation of metabolites
include accumulation of protons, lactate, inorganic phosphates, and calcium which
directly interfere with contractile mechanisms of the muscle (Baldwin et al., 2005).
Cancer-related fatigue theories indicate that these same physiological mechanisms may
be ongoing in cancer patients independent of physical activity as a result of the cancer
and/or its treatment (Saligan et al., 2015).
19
Cancer-Related Fatigue
Muscular force and strength may be related but can be differentiated from
perceived fatigue (Kasper & Sarna, 2000). Different from the definitions of muscular
fatigue, CRF has been defined by the National Comprehensive Cancer Network as a
persistent, subjective feeling of tiredness related to cancer and cancer treatment that
interferes with usual functioning (Mock et al., 2000). Characterizations of the symptom
include feelings of weakness, tiredness, and lack of energy. Additionally, CRF it is
different from muscular fatigue as it is not relieved by rest or sleep and is not related to
physical exertion (Glaus, Crow, & Hammond, 1996). Current measurements of CRF are
subjective in nature and are assessed in the form of a survey. There is a lack of consensus
on the most appropriate CRF assessment tool with more than 20 instruments currently
being used in various settings. Thus, a lack of consensus exists as to which instrument is
most appropriate for this population. Because of this lack of consensus and variation of
measurement, prevalence can vary widely dependent on the scale used. Additionally,
these scales vary widely on the number of questions and dimensions of fatigue that are
assessed (Minton & Stone, 2008).
In a recent review, Minton and Stone (2008) identified all current CRF scales and
divided them into unidimensional and multidimensional. Unidimensional scales cover
only physical aspects of fatigue whereas multidimensional scales cover between two and
five different aspects of fatigue. The five unidimensional scales that were identified as
having the highest quality included the following: European Organization for Research
and Treatment of Cancer (EORTC) QLQ C30 (Aaronson et al., 1993), the Fatigue
Severity Scale (Krupp, Larocca, Muirnash, & Steinberg, 1989), the Functional
20
Assessment of Cancer Therapy Fatigue (FACT-F) (Yellen, Cella, Webster, Blendowski,
& Kaplan, 1997), the Profile of Mood States (McNair, 1971), and the Brief Fatigue
Inventory (BFI) (Mendoza et al., 1999). Benefits to unidimensional scales are that they
are quick to administer, widely used, and have robust psychometric data to support their
use. Disadvantages include that measurement is limited to a sensation of physical
impairment and therefore only covers one dimension of a multidimensional symptom.
The review identified nine quality multidimensional scales including the following:
Fatigue Questionnaire (FQ) (Chalder et al., 1993), the Fatigue Symptom Inventory (FSI)
(Hann et al., 1998), the Lee Fatigue Scale (K. A. Lee, Hicks, & Ninomurcia, 1991), the
Multidimensional Assessment of Fatigue (MAF) (Belza, 1995), the Multidimensional
Fatigue Inventory (MFI-20) (Smets, Garssen, Bonke, & Dehaes, 1995), the
Multidimensional Fatigue Symptom Inventory short form (MFSI-30) (Stein, Martin,
Hann, & Jacobsen, 1998), the Schwartz Cancer Fatigue Scale (A. L. Schwartz, 2003), the
Wu Cancer Fatigue Scale (Wu & McSweeney, 2004), and the revised Piper Fatigue Scale
(PFS) (Piper et al., 1998). Multidimensional scales are not used as widely as the
unidimensional scales.
While they offer an advantage by covering more dimensions, they are often
lengthier to administer. Additionally, while the measurement of other dimensions is
deemed important, their results are not currently used in clinical practice (Minton &
Stone, 2008). Of these scales the FACT-F, BFI, and PFS are the best validated fatigue
instruments for use in cancer patients (Seyidova-Khoshknabi, Davis, & Walsh, 2010).
21
Objective Measurement of Muscular Fatigue
Non-cancer. Reliable measurement of muscle fatigue is dependent on the
measurement of force generating capacity of the muscle as obtained through maximal
voluntary effort or electrical tetanic stimulation. Maximal voluntary isometric
contractions (MVIC’s) are often used for fatigue assessment in humans and commonly
tested with knee extension exercises as the leg can be kept in testing position. The
biomechanics of testing other muscle groups and areas is more difficult and therefore the
use of MVIC’s to assess other muscle groups is less clear. Certain limitations arise when
assessing maximal voluntary contractions since force output is partly dependent on the
motivation of the subject. Therefore, it has been suggested that maximal voluntary
contractions should instead be considered maximal evocable force (Vollestad, 1997).
In addition to force generation capacity, the ability to generate power is another
important measurement of fatigue. Concentric contractions are more demanding
energetically than isometric contractions as dynamic movement requires faster rates of
ATP regeneration (Woledge, Curtin, & Homsher, 1985). Assessment of maximal power
output can be done through constant velocity cycle ergometers or an isokinetic
dynamometer and will elicit measurement of torque and total work (Vollestad, 1997). An
advantage to using dynamic movement and concentric contraction for fatigue assessment
is that the movement patterns more accurately mimic exercise and normal activities of
daily living than isometric contractions (Christie, Snook, & Kent-Braun, 2011).
Maximal force or power can also be examined by electrical stimulation of alpha
motor neurons innervating the muscle directly. This type of assessment measures tetanic
force though modulation of high frequency stimulation and thus high frequency fatigue.
22
Because different muscle fiber types have different twitch potentiation, interpretation
using this technique can be difficult. The advantage of this method, however, is that it
bypasses central drive and offers comparison of central fatigue to that of peripheral
fatigue. In addition to tetanic force, twitch force has been used to study the loss of force
generating capacity and is a measure of low frequency fatigue (Vollestad, 1997). A direct
measurement of peripheral fatigue can be conducted by examining the differences in
twitch force before and after a fatiguing exercise. If the twitch force is significantly less
following the fatiguing exercise, results suggest a loss of force generating capacity and
serious muscle fatigue. Other twitch properties such as a slowed rate of contraction and
relaxation can also indicate fatigue (Kisiel-Sajewicz et al., 2012). Early investigations in
fatigue by Edwards, Hill, Jones, and Merton (1977) showed a faster decline in twitch
force compared to tetanic force. Recovery of twitch force took much longer than that of
tetanic force. Stimulation of muscle or nerve with different frequencies may provide
estimates of reduction in efficiency of the signal from the excitation action potential to
binding of calcium to contractile proteins in fatigued muscle (Vollestad, 1997).
Cancer. As mentioned earlier, many factors contribute to the symptom of fatigue
including biological factors and psychosocial factors. Therefore, when assessing CRF in
a clinical setting, both objective and subjective assessment should be used (Ahlberg et al.,
2003). Studies measuring objective fatigue, however, are minimal compared to the
amount of literature citing the use of surveys to assess CRF. Considering that many
factors can contribute to muscle fatigue, the lack of an objective measurement of CRF
further hinders our understanding (Yavuzsen et al., 2009). In addition to the underlying
23
factors associated with CRF, decreased physical activity as often seen in cancer patients
can also be a contributing factor to increased fatigability (Bogdanis, 2012).
An exploratory pilot study by Kasper and Sarna (2000) demonstrated differences
in physiological and behavioral assessment of fatigue dimensions; however, this study
was only done in breast cancer patients who underwent chemotherapy, and the study only
involved three patients. While this study mentioned the use of a fatigue index
methodology, authors only discussed differences in mean isometric strength rather than
skeletal muscle fatigue as a result of chemotherapy treatments (Kasper & Sarna, 2000).
A study by Yavuzsen et al. (2009) investigated whether CRF was a result of
peripheral or central fatigue and compared results to a control group. Results from this
study found that patients with CRF had greater perceived fatigue and decreased isometric
contraction time compared to controls. Results also indicated lower amounts of muscle
fatigue in CRF patients compared to controls, as measured through relative twitch force,
which the researchers deemed resultant of central fatigue (Yavuzsen et al., 2009). A
similar study by Kisiel-Sajewicz et al. (2012) used EMG, mean power frequency, and
twitch force data to evaluate physiological fatigue in cancer patients who experienced
CRF. Results from this study suggest that patients experiencing CRF do not undergo as
much muscle fatigue as healthy individuals even though they feel as if their muscles are
more exhausted, which are similar to findings by Yavuzsen et al. (2009). In both studies,
CRF patients had shorter isometric sustained contractions than healthy subjects due to
earlier perceived physical exhaustion. Results of the study by Kisiel-Sajewicz et al.
(2012) were similar to those of Yavuzsen et al. (2009) in that central nervous system
fatigue plays a stronger role in limiting muscle performance in patients with CRF. One
24
limitation to the generalizability of both of the aforementioned studies is the use of
isometric contractions rather than a dynamic assessment.
In addition to muscle fatigue, there in an increased need to investigate whether
there is an independent or dependent relationship between CRF, muscle strength, and
muscle mass. A study by Kilgour et al. (2010) investigated whether or not CRF is related
to specific objective measures of muscle mass and strength in patients with advanced
cancer. Hand-grip strength was used to measure upper body strength and an isokinetic
dynamometer was used to measure lower body strength. Results showed CRF to be
significantly and negatively correlated with skeletal muscle mass and strength. When
corrected for muscle quality, which is force relative to mass, the correlation was no
longer significant. Furthermore, this correlation between CRF and strength was only seen
in men and not in women (Kilgour et al. 2010). Results from these investigations indicate
that CRF is not solely a subjective feeling and support the use and validation of objective
measurements.
Causes of Cancer Related Fatigue
The pathophysiology and mechanisms of CRF remains unclear (X. S. Wang,
2008). As previously mentioned, skeletal muscle structure and function is affected by
both the cancer itself and its treatment modalities, and fatigue is understood also to be
caused by both mechanisms. In addition to mechanisms underlying muscular fatigue,
other theories exist regarding CRF that are independent of muscular function including
the following: dysregulation of circadian rhythm, hypothalamic-pituitary-adrenal-axis,
anemia, vagal-afferent activation, and ATP regeneration (Ryan et al., 2007; Saligan et al.,
2015; X. S. Wang, 2008). Clinical studies have investigated factors related to both
25
treatment and the disease including pain, depression, anxiety, cachexia, as well as other
psychological and physical conditions. Despite these investigations there is still little
understanding into reliable physiological markers as objective fatigue measures (X. S.
Wang, 2008).
Sleep disturbance is commonly reported in cancer patients and may result in an
altered circadian rhythm. Clinical observations have investigated cortisol release and
flattened circadian rhythms to be associated with an increase in fatigue (Ryan et al.,
2007). Bower et al. (2005) investigated cortisol secretion in breast cancer survivors and
found that patients with fatigue had a significantly flatter cortisol release and a slower
decline in cortisol throughout the day than those without fatigue. Several studies
investigated activity levels, sleep disturbance and fatigue and found an inverse
relationship between fatigue and activity levels and a positive relationship between
fatigue and sleeplessness in cancer patients (Berger, 1997; Mormont et al., 1998;
Mormont & Waterhouse, 2002).
Cancer and its treatment may lead to a decrease in ATP regeneration and
accumulation of metabolic byproducts in skeletal muscle affecting contractile ability
(Andrews, Morrow, Hickok, Roscoe, & Stone, 2004). Studies in patients with chronic
fatigue syndrome have shown reduced oxidative metabolism (Lane, Barrett, Taylor,
Kemp, & Lodi, 1998) and reduced skeletal muscle concentrations of ATP (Pastoris et al.,
1997), however, evidence in the cancer population is limited. One study reported reduced
ATP levels in skeletal muscle of patients with cancer in addition to altered protein muscle
metabolism (Collins, Bing, McCulloch, & Williams, 2002; Giordano et al., 2003).
Limitations of these findings, however, are that cancer patients may have reduced
26
nutritional intake leading to decreased ATP regeneration (Ryan et al., 2007). A study
investigating ATP infusions in lung cancer patients found improved muscular strength
and quality of life indicating that perhaps this method could be used as a therapeutic
modality (Agteresch, Dagnelie, van der Gaast, Stijnen, & Wilson, 2000).
Effect of Exercise on Cancer-Related Fatigue
Aerobic Exercise
A number of exercise interventions in cancer patients have used a combination of
both aerobic and resistance training. To investigate effects of each type of activity, they
will be discussed separately. There is a large body of literature on aerobic exercise and its
effects on CRF; however, there remains substantial variability in the outcomes. A recent
review by Tian, Lu, Lin, and Hu (2016) included 26 studies that examined the effects of
aerobic exercise on CRF and combined the results. Overall, aerobic exercise had a small
but statistically significant positive effect which suggests that aerobic exercise could be
beneficial in reducing CRF. Specifically, aerobic exercise was found effective in patients
with nasopharyngeal carcinoma but overall was not found significant for breast cancer,
prostate cancer, or colorectal cancer. Limitations to a study like this include different
measurements of fatigue in addition to different modes, duration, and intensity of
exercise. In this meta-analysis the most widely used fatigue scale was the FACT-F which
interestingly found no significant effects on CRF with aerobic exercise.
Studies using the BFI or PFS did, however, find significant effects of exercise on
CRF (Tian et al., 2016). Therefore, the results of a non-significant effect of aerobic
exercise should be cautioned as this study and others have shown that the FACT-F is not
as appropriate for measuring CRF in breast or colorectal patients (Can, Durna, &
27
Aydiner, 2004; Tian et al., 2016). Additionally, the results of this meta-analysis are not
consistent with the findings of other reviews which have shown significant positive
effects of aerobic exercise in breast cancer patients (Cramp & Byron-Daniel, 2012;
McMillan & Newhouse, 2011; Velthuis et al., 2010; Zou, Yang, He, Sun, & Xu, 2014).
Evidence of the effects of exercise on CRF remains unclear in cancers of the prostate,
colon, and blood (J. C. Brown, Huedo-Medina, et al., 2012; Cramer, Lauche, Klose,
Dobos, & Langhorst, 2014; Velthuis et al., 2010). A meta-analysis by Velthuis et al.
(2010) showed that supervised exercise programs were more effective in reducing CRF
than home-based exercise programs in breast cancer patients. Interestingly, the type of
exercise did not influence the beneficial effects on CRF indicating that the type of
exercise can be tailored to the individual (Tian et al., 2016).
Resistance Training
Compared to the research on aerobic training alone and CRF, there are fewer
studies that include only resistance training with CRF as an outcome. As mentioned
previously, resistance exercise is known to improve muscular function in cancer
survivors. A recent study by M. E. Schmidt et al. (2015) investigated the effects of a 12
week resistance exercise program on fatigue in breast cancer patients undergoing
chemotherapy. The Fatigue Assessment Questionnaire (FAQ) was used as a
multidimensional assessment of fatigue. Results from this study showed a decrease in
fatigue, however, not significant. A study by Courneya et al. (2007) found similar results
when comparing aerobic to resistance exercise in breast cancer patients currently
undergoing chemotherapy. Patients were randomized to a usual care, aerobic, or
resistance intervention. Results showed that neither modality significantly reduced CRF.
28
There no significant difference was observed between the aerobic or resistance group
indicating that neither training modality was more effective at reducing in CRF. A similar
study by Segal et al. (2009) compared aerobic to resistance exercise in men undergoing
radiotherapy for prostate cancer. Participants in this study were also randomized to a
usual care, aerobic, or resistance exercise intervention. In contrast to the study by
Courneya et al. 2007, results from Segal et al. (2009) showed both the aerobic and
resistance intervention significantly improved CRF, however, no significant differences
were found between exercise groups. These studies are also consistent with the metaanalysis by Velthuis et al. (2010) which showed a small but non-significant reduction in
CRF with resistance exercise in both prostate and breast cancer patients.
In contrast, a meta-analysis by J. C. Brown, Huedo-Medina, et al. (2012)
examined the effect of exercise interventions on CRF and found that the greatest
reductions in CRF occurred in patients who participated in moderate intensity or higher
resistance exercise. Interventions using low intensity resistance exercise showed no
significant reduction in CRF (J. C. Brown, Huedo-Medina, et al., 2012). Additionally,
two recent studies found significant reduction in fatigue among breast cancer patients
after they participated in a resistance training program (Hagstrom et al., 2016; Steindorf
et al., 2014). While current exercise guidelines for cancer survivors recommend
complimenting resistance exercise with aerobic exercise (Schmitz et al., 2010) other
organizations like the American Cancer Society make little mention of including
resistance exercise (Doyle et al., 2006). Mechanisms for the effectiveness of resistance
exercise are likely due to the attenuation of muscle wasting, increased protein synthesis,
and improvement of the cytokine response (J. C. Brown, Huedo-Medina, et al., 2012).
29
Considering the evidence of the effects of aerobic and resistance exercise, as
recommended by the American College of Sports Medicine (ACSM) guidelines, a
rehabilitation program that includes a combination of aerobic and resistance exercise
seems most efficacious to have the greatest effect on reducing CRF.
Physical Activity and its Effects on Skeletal
Muscle Structure and Function
Repeated bouts of muscle contraction are an intense stimulus for physiological
adaptation. Over time and with frequent exercise training sessions, skeletal muscle
demonstrates a wide variety of functional adaptations in response to repeated muscle
contractions. Training induced adaptations include changes in contractile apparatus,
contractile proteins, metabolic adaptations, changes to intracellular signaling,
transcription and translation, and modifications to mitochondrial size, density, and
function. At the whole body level, training induces changes to size, strength, and power
output of skeletal muscle in addition to modifications of fiber types. In general, the term
exercise encompasses a variety of muscle contraction types and includes several
modifiable variables including frequency, intensity, modality, and duration. Additionally,
the exercise may refer to both aerobic and resistance types of activities. Aerobic exercise
generally consists of high frequency, low power output contractions whereas resistance
training generally consists of low frequency, high power output contractions. Therefore,
adaptations and molecular responses are different, dependent on the type of activity in
addition to frequency, intensity, modality and duration (Egan & Zierath, 2013).
Adult human skeletal muscle is generally composed of equal proportions of slow
(Type I) and fast (Type II) fibers. Slow fiber types have a higher mitochondrial content
30
and are more fatigue resistant than fast fibers. Fast twitch fibers can be divided into two
subtypes of Type IIa and Type IIx where Type IIa have a greater oxidative capacity and
are more fatigue resistant than Type IIx fibers, but more fatigable and have less oxidative
capacity than Type I fibers. Training can induce adaptations to fiber types in addition to
motor unit types; however it has not been shown to produce any major shifts in
distribution of slow and fast fibers in skeletal muscle (B. Saltin & Gollnick, 1983).
Aerobic Exercise
In general, known alterations of skeletal muscle in response to endurance training
are increases in Type I fiber type area (Costill, 1972; Gollnick et al., 1973; Häkkinen &
Keskinen, 1989; Patton, Kraemer, Knuttgen, & Harman, 1990; B Saltin et al., 1976),
decreases in Type II fiber type area (Howald, Hoppeler, Claassen, Mathieu, & Straub,
1985), increases in mitochondrial number and size (Holloszy, 1967; B. Saltin & Gollnick,
1983), and increases in capillary density (Hermansen & Wachtlova, 1971; B. Saltin &
Gollnick, 1983). A majority of these adaptations are regulated by the alterations of
muscle specific enzymes that regulate energy metabolism and therefore have a larger
impact on muscular function than structure (Taylor & Bachman, 1999). The importance
of these adaptations is seen as improved ability to produce ATP via oxidative
phosphorylation, decreased lactic acid production at a given intensity, increased use of fat
for energy allowing for sparing of carbohydrate, and improved efficiency in extracting
oxygen from the blood. Increased oxidative capacity improves overall muscle
metabolism and has been shown to improve insulin sensitivity (Bogdanis, 2012).
The benefits of aerobic exercise on cardiovascular fitness and health in
individuals and older adults is well understood (Chodzko-Zajko et al., 2009; Garber et al.,
31
2011; Haskell et al., 2007). The influence of aerobic training on skeletal muscle mass and
function is less clear as some investigations have found no influence (Jubrias, Esselman,
Price, Cress, & Conley, 2001; Short, Vittone, Bigelow, Proctor, & Nair, 2004; Sipila &
Suominen, 1995; Verney, Kadi, Saafi, Piehl-Aulin, & Denis, 2006) and others citing
significant muscular hypertrophy (Harber et al., 2009; Konopka et al., 2010; Lovell,
Cuneo, & Gass, 2010; R. S. Schwartz et al., 1991). It was unclear if adaptations were
specific to age or sex, which is a limitation in these studies. A study by Harber et al.
(2012) examined the influence of aerobic training on whole muscle size and contractile
function in both younger and older men. Results found improved aerobic capacity in both
age groups, significantly increased whole muscle hypertrophy independent of age, and
improved peak power of both slow and fast fibers. These results support earlier findings
that aerobic exercise training can improve Type IIa contractile function and aerobic
training can combat loss of muscle mass and function due to aging. Longer duration
training studies have also shown that aerobic exercise increases muscle protein synthesis
and supports evidence that aerobic training has the potential to increase muscular mass
and strength (Harber et al., 2010; B. F. Miller et al., 2005).
Resistance Training
Overall, aerobic exercise results in little or no gain in muscle mass and strength
whereas major neuromuscular adaptations result from resistance training. As with aerobic
adaptations, the extent of adaptation relies largely on the pre-training state of the
individual along with the type, intensity, volume, task, and duration of training. Although
the literature on resistance training is extensive, a general understanding exists regarding
adaptations of increased strength, power, muscle mass, and muscular endurance (Baechle
32
& Earle, 2008). The first 6-8 weeks of training result in increases in strength with much
smaller if any increase in muscle size or cross-sectional area. This suggests that the early
increases in strength are due to neural adaptations (Staron et al., 1994). These increases in
neural function are largely a result of increased motor unit recruitment and firing rate (D.
A. Jones, Rutherford, & Parker, 1989). A study by Adams, Harris, Woodard, and Dudley
(1993) showed only 70% of muscle was activated during maximal effort in untrained
subjects indicating potential for increased recruitment. Training has shown to increase the
amount of muscle activated demonstrating an increased potential to recruit larger and
more fast twitch motor units (Pensini, Martin, & Maffiuletti, 2002).
As the duration of training increases, hypertrophy of muscle fibers plays a larger
role in increasing strength than neural adaptations. Hypertrophy refers to enlargement of
skeletal muscle and occurs due to increased protein synthesis which increases contractile
proteins allowing for increases in the size of myofibrils (MacDougall et al., 1995;
MacDougall, Sale, Elder, & Sutton, 1976). Resistance training also increases the amount
of glycolytic enzymes and thus cytosolic area further increasing muscle size
(MacDougall, Ward, Sale, & Sutton, 1977). Additional adaptations include a decrease in
mitochondrial density that does not result in a decrease in number of mitochondria
(Baechle & Earle, 2008). A study by MacDougall et al. (1978) found a 26% reduction in
mitochondrial density as well as a 25% reduction in mitochondrial volume to
mitochondrial fiber ratio. These changes were also accompanied by significant increases
in both fast and slow fiber type area. Conclusions indicated that the mitochondrial density
was decreased due to the increase in myofibrilar size (MacDougall et al., 1978).
33
Additional adaptations to resistance training include fiber type transitions that
contribute to increased muscular strength and power. Both Type I and Type II fibers are
recruited during resistance training and in general cross sectional area of both fiber types
is increased following training, however, not equally (Baechle & Earle, 2008). Following
resistance training, there has been shown a greater increase in Type II fibers than Type I
fibers (Hather, Tesch, Buchanan, & Dudley, 1991). Evidence of complete shifts in fiber
type from training remains equivocal. Current evidence supports fiber type shifts from IIx
to IIa following resistance training or to a more hybrid or intermediate type of fiber rather
than a complete shift in true fiber type from II to I (Campos et al., 2002; N. Wang,
Hikida, Staron, & Simoneau, 1993).
Cancer Survivors
Cancer and its treatments, as mentioned, result in decreased aerobic capacity,
decreased strength and flexibility, muscle atrophy, fatigue, depression, and an overall
decrease in quality of life (Burnham & Wilcox, 2002). Exercise has been shown to have
beneficial physiological effects and it can be considered as a therapeutic intervention for
cancer survivors (Wolin, Schwartz, Matthews, Courneya, & Schmitz, 2012). Specifically,
exercise has the capacity to directly modify skeletal muscle and potentially reverse
dysfunction. The repeated muscular contractions that take place during both aerobic and
resistance exercise stimulate physiological adaptations such as increased protein
synthesis, muscular hypertrophy, changes in contractile and mitochondrial function,
metabolic changes, and modifications to signaling pathways (Christensen et al., 2014).
Therefore, physical activity could be of particular importance to advanced stage and
cachectic patients due to the potential to offset or increase muscle mass and strength
34
(Stene et al., 2013). In 2009, the American College of Sports Medicine established
exercise guidelines for cancer survivors based on a large body of evidence. These
guidelines suggest that exercise is safe for survivors and could assist in reduction of side
effects and morbidities from cancer and its treatment. Current guidelines are consistent
with the 2008 Physical Activity Guidelines for Americans recommending 150 minutes of
moderate intensity aerobic activity or 75 minutes of vigorous activity in addition to at
least two days of resistance training per week (Committee, 2008). The American College
of Sports Medicine guidelines also note that there may be other considerations with
cancer survivors that would alter these recommendations based on the survivors’
condition. Additionally, exercise programs should be adapted for the individual based on
health status, cancer treatment type, and disease trajectory (Schmitz et al., 2010).
Investigations into physical activity in cancer survivors suggest that the majority
of side effects from cancer and treatments appear to be ameliorated by exercise. Several
review studies show strong evidence that exercise is an effective tool for rehabilitation
after cancer (Burnham & Wilcox, 2002; Courneya, 2003; Fong et al., 2012; Speck et al.,
2010; Stevinson, Lawlor, & Fox, 2004). The majority of evidence, however, examining
exercise and physical functioning in cancer patients has only evaluated the effects of
aerobic exercise (Al-Majid & Waters, 2008). A review by Courneya (2003) evaluated
exercise in cancer survivors. At the time of the review, the author found 28 studies of
exercise in breast cancer patients and 19 in other cancers. Of these 47 studies, only three
included resistance training interventions and of these three, two reported increases in
muscular strength. The majority of studies in this review focused on outcomes of aerobic
exercise capacity, body composition, and psychological well-being. Another review by
35
Stevinson et al. (2004) evaluated 33 controlled exercise trials and concluded that exercise
improves physical function; however, there was no discussion on improvements to
skeletal muscle function. More recently, Fong et al. (2012) evaluated physical activity in
cancer survivors where only seven studies reported outcomes of physical functioning
related to strength with no investigations into specific muscle function or muscle fatigue.
While endurance exercise has a wide range of benefits, it has not been shown to increase
muscle mass or muscle strength. Despite the evidence that muscle wasting and
dysfunction contribute largely to CRF and a number of studies examining muscular
strength in cancer survivors, few have examined the role of exercise in cachectic patients
(J. C. Brown, Winters‐Stone, et al., 2012).
As previously mentioned, resistance and aerobic exercise modulate changes in
muscle function differently. A growing body of evidence is supported by controlled trials
that have shown resistance training improves muscular strength in oncology patients,
however, evidence on increased muscle mass is mixed. A study by Segal et al. (2009)
evaluated the effects of a 24 week resistance training program in prostate cancer patients.
Results showed a 22% increase in upper body strength and a 24% increase in lower body
strength. Similar results were seen in a study done with breast cancer patients by
Courneya et al. (2007), where a 25-35% improvement in muscular strength was seen after
17 weeks of resistance training when compared to controls. The same study showed that
while aerobic training did not result in improved strength, improvements in aerobic
fitness and body composition were seen in comparison to the control group (Courneya et
al., 2007). A study by Quist et al. (2012) combined high intensity aerobic training with
high intensity resistance training and found a 17% increase in muscular strength after
36
only six weeks of training. A number of other investigations have shown increases in
muscular strength following a physical activity intervention in cancer survivors both
during and after treatment (Adamsen et al., 2009; Battaglini et al., 2007; Hagstrom et al.,
2016; Jarden, Baadsgaard, Hovgaard, Boesen, & Adamsen, 2009; Oldervoll et al., 2011;
Schmitz et al., 2009; A. L. Schwartz & Winters-Stone, 2009; A. L. Schwartz, WintersStone, & Gallucci, 2007; Strasser, Steindorf, Wiskemann, & Ulrich, 2013). In contrast,
several other studies showed no significant increase in muscular strength following a
physical activity intervention (Coleman et al., 2003; Mustian et al., 2009; Wiskemann et
al., 2011); however, these interventions were also home-based, unsupervised
interventions.
In addition to increases in muscular strength, a body of evidence shows resistance
training increases muscle mass in cancer patients; however, the evidence is not as clear as
it is for strength. Prostate cancer patients have shown increases in muscle mass between
0.8 – 1.7 kg (Hanson et al., 2012; Segal et al., 2009) and breast cancer patients increased
muscle mass by 0.8 kg during chemotherapy (Courneya et al., 2007) following a
resistance training intervention. Several other investigations have shown increases in
muscle mass and volume following a combined aerobic and resistance exercise
intervention (Battaglini et al., 2007; Coleman et al., 2003). In contrast, several other
studies showed no significant increases in muscle mass following a resistance training
intervention in cancer survivors; however, one of these studies only involved a four week
intervention (Cunningham et al., 1986) and the other two were home based interventions
(Demark-Wahnefried et al., 2008; Mustian et al., 2009). At this time, there are no
published studies investigating the effects of exercise at the fiber level in cancer patients.
37
However, there are three ongoing studies looking to evaluate this topic (Christensen et
al., 2014; L. W. Jones, Douglas, et al., 2010; L. W. Jones, Eves, et al., 2010; Thorsen et
al., 2012). Overall the evidence is stronger for increased muscular strength in the absence
of muscular hypertrophy indicating improvements in strength may be partly attributable
to improved neural adaptations and motor unit activation (J. C. Brown, Winters‐Stone, et
al., 2012; Christensen et al., 2014).
Two studies examined strength outcomes following an aerobic only intervention
in cancer patients. Both investigations showed significant decreases in muscular strength
(Baumann, Kraut, Schule, Bloch, & Fauser, 2009; Mello, Tanaka, & Dulley, 2003).
While aerobic exercise does not have as large an impact on increasing muscle mass or
strength in cancer patients, it has shown to improve overall physical function,
psychological function, reduce inflammation, reduce cardiotoxicities, and improve
prognosis which are also important factors for cancer survivors (Christensen et al., 2014;
L. W. Jones et al., 2009).
This review of literature reveals the need to for continued research into the
mechanisms, treatment, and assessment methods surrounding CRF. Enhancing our
understanding of muscle function and how it relates to CRF can assist clinicians in
designing the appropriate exercise program for survivors experiencing this phenomenon.
Furthermore, understanding the effects of exercise on muscle fatigue in this population
can further our understanding of cancer rehabilitation and its effects on muscular
function.
38
CHAPTER III
METHODS
Study procedures were approved by the University of Northern Colorado’s (UNC)
Institutional Review Board (see Appendix A). Participants in this study were 155 males
and females over the age of 18 who had been previously diagnosed with cancer.
Participants were referred to the University of Northern Colorado Cancer Rehabilitation
Institute (UNCCRI) from local oncologists as individuals who were either undergoing or
had undergone chemotherapy, radiation, surgery, immunotherapy or a combination of
treatments. Prior to participation, individuals were informed of the study procedures and
signed an informed consent to participate in an initial assessment in addition to exercise
training (see Appendix B). A separate informed consent specific to this study was signed
by participants (see Appendix C).
Procedures
Medical history was obtained prior to the initial assessment and included cancer
type, stage, medications, and all treatments. Cancer survivors completed three different
initial assessments of fatigue including measurements of self-reported and physiological
fatigue. Anthropometric data were also collected. Height was measured by a digital freestanding stadiometer (InBody, Cerritos, CA). Weight and body composition were
measured by bioelectrical impedance (In-Body, Cerritos, CA). Scores of subjective
fatigue were established via the revised Piper Fatigue Scale (PFS) which evaluates total
39
CRF (PFST), as well as subscales of fatigue including sensory, affective, behavior,
cognitive and mood. The individual subscales together consist of 22 questions with the
average score representing total fatigue. Each of the 22 questions was scaled from 0 to
10. A score of 0 indicated that the patient was not experiencing any fatigue, a score of 1
to 3 indicated mild fatigue, a score from 4 to 6 indicated moderate fatigue, and a score of
>7 indicated severe fatigue. The PFS has been shown to be valid and reliable measure of
CRF in cancer patients (Piper et al., 1998).
The behavioral/severity subscale (PFSB) included six questions that assessed the
impact of fatigue on school/work, social interaction, and the overall interference with
enjoyable activities. The affective (PFSA) subscale included five questions that assessed
the extent to which fatigue affects emotional meaning. The sensory (PFSS) subscale
included five questions that assessed mental, physical, and emotional symptoms of
fatigue. The cognitive/mood subscale (PFSC) included six questions that assessed the
impact of fatigue on concentration, memory, and mental clarity (Piper et al., 1998) (see
Appendix D)
Following completion of the PFS, assessment of hand grip fatigue was conducted
through the use of a hand dynamometer. The use of a hand dynamometer has been shown
to be a valid and reliable method to measure handgrip strength in cancer patients (D. J.
Brown, McMillan, & Milroy, 2005; Innes, 1999; Trutschnigg et al., 2008). The
dynamometer (Layfayette/TEC, Layfayette IN) handle was first sized to correctly fit the
hand of the participant. Muscular fatigue was measured using a protocol of 15 maximum
contractions at a rate of one contraction every two seconds. A metronome in addition to
verbal cues was used to keep participant on pace. Both left and right hands were recorded
40
as well as a note of which was the dominant hand. Values in kilograms (kg) were
recorded for each contraction and a fatigue index (FI) was calculated using the averages
of the two highest and two lowest recorded values. Once the averages were calculated
they were inserted into the following equation to determine fatigue index: FI (%) =
[(highest – lowest)/highest]*100 (Beam & Adams, 2011).
Following hand dynamometry assessment, participants were escorted to UNC’s
Biomechanics Lab to participate in lower body muscular fatigue testing. Isokinetic torque
of the knee extensor muscles was measured using a Biodex© dynamometer (Biodex
Medical Inc., Shirley, NY). The use of isokinetic dynamometers has been shown to be
valid and reliable (Drouin, Valovich-mcLeod, Shultz, Gansneder, & Perrin, 2004; Innes,
1999) and has previously been used to measure lower body strength measurements in
patients with cancer (Kilgour et al., 2010; Weber et al., 2009; Wilcock et al., 2008).
Subjects were instructed to sit upright and the dynamometer was correctly fitted to each
participant. The lateral femoral epicondyle was used as a landmark for positioning the
knee joint with axis of rotation of the dynamometer. To prevent additional body
movement, straps were used to secure the testing leg and trunk to the dynamometer chair.
The testing leg was then secured to the leg attachment above the ankle. Range of motion
was determined by having the participant extend and flex his or her leg as far as possible
without discomfort. Correction for limb weight was obtained by measuring torque
exerted on the dynamometer with the knee fully extended and relaxed. Subjects were
instructed on the protocol and were be asked to give maximum effort for each repetition
during each set of exercises. The first two sets consisted of five warm-up repetitions at
speeds of 180°/s and 120°/s, respectively. Each of the warm-up sets were then followed
41
by 90 seconds of rest. The third set served as the fatigue protocol which consisted of 15
maximal repetitions at 60°/s. The dynamometer was then repositioned and the same
procedures were performed on the opposite side. Throughout the test, visual and verbal
encouragement was given by the test administrator. A familiarization session was
conducted prior to the testing session to allow the participant to become familiar with the
protocol. A minimum of two rest days was given between the familiarization protocol
and the testing protocol. MATLAB® R2014a (Mathworks Inc., Natick, MA) was used to
extract the data output from the Biodex© and identify peak torque from each repetition.
The same method of determining FI for upper body (HFI) was used for the lower body
(QFI).
After completing the above pre-assessments, participants completed an
individualized, prescriptive exercise intervention that took place at UNCCRI. Each
exercise intervention was conducted by trained Cancer Exercise Specialists for three
months within the standard UNCCRI program. At the end of each 12-week session,
participants were again asked to complete the aforementioned battery of assessments to
determine whether the 12-week intervention had any effects on functional performance.
Intervention
The exercise intervention consisted of a one-hour period that included aerobic
training, resistance strength training, balance, and flexibility training. Each participant
took part in the intervention no more than three times per week and on non-consecutive
days. Each session included 20 minutes of aerobic training, 30 minutes of resistance
training, and 10 minutes was set aside for flexibility. Aerobic and resistance training was
progressive and intensity was dependent on the treatment status of the participant.
42
UNCCRI has a phase program which consists of four phases. Entry into each phase
depends on treatment status at entry into the program and subsequently completion of 12
weeks of supervised training.
An initial assessment to estimate maximal strength or one repetition maximum
(1RM) was performed on the following resistance machines: chest press, shoulder press,
seated row, lat pull down, leg extension, leg curl, and leg press. A percentage of the
individual’s heart rate reserve (HRR) and estimated 1RM was used to prescribe exercise
intensity for each 12 weeks of the program. Heart rate reserve is the difference between
an individual’s maximum heart rate and their resting heart rate and the formula for
calculating HRR is as follows: HRR = HRmax – HRrest. The formula for calculating
exercise heart rate for a specific percentage of HRR is as follows: Exercise HR = % of
target intensity (HRmax – HRrest) + HRrest. Using a percentage of HRR has been used as a
common method of determining exercise intensity for prescriptive exercise (Karvonen,
Kentala, & Mustala, 1957).
Individuals still undergoing radiation or chemotherapy treatment were classified
as Phase 1 and began at an intensity of 30-45% HRR and 1-RM. Individuals beginning
the intervention for the first time that were not currently in treatment were classified as
Phase 2 and began at 40-60% of their HRR and 1RM. Those individuals graduating from
Phase 2 entered Phase 3 and began at 60-85% of their HRR and 1RM. Individuals
graduating from Phase 3 entered Phase 4 and began at 65-95% of their HRR and 1RM.
Progression of Phase 1 for the 12 weeks was 5% for cardiovascular training and 10-15%
for muscular strength. Progression of Phase 2 was 10-20% for cardiovascular training and
30-50% for muscular strength. Progression of Phase 3 was 5-10% for cardiovascular
43
training and 30-50% for muscular strength. In Phase 4, progression aimed to be continual
with an improvement of more than 5% in both cardiovascular endurance and muscular
strength by the end of 12 weeks of training.
Modes of aerobic exercise included the following: treadmill walking and running
(Trackmaster ®TMX424, Jas Fitness Systems), walking outside, stationary bikes
(Monark®), recumbent stepper (Nu Step®, BioStep®), AquaCiser (Ferno Aquaciser®II),
and arm ergometer (SCIFIT®). Modes of resistance training included the following:
weight machines (Cybex®), free weights (dumbbells), Thera bands (Power Systems®
Versa Tubes®), body weight exercises, fitness balls (Gymnic® Fitball and Physio-Roll),
and medicine balls (Power Systems®). Modes of balance exercise included dyna disc
exercises, wobble disks, balance boards, Bosu® ball, and foam pad exercises. Flexibility
training included static stretching, wall mounted range of motion wheel, and wall
mounted stretching ropes. All exercise was supervised and heart rate and oxygen
saturation were continuously monitored by Cancer Exercise Specialists and UNCCRI
staff. Heart rate monitors (Polar®) were used to monitor heart rate and pulse oximeters
were used to monitor oxygen saturation (Prestige Medical, Northridge, CA). Detailed
records of each exercise session including heart rate, blood pressure, and oxygen
saturation responses were documented by the Cancer Exercise Specialist for each
participant. Safety of the participants during the exercise intervention was a top priority.
Statistical Analysis
IBM® SPSS® Statistics version 23 (IBM® Armonk, NY) and SAS® version 9.4
(Cary, NC) were used for all analyses. To determine if muscular fatigue was correlated to
a survey measure of fatigue, Pearson correlations were used between upper and lower
44
body fatigue indexes and total CRF scores (PSFT) as assessed though the revised Piper
Fatigue Scale (PFS). Correlations between fatigue indexes and each of the four subscales
of the PFS including sensory (PFSS), affective (PFSA), behavior (PFSB), and
cognitive/mood (PFSC) was also made. Similarly, correlations were examined between
peak quadriceps torque (PQF) (N.m) and PFST as well as between peak handgrip force
(PHF) and each of the previously mentioned PFS subscales. R values and associated p
values were used to determine correlation strength. To determine the effect of the
exercise intervention on these same variables, a repeated measures multivariate analysis
of variance (RMANOVA) was utilized following 12 and 24 weeks of exercise training.
Planned contrasts evaluated pre-training to 12 weeks, 12 weeks to 24 weeks, and pretraining to 24 weeks.
45
CHAPTER IV
MANUSCRIPT I
RELATIONSHIPS BETWEEN MUSCULAR AND
PSYCHOLOGICAL ASSESSMENT OF
CANCER-RELATED FATIGUE
Abstract
Despite its prevalence, cancer-related fatigue (CRF) is seldom assessed and treated in
clinical practice. The etiology of CRF has made the accurate assessment process a
substantial challenge. Self-reported measures are widely used and accepted for CRF
assessment, however, these are not objective measures of fatigue. Direct assessment of
fatigue through functional testing of muscle could provide further insight into how cancer
survivors experience fatigue, which could lead to improved exercise-based interventions
that target this debilitating side effect of cancer and cancer treatments. PURPOSE: To
evaluate the relationship between subjective self-reported fatigue measures and
objectively-measured muscular fatigue in cancer survivors. METHODS: A total of 155
cancer survivors (aged 60 ± 13 years) were asked to complete the revised Piper Fatigue
Scale (PFS) which was composed of a total CRF score (PFST) and four subscale scores:
behavioral/severity (PFSB), affective (PFSA), sensory (PFSS), and cognitive/mood
(PFSC). A handgrip fatigue index (HFI) composed of 15 maximal repetitions was
completed by each participant. Participants also completed 15 maximal isokinetic knee
extensions at a joint velocity of 60 deg∙s-1 which was used for determining a quadriceps
46
fatigue index (QFI). Each fatigue index was computed as the difference between the
average of the first two cycles and the average of the last two cycles divided by the
average of the first two cycles and expressed as a percentage. RESULTS: Significant
positive relationships between the HFI and PFST (r = .303; p < .001), PFSB (r = .287; p
< .001), PFSA (r = .220; p < .001), PFSS (r = .352; p < .001), and PFSC (r = .301; p <
.001) were observed. In addition, peak hand force (PHF) was significantly negatively
correlated to PFST (r = -.177; p = .027), PFSB (r = -.209; p = .009) and PFSS (r = -.194,
p = .015). No significant relationships were observed between PFS and QFI (r = -.034 p =
.378). CONCLUSION: Results from this study suggest that objective measures of upper
body fatigue, as measured though a hand dynamometer, are significantly related to
subjective feelings of cancer-related fatigue (CRF) and could potentially serve as an
objective measure of fatigue in cancer survivors.
Key Words: FATIGUE INDEX, DYNAMIC FATIGUE ASSESSMENT, PIPER
FATIGUE SCALE, MUSCULAR FATIGUE
47
Introduction
An estimated 11 million cancer survivors are currently living in the United States.
Due to increases in technology, improvements in treatment and detection methods, the 5year relative survival rates for all cancers have been gradually improving over the last
few decades (R. Siegel, J. Ma, Z. Zou, & A. Jemal, 2014). Thus, individuals diagnosed
with cancer are living longer following treatment which has resulted in a greater number
of cancer survivors living longer following treatment. Despite decreases in mortality,
survivors still suffer from the side effects from of chemotherapy, radiation, surgery,
hormone therapy, or a combination of these treatments. Cancer treatment is known to
negatively affect many dimensions of an individual’s life including decreased functional
capacity and increased fatigue (J. C. Brown, Winters‐Stone, et al., 2012).
Cancer survivors frequently report one or more symptoms that affect quality of
life, with the most commonly reported symptom being cancer related fatigue (CRF).
Fatigue is a difficult symptom to define and can include at least two different dimensions.
The first dimension is a subjective state of fatigue and characterized by a feeling of
weakness and a perception of a decreased ability to perform physical tasks. The second
dimension can be defined as an objective measure of decrement in mental or physical
performance due to a repeated or prolonged activity. This decrement of performance has
also been associated as a common symptom with various chronic diseases. Cancer related
fatigue is different in that it is characterized by extreme exhaustion that is not related to
activity (P. C. Stone et al., 1998). Other evidence has suggested that cancer patients could
experience three dimensions of fatigue including cognitive, affective, and physical
dimensions (Glaus et al., 1996; Ream & Richardson, 1997).
48
Several mechanisms underlying CRF have been proposed; however, the
pathophysiology is still largely unknown (Saligan et al., 2015). Tumor factors and
cytokines associated with cancer biology and treatments may influence increases in
protein degradation in cancer survivors that is associated with loss of muscular strength
(Cantarero-Villanueva et al., 2012). Skeletal muscle structure and function is negatively
affected by both the cancer itself and its treatment modalities, and fatigue is understood
also to be caused by both mechanisms. In addition to mechanisms underlying muscular
fatigue, other theories exist regarding CRF that are independent of muscular function
including the following: dysregulation of circadian rhythm, hypothalamic-pituitaryadrenal-axis, anemia, vagal-afferent activation, and ATP regeneration (Ryan et al., 2007;
Saligan et al., 2015; X. S. Wang, 2008). Clinical studies have investigated factors related
to both treatment and the disease including pain, depression, anxiety, cachexia, as well as
other psychological and physical conditions. Despite these investigations there is still
little understanding into reliable physiological markers as objective fatigue measures (X.
S. Wang, 2008). Overall, the dimensions of CRF seem to involve the dysregulation of
physiological, biochemical, and psychological mechanisms (Ryan et al., 2007; Weis &
Horneber, 2015).
As many as 95% of cancer patients report CRF as a symptom from the cancer
itself or due to the side effects of treatment. Despite its prevalence, CRF is seldom
assessed and treated in clinical practice (Portenoy & Itri, 1999; Weis & Horneber, 2014).
Due to the subjective and multifactorial causes of CRF, accurate assessment is a
significant challenge. Currently, self-report measures are widely used and generally
accepted as an assessment of CRF; however, these tests only measure one dimension of
49
psychological fatigue. While multidimensional surveys attempt to assess a physical
fatigue dimension, outcomes are still of a subjective nature. Numerous studies in cancer
patients have reported a strong relationship between fatigue and psychological stress such
as depression and reduced quality of life (Blakely et al., 1991; L. F. Brown & Kroenke,
2009; Bruera et al., 1989; Derogatis et al., 1983; P. C. Stone et al., 1998; Visser & Smets,
1998). However, psychological stress alone cannot explain most of the fatigue felt by
cancer patients. Considering fatigue is the most frequent symptom experienced by
patients with cancer, an accurate measure of CRF is critical to understanding the science
behind fatigue and to aid in assessment and treatment strategies (P. C. Stone et al., 1998).
Because grip strength is related to many activities of daily living, it is often used
in clinical settings to assess overall strength (Nicolay & Walker, 2005). Handgrip
strength has been shown to be decreased in colorectal and prostate cancer patients;
however, more research is needed to better understand whether handgrip strength can be
used as an indicator of fatigue in cancer survivors (Cantarero-Villanueva et al., 2012).
Considering most daily activities require continuous, dynamic movements rather than
continual static holding as assessed in maximum grip strength, testing of handgrip
endurance may be a better indicator of fatigue than maximal grip strength. Few studies
have yet to examine measurements of dynamic grip endurance, and no study was found
that compared psychological fatigue measurements to handgrip fatigue.
Exertional fatigue has been shown to have a negative association with skeletal
muscle mass and strength; however, it is still unknown if there is an association with
these variables and CRF (Kilgour et al., 2010). Additionally, there is evidence linking
muscular-related activities such as cardiovascular and resistance training to reducing CRF
50
(Dimeo, 2001; Tian et al., 2016; Velthuis et al., 2010). Considering what is currently
known about CRF and cachexia, it is surprising that a relationship between muscular
strength or muscle mass and CRF has yet to be established. Linking muscle parameters
and CRF might partially, yet effectively explain the degree of exhaustion felt by cancer
survivors (Kilgour et al., 2010).
Since fatigue seems to be associated with a physiological component, a growing
number of studies are investigating physical activity as a treatment intervention. Exercise
training has been reported to be beneficial in cancer survivors as it improves functional
capacity and muscular strength (van Weert et al., 2006). Physical activity has been shown
to reduce fatigue (Haas, 2011; M. E. Schmidt et al., 2012; Schneider et al., 2007a, 2007b)
and increase strength (Courneya et al., 2007; Segal et al., 2003; Speck et al., 2010). As
mentioned, there is a substantial amount of evidence linking physiological mechanisms to
CRF (Ryan et al., 2007; Saligan et al., 2015; X. S. Wang, 2008; Weis & Horneber, 2015).
Therefore, it is interesting that current assessments leave out the evaluation of a
physiologic component that could be a contributing factor.
Considering the multi-dimensional causes of fatigue, an accurate measure of
physiological fatigue is also necessary to determine best treatment methods (P. C. Stone
& Minton, 2008). The relationships, however, between in self-reported fatigue and
muscular fatigue have yet to be investigated. Considering the development cancerspecific subjective fatigue scales, it is of interest to consider the physiological origin of
CRF. In addition, a lack of research exists in the area of muscular and physiological
assessment of fatigue and how it relates to the subjective or psychological perception.
51
Therefore, the purpose of this study was to evaluate the relationship between objectivelymeasured muscular fatigue and self-reported psychological fatigue.
Methods
Study procedures were approved by the University of Northern Colorado’s (UNC)
Institutional Review Board. Participants in this study were males and females over the
age of 18 who had been previously diagnosed with cancer. Participants were referred to
the University of Northern Colorado Cancer Rehabilitation Institute (UNCCRI) from
local oncologists as individuals who were either undergoing or had undergone
chemotherapy, radiation, surgery, hormone therapy, immunotherapy or a combination of
treatments. Current participants in the UNCCRI program were also recruited prior to their
re-assessment within the program. Written and verbal study information was given to
subjects before participation. An informed consent was then signed by participants.
Medical history consisting of cancer type, stage, and treatments were obtained prior to
assessments. Anthropometric data were collected during the patient’s initial assessment
which included age, height, weight, and body composition. Body composition was
analyzed by the use of bioelectric impedance (InBody, Cerritos, CA)
A total of 155 cancer survivors (60 ± 13 years of age) completed three different
initial assessments of fatigue including both measurements of psychological and
physiological fatigue. Scores of fatigue were established via the revised Piper Fatigue
Scale (PFS) which is a multidimensional scale to evaluate total CRF as well as subscales
of fatigue including sensory, affective, behavior, cognitive and mood (Piper et al., 1998).
The individual subscales together consist of 22 questions with the average score
representing total CRF (PFST). Each of the 22 questions was scaled from 0 to 10. A score
52
of 0 indicates that the patient was not experiencing any fatigue, a score of 1 to 3 indicates
mild fatigue, a score from 4 to 6 indicates moderate fatigue, and a score of > 7 indicates
severe fatigue. The behavioral subscale (PFSB) included six questions that assessed
impact of fatigue on school/work, social interaction, and the overall interference with
enjoyable activities. The affective (PFSA) subscale included five questions that assessed
fatigue affected emotional meaning. The sensory (PFSS) subscale included five questions
that assessed mental, physical, and emotional symptoms of fatigue. The cognitive/mood
subscale (PFSC) included six questions that assessed fatigue impact on concentration,
memory, and mental clarity. The PFS has been shown to be a valid and reliable measure
of CRF in cancer patients (Piper et al., 1998).
Following completion of the PFS, participants completed an assessment of upper
body fatigue using a hand dynamometer protocol consisting of 15 repetitions requiring
maximal voluntary effort. The dynamometer (Layfayette/TEC, Lafayette IN) handle was
first sized to correctly fit the hand of the participant and the dominant hand was identified
as the hand used for writing. With a metronome set to the a pace of 60 beats per minute,
participants were instructed to squeeze the hand dynamometer as hard as possible while
maintaining the constant pace of one repetition every other beat until 15 repetitions were
completed. The task was then repeated on the opposite hand. Values in kg were recorded
and a fatigue index (FI) was calculated using the averages of the two highest and two
lowest recorded values. Once the averages were calculated they were put into the
following equation to determine fatigue index: FI (%) = [(highest – lowest)/highest]*100.
Following hand dynamometry assessment, participants were asked to complete
lower body muscular fatigue testing. Isokinetic torque of the knee extensors was
53
measured on a Biodex© (Biodex Medical Inc., Shirley, NY) dynamometer. Subjects sat
upright and were fitted to the dynamometer using the lateral femoral epicondyle as a
landmark for positioning the knee joint with axis of rotation of the dynamometer. To
prevent additional body movement, straps were used to secure the testing leg and trunk to
the dynamometer chair. Correction for limb weight was obtained by measuring torque
exerted on the dynamometer with the knee fully extended and relaxed. Subjects were
instructed to give maximum effort for each repetition during each set of exercises and 90
seconds of rest was given between sets. The first two sets consisted of five warm-up
repetitions at speeds of 180°/s and 120°/s, respectively. The third set consisted of the
fatigue protocol and consisted of 15 repetitions at 60°/s. The dynamometer was then
repositioned and the same procedures were performed on the opposite side. A
familiarization session was conducted prior to the testing session to allow the participant
to become familiar with the protocol. Dominant limb was determined at the
familiarization session by asking the participant which leg they would use to kick a ball.
A minimum of two rest days were given between the familiarization protocol and the
testing protocol.
MATLAB® R2014a (Mathworks Inc., Natick, MA) was used to analyze Biodex©
data output and identify peak torque (N.m) from each repetition. The same method of
determining FI for upper body (HFI) was used for the lower body (QFI). Lean muscle
mass was determined by body fat percentage and body weight. IBM® SPSS® Statistics 20
(IBM® Armonk, NY) was used for data analysis.
54
Results
Data are presented as means ± SD. While both dominant and non-dominant limbs
were tested, only dominant limb data were used for the analysis. Initial characteristics of
participants are listed in Table 1. Treatment history and clinical characteristics are
presented in Table 2. Fatigue indices, muscular strength, and muscle mass for all subjects
are presented in Table 3. Lastly the individuals in each fatigue classification are presented
in Table 4.
Table 1
Subject Characteristics
Age in years (mean ± SD)
60 ± 13
Mass in kg (mean ± SD)
77 ± 19
Height in cm (mean ± SD) 165 ± 14
Female (n)
97
Male (n)
58
Total (N)
155
55
Table 2
Treatment History and Clinical Characteristics
Variables
n
%
Cancer stage
0
I
II
III
IV
2
39
46
41
26
1
25
30
26
17
Chemotherapy
Yes
113 73
No
42
27
86
69
55
45
Radiation
Yes
No
Surgery
Yes
No
122 79
33 21
In-treatment
19 12
Out of treatment
136 88
Months since treatment (mean ± SD) 12 ± 20
Table 3
Muscle Mass, Strength, and Fatigue
Variables
Mean ± SD
Lean muscle mass (kg)
51 ± 13
Handgrip strength (kg)
18 ± 7
Quadriceps strength (N.m)
150 ± 53
Hand fatigue index (%)
33 ± 16
Quadriceps fatigue index (%) 34 ± 10
56
Table 4
PFS Fatigue Classifications
Variables
n
None
19
Mild
71
Moderate
55
Severe
10
Higher PFST scores showed a significant moderate correlation with higher HFI (r
= .303, p < .001). Significant correlations between the HFI and PFS subscales PFSB (r =
.287; p < .001), PFSA (r = .220; p < .001), PFSS (r = .352; p < .001), and PFSC (r =
.301; p < .001) were also observed. Peak hand force (PHF) was significantly negatively
correlated to PFST (r = -.177; p = .027), PFSB (r = -.209; p = .009) and PFSS (r = -.194,
p = .015). Fatigue indices of the hand and quadriceps were not significantly correlated to
each other (r = .021, p = .791); however, PHF and peak quadriceps force (PQF) were
significantly positively correlated (r = .198, p = .014). More advanced cancer stage
showed significant correlations with PFST (r = .181; p = .025), PFSA (r = .212; p <
.001), PFSS (r = .185; p = .022), and PFSC (r = .160; p = .048) but none of the fatigue
indices. Cancer stage also showed significant positive correlations with PHF (r = .235; p
= .002) and lean muscle mass (LMM) (r = .214; p = .011). LMM also showed a
significant positive correlation with PHF (r = .206; p = .010) and PQF (r = .601; p <
.001). QFI was not significantly correlated to PFST (r = -.034, p = .678) or any of the
PFS subscales. A correlation matrix representing all dependent variables is shown in
Table 5.
57
Table 5
Pearson Correlation Matrix for Main Study Variables
PFSB PFSA PFSS PFSC HFI
QFI
**
**
**
**
**
PFST .918
.923
.911
.904
.303
-.034
**
**
**
**
PFSB
.794
.778
.745
.287
-.037
PFSA
.816** .797** .220** -.034
PFSS
.803** .352** -.021
PFSC
.301** -.018
HFI
-.021
QFI
PHF
PQF
LMM Stage
-.112
.069
.181*
-.209** -.126
33
-.134
-.105
.081
.155
.037
.212**
-.194*
-.091
.089
.185*
-.109
-.097
.021
.160*
-.525** -.004
.012
.053
-.108
-.096
-.177
*
.070
PHF
.198
*
.206
*
.235**
.601** .119
PQF
.214**
LMM
*
.034
Correlation is significant at the .05 level (2-tailed)
Correlation is significant at the .01 level (2-tailed)
**
Figure 1 represents the correlation between HFI and PFS while Figure 2
represents the correlation between QFI and PFS.
r = .303; p < .001
Piper Faituge Scale (score)
9
8
7
6
5
4
3
2
1
0
0
10
20
30
40
50
60
70
80
90
Hand Fatigue Index (%)
Figure 1. Scatterplot of hand fatigue index versus total Piper Fatigue Scale scores. Dotted
line represents the line of best fit.
58
r = -.034; p = .678
Piper Fatigue Scale (score)
9
8
7
6
5
4
3
2
1
0
0
10
20
30
40
50
60
70
80
Quadriceps Fatigue Index (%)
Figure 2. Scatterplot of quadriceps fatigue index versus total Piper Fatigue Scale scores.
Dotted line represents the line of best fit.
Discussion
Several studies have reported observed reductions in muscle mass and function
due to cancer and its treatments (Christensen et al., 2014; Kilgour et al., 2010; Weber et
al., 2009). The relationship, however, to muscle function and subjective feeling of fatigue
remains unclear and was supported by this study which showed that upper body local
muscular fatigue was associated with CRF.
Results from this present study show that muscular fatigue of the upper body as
assessed by handgrip measures is significantly correlated to subjective feelings of fatigue.
Results showed a small to moderate correlation between higher levels of subjective
fatigue and upper body measures of fatigue. Additionally, higher levels of handgrip
strength were significantly associated with lower subjective feelings of fatigue. No
significant relationships were found between lower body fatigue measurement, lower
body strength, and any of the survey results. These differences between upper body
59
fatigue and lower body fatigue relationships may be due to the number of survivors
diagnosed and treated for cancers which largely affect strength of the upper body, such as
breast cancer. Results from this study also show that cancer stage is not related to
muscular fatigue measures but shows a significant relationship with subjective fatigue
scores. Increases in cancer stage were positively associated with higher levels of lean
mass. Among participants in this study, it does not appear that more malignant diagnoses
resulted in decreases in muscle mass. This result is not in agreement with other studies
indicating those with more advanced stages of cancer have lower levels of muscle mass
(Cao et al., 2010; Freedman et al., 2004; Greenspan et al., 2005; Reis et al., 2009). While
some relationship appears to exist between stage what cancer stage and type of
malignancy, these alone cannot explain a majority of the fatigue variation reported by
individuals (P. Stone, Richards, A'hern, & Hardy, 2000).
A similar study by Kilgour et al. (2010) evaluated whether CRF was associated
with skeletal muscle mass as well as upper and lower body muscular strength in advanced
cancer. Results from our study are similar to that of Kilgour et al. (2010) who found that
lower levels of both handgrip strength and leg strength were found to be associated with
higher levels of CRF in patients with advanced cancer; however, results from our study
were not significant for lower body measures. Handgrip and Biodex lower body
measurements were used similarly to the present study; however, outcome measures were
maximal strength rather than fatigue index. Additionally, the present study did not focus
on advanced staged cancer but rather all stages. Results from Kilgour et al. (2010) found
lower levels of lean body mass to be related to higher levels of CRF; however, this
outcome was not observed in the present study.
60
Similar to this study, correlations between isometric handgrip strength and fatigue
have been observed in other studies in the cancer population (P. Stone et al., 2000; K. M.
Winters-Stone, Bennett, Nail, & Schwartz, 2008). Results from this study are in contrast
to others who found no correlation between handgrip strength and subjective fatigue
measurement (D. J. Brown et al., 2005; P. Stone, Hardy, Broadley, Kurowska, & A'Hern,
1999). It is important to note, however, that this was the first known study to use a
dynamic assessment and compute a fatigue index rather than maximal strength or
isometric testing in comparison to subjective CRF scores.
Relationships between lower body strength/fatigue and subjective feelings of
fatigue have received very little attention in the cancer population as the aforementioned
studies used only handgrip strength as a measure of muscle function. Two other known
studies have assessed quadricep strength in cancer survivors (Weber et al., 2009; Wilcock
et al., 2008) with only one other study (Kilgour et al. 2010) comparing both quadriceps
strength and a subjective fatigue measures. Other studies have utilized functional tests
such as the sit-to-stand (D. J. Brown et al., 2005; K. M. Winters-Stone et al., 2008) and
found correlation with subjective fatigue. Additionally, studies have also used the 6minute walk test (Toth et al., 2013) and the 12-minute walk tests as measures of lower
body fatigue (K. M. Winters-Stone et al., 2008). The current study is the only study
known to use an objectively measured lower body fatigue measurement in this population
rather than using strength or endurance tests as an outcome.
Fatigue is a common adverse side effect of cancer and its therapy. However,
specific physiological mechanisms underlying CRF remain unclear. Some proposed
mechanisms have included those discussing reductions in skeletal muscle protein stores,
61
cytokines, detraining, anemia, and muscle wasting (Ryan et al., 2007; Saligan et al.,
2015). Cancer-related cachexia is common in cancer patients and is characterized by
muscle wasting due to cancer treatments and reduced activity. Significant muscle wasting
affects approximately 50% of individuals with cancer (Fearon et al., 2011). While we did
not screen for cachexia, muscle mass was not related to either subjective or physiological
fatigue measures. In contrast, individuals in this study who had been diagnosed with
more advanced stages of cancer had higher amounts of muscle mass.
There is no universally accepted standard for CRF measurement yet all current
CRF measurement tools exist in self-report format. When assessing CRF both subjective
and objective data should be included; however at this time there is not a validated
objective CRF measurement. One limitation to this study is that only one self-report
measurement was used in the PFS. While in practice, the PFS is used to assess CRF over
a variety of cancers, it was originally developed and validated for breast cancer survivors.
Perhaps a different survey evaluation would more closely correlate to muscular fatigue
than the PFS. Despite these limitations with the survey, it has been shown to be the most
comprehensive and multi-dimensional method available for use as a research instrument
in the cancer population (Ahlberg et al., 2003).
Recent research has focused on determining whether CRF is more expressed as
peripheral fatigue versus central fatigue. The cause of peripheral fatigue is failure of the
muscle contraction mechanism or metabolic changes within the muscle. Central fatigue is
caused by loss of muscle contraction due to mechanisms involved in the neuromuscular
junction and communication between the neuron and the muscle (Yavuzsen et al., 2009).
Perhaps the lack of a meaningful relationship between subjective and physiological
62
fatigue is that peripheral fatigue was tested in this study, while other studies suggest that
central fatigue may play a larger role in CRF than peripheral fatigue (Kisiel-Sajewicz et
al., 2012; Yavuzsen et al., 2009). Further evidence is needed however to confirm
physiological mechanisms in muscular CRF.
It is possible that the lack of a meaningful relationship between subjective and
physiological fatigue measures of the lower body could be due to voluntary activation.
Submaximal activation (i.e., an inability to maximally activate muscle) is not uncommon
in adults despite the inclusion of verbal encouragement. A study by Nordlund,
Thorstensson, and Cresswell (2004) found a large variability in voluntary activation
suggesting that individuals who cannot fully activate their muscles may fatigue less but
are also able to generate much less force and power. Additionally, a common observation
when examining fatigue is that those who can generate a higher force generally fatigue
quicker. Despite this information we did not observe such a phenomenon in this
population. Individuals who had a higher peak force of both the hand and quadriceps
showed lower amounts of both subjective and muscular fatigue, which was consistent
with our hypothesis.
Many clinicians rely on subjective, self-reported measures for outcomes of CRF.
A number of theorized CRF fatigue mechanisms; however, are known to be caused by
physiological mechanisms. Therefore a physical measure of fatigue, in addition to the
self-reported measures, may enhance the clinician’s assessment of CRF. This is important
considering cancer-specific assessments of fatigue directly dictate the exercise
prescription and dosage of exercise prescribed for cancer survivors. By having more
specific CRF data, clinicians would be able to create more precise exercise prescriptions
63
to enhance the efficacy of exercise-based cancer rehabilitation programs. Results from
this study found a quick and easy to adminsiter handgrip assessment to be a superior
objective measure to a more lengthy isokinetic assessment that also requires large and
expensive equipment.
The majority of subjects in this study reported mild-to-moderate CRF in regards
to self-reported measures. An additional limitation of this study is the number of subjects
currently undergoing chemotherapy and radiotherapy. CRF is experienced to the greatest
extent during treatment and many physiological impairments lessen as time from
treatment increases. This could have contributed to the muted HFI and QFI results.
In summary, upper body muscular fatigue as assessed though handgrip measures
are correlated with subjective CRF experienced by cancer survivors. Future studies
should evaluate changes in PFS and CRF following an exercise intervention. Further
investigation into whether CRF is more related to central or peripheral mechanisms is
also warranted. Finding the optimal method for treating CRF remains an important
research topic. It is still believed that due to the physical mechanisms associated with
CRF, a secondary physiological measure of fatigue is needed. Continued investigation
into muscular dysfunction and its relationship to CRF may assist clinicians in
individualizing treatment methods and further our understating of mechanisms and the
pathophysiology that causes CRF in cancer survivors.
References
Ahlberg, K., Ekman, T., Gaston-Johansson, F., & Mock, V. (2003). Assessment and
management of cancer-related fatigue in adults. The Lancet, 362(9384), 640-650.
64
Blakely, A. A., Howard, R. C., Sosich, R. M., Murdoch, J. C., Menkes, D. B., & Spears,
G. F. (1991). Psychiatric symptoms, personality and ways of coping in chronic
fatigue syndrome. Psychological Medicine, 21(02), 347-362.
Brown, D. J., McMillan, D. C., & Milroy, R. (2005). The correlation between fatigue,
physical function, the systemic inflammatory response, and psychological distress
in patients with advanced lung cancer. Cancer, 103(2), 377-382.
Brown, J. C., Winters‐Stone, K., Lee, A., & Schmitz, K. H. (2012). Cancer, physical
activity, and exercise. Comprehensive Physiology.
Brown, L. F., & Kroenke, K. (2009). Cancer-related fatigue and its associations with
depression and anxiety: a systematic review. Psychosomatics, 50(5), 440-447.
doi:10.1176/appi.psy.50.5.440
Bruera, E., Brenneis, C., Michaud, M., Rafter, J., Magnan, A., Tennant, A., . . .
Macdonald, R. N. (1989). Association between asthenia and nutritional status,
lean body mass, anemia, psychological status, and tumor mass in patients with
advanced breast cancer. Journal of Pain and Symptom Management, 4(2), 59-63.
Cantarero-Villanueva, I., Fernández-Lao, C., Díaz-Rodríguez, L., Fernández-de-lasPeñas, C., Ruiz, J. R., & Arroyo-Morales, M. (2012). The handgrip strength test
as a measure of function in breast cancer survivors: relationship to cancer-related
symptoms and physical and physiologic parameters. American Journal of
Physical Medicine & Rehabilitation, 91(9), 774-782.
Christensen, J., Jones, L., Andersen, J., Daugaard, G., Rorth, M., & Hojman, P. (2014).
Muscle dysfunction in cancer patients. Annals of Oncology, 25(5), 947-958.
65
Courneya, K. S., Segal, R. J., Mackey, J. R., Gelmon, K., Reid, R. D., Friedenreich, C.
M., . . . McKenzie, D. C. (2007). Effects of aerobic and resistance exercise in
breast cancer patients receiving adjuvant chemotherapy: A multicenter
randomized controlled trial. Journal of Clinical Oncology, 25(28), 4396-4404.
doi:10.1200/jco.2006.08.2024
Derogatis, L. R., Morrow, G. R., Fetting, J., Penman, D., Piasetsky, S., Schmale, A. M., .
. . Carnicke, C. L. (1983). The prevalence of psychiatric disorders among cancer
patients. Journal of the American Medical Association, 249(6), 751-757.
Dimeo, F. C. (2001). Effects of exercise on cancer‐related fatigue. Cancer, 92(S6), 16891693.
Fearon, K. C., Strasser, F., Anker, S. D., Bosaeus, I., Bruera, E., Fainsinger, R. L., . . .
Baracos, V. E. (2011). Definition and classification of cancer cachexia: an
international consensus. The Lancet Oncology, 12(5), 489-495.
Glaus, A., Crow, R., & Hammond, S. (1996). A qualitative study to explore the concept
of fatigue/tiredness in cancer patients and in healthy individuals. Supportive Care
in Cancer, 4(2), 82-96.
Haas, B. K. (2011). Fatigue, self-efficacy, physical activity, and quality of life in women
with breast cancer. Cancer Nursing, 34(4), 322-334.
Kilgour, R. D., Vigano, A., Trutschnigg, B., Hornby, L., Lucar, E., Bacon, S. L., &
Morais, J. A. (2010). Cancer-related fatigue: The impact of skeletal muscle mass
and strength in patients with advanced cancer. Journal of Cachexia: Sarcopenia
and Muscle, 1(2), 177-185. doi:10.1007/s13539-010-0016-0
66
Kisiel-Sajewicz, K., Davis, M. P., Siemionow, V., Seyidova-Khoshknabi, D., Wyant, A.,
Walsh, D., . . . Yue, G. H. (2012). Lack of muscle contractile property changes at
the time of perceived physical exhaustion suggests central mechanisms
contributing to early motor task failure in patients with cancer-related fatigue.
Journal of Pain and Symptom Management, 44(3), 351-361.
doi:10.1016/j.jpainsymman.2011.08.007
Nicolay, C. W., & Walker, A. L. (2005). Grip strength and endurance: Influences of
anthropometric variation, hand dominance, and gender. International Journal of
Industrial Ergonomics, 35(7), 605-618.
Nordlund, M. M., Thorstensson, A., & Cresswell, A. G. (2004). Central and peripheral
contributions to fatigue in relation to level of activation during repeated maximal
voluntary isometric plantar flexions. Journal of Applied Physiology, 96(1), 218225. doi:10.1152/japplphysiol.00650.2003
Pincivero, D. M., Gandaio, C. B., & Ito, Y. (2003). Gender-specific knee extensor torque,
flexor torque, and muscle fatigue responses during maximal effort contractions.
European Journal of Applied Physiology, 89(2), 134-141.
Pincivero, D. M., Gear, W. S., & Sterner, R. L. (2001). Assessment of the reliability of
high-intensity quadriceps femoris muscle fatigue. Medicine & Science in Sports &
Exercise, 33(2), 334-338.
Piper, B. F., Dibble, S. L., Dodd, M. J., Weiss, M. C., Slaughter, R. E., & Paul, S. M.
(1998). The revised Piper Fatigue Scale: Psychometric evaluation in women with
breast cancer. Paper presented at the Oncology Nursing Forum.
67
Portenoy, R. K., & Itri, L. M. (1999). Cancer-related fatigue: guidelines for evaluation
and management. The Oncologist, 4(1), 1-10.
Ream, E., & Richardson, A. (1997). Fatigue in patients with cancer and chronic
obstructive airways disease: a phenomenological enquiry. International Journal
of Nursing Studies, 34(1), 44-53.
Ryan, J. L., Carroll, J. K., Ryan, E. P., Mustian, K. M., Fiscella, K., & Morrow, G. R.
(2007). Mechanisms of cancer-related fatigue. The Oncologist, 12(1), 22-34.
Saligan, L. N., Olson, K., Filler, K., Larkin, D., Cramp, F., Sriram, Y., . . . Kamath, J.
(2015). The biology of cancer-related fatigue: A review of the literature.
Supportive Care in Cancer, 23(8), 2461-2478.
Schmidt, M. E., Chang-Claude, J., Vrieling, A., Heinz, J., Flesch-Janys, D., & Steindorf,
K. (2012). Fatigue and quality of life in breast cancer survivors: Temporal courses
and long-term pattern. Journal of Cancer Survivorship, 6(1), 11-19.
Schneider, C. M., Hsieh, C. C., Sprod, L. K., Carter, S. D., & Hayward, R. (2007a).
Effects of supervised exercise training on cardiopulmonary function and fatigue in
breast cancer survivors during and after treatment. Cancer, 110(4), 918-925.
Schneider, C. M., Hsieh, C. C., Sprod, L. K., Carter, S. D., & Hayward, R. (2007b).
Exercise training manages cardiopulmonary function and fatigue during and
following cancer treatment in male cancer survivors. Integrative Cancer
Therapies, 6(3), 235-241.
Segal, R. J., Reid, R. D., Courneya, K. S., Malone, S. C., Parliament, M. B., Scott, C. G.,
. . . D’Angelo, M. E. S. (2003). Resistance exercise in men receiving androgen
68
deprivation therapy for prostate cancer. Journal of Clinical Oncology, 21(9),
1653-1659.
Siegel, R., Ma, J., Zou, Z., & Jemal, A. (2014). Cancer statistics, 2014. CA: A Cancer
Journal for Clinicians, 64(1), 9-29.
Speck, R. M., Courneya, K. S., Masse, L. C., Duval, S., & Schmitz, K. H. (2010). An
update of controlled physical activity trials in cancer survivors: A systematic
review and meta-analysis. Journal of Cancer Survivorship, 4(2), 87-100.
doi:10.1007/s11764-009-0110-5
Stone, P., Hardy, J., Broadley, K., Kurowska, A., & A'Hern, R. (1999). Fatigue in
advanced cancer: a prospective controlled cross-sectional study. British Journal of
Cancer, 79(9-10), 1479.
Stone, P., Richards, M., A'hern, R., & Hardy, J. (2000). A study to investigate the
prevalence, severity and correlates of fatigue among patients with cancer in
comparison with a control group of volunteers without cancer. Annals of
Oncology, 11(5), 561-567.
Stone, P. C., & Minton, O. (2008). Cancer-related fatigue. European Journal of Cancer,
44(8), 1097-1104. doi:10.1016/j.ejca.2008.02.037
Stone, P. C., Richards, M., & Hardy, J. (1998). Fatigue in patients with cancer. European
Journal of Cancer, 34(11), 1670-1676.
Tian, L., Lu, H. J., Lin, L., & Hu, Y. (2016). Effects of aerobic exercise on cancer-related
fatigue: A meta-analysis of randomized controlled trials. Supportive Care in
Cancer, 24(2), 969-983.
69
Toth, M. J., Miller, M. S., Callahan, D. M., Sweeny, A. P., Nunez, I., Grunberg, S. M., . .
. Dittus, K. (2013). Molecular mechanisms underlying skeletal muscle weakness
in human cancer: Reduced myosin-actin cross-bridge formation and kinetics.
Journal of Applied Physiology, 114(7), 858-868.
doi:10.1152/japplphysiol.01474.2012
van Weert, E., Hoekstra-Weebers, J., Otter, R., Postema, K., Sanderman, R., & van der
Schans, C. (2006). Cancer-related fatigue: Predictors and effects of rehabilitation.
The Oncologist, 11(2), 184-196.
Velthuis, M. J., Agasi-Idenburg, S. C., Aufdemkampe, G., & Wittink, H. M. (2010). The
effect of physical exercise on cancer-related fatigue during cancer treatment: A
meta-analysis of randomised controlled trials. Clinical Oncology, 22(3), 208-221.
doi:10.1016/j.clon.2009.12.005
Visser, M., & Smets, E. (1998). Fatigue, depression and quality of life in cancer patients:
how are they related? Supportive Care in Cancer, 6(2), 101-108.
Wang, X. S. (2008). Pathophysiology of cancer-related fatigue. Clinical Journal of
Oncology Nursing, 12, 11-20.
Weber, M. A., Krakowski-Roosen, H., Schröder, L., Kinscherf, R., Krix, M., KoppSchneider, A., . . . Hildebrandt, W. (2009). Morphology, metabolism,
microcirculation, and strength of skeletal muscles in cancer-related cachexia. Acta
Oncologica, 48(1), 116-124.
Weis, J., & Horneber, M. (2014). Cancer-Related Fatigue: Springer.
Weis, J., & Horneber, M. (2015). Etiology and Pathogenesis of Cancer-Related Fatigue
Cancer-Related Fatigue (pp. 11-17): Springer.
70
Wilcock, A., Maddocks, M., Lewis, M., Howard, P., Frisby, J., Bell, S., . . . Mockett, S.
(2008). Use of a Cybex NORM dynamometer to assess muscle function in
patients with thoracic cancer. BMC Palliative Care, 7(1), 3.
Winters-Stone, K. M., Bennett, J. A., Nail, L., & Schwartz, A. (2008). Strength, physical
activity, and age predict fatigue in older breast cancer survivors. Paper presented
at the Oncology Nursing Forum.
Yavuzsen, T., Davis, M. P., Ranganathan, V. K., Walsh, D., Siemionow, V., Kirkova, J., .
. . Yue, G. H. (2009). Cancer-related fatigue: Central or peripheral? Journal of
Pain and Symptom Management, 38(4), 587-596.
doi:10.1016/j.jpainsymman.2008.12.003
71
CHAPTER V
MANUSCRIPT II
EFFECTS OF EXERCISE TRAINING ON PHYSIOLOGICAL
AND PSYCHOLOGICAL MEASUREMENTS OF
CANCER-RELATED FATIGUE
Abstract
The effect of exercise on objectively measured muscular fatigue has yet to be studied in
cancer patients. Evaluating how exercise modulates psychological and physiological
fatigue dimensions either similarly, or differently, could aid in our understanding of how
exercise reduces fatigue in cancer patients. PURPOSE: To evaluate the relationship
between subjective self-reported psychological fatigue measures and objectivelymeasured muscular fatigue in cancer survivors following a 24 week exercise intervention.
METHODS: A total of 21 cancer survivors (62 ± 14 years of age) were asked to
complete both physiological and psychological measures of fatigue prior to and following
the exercise intervention. Participants completed the revised Piper Fatigue Scale (PFS)
which produces a total score (PFST) and four subscale scores: behavioral/severity
(PFSB), affective (PFSA), sensory (PFSS), and cognitive/mood (PFSC). A handgrip
fatigue index (HFI) was determined for each participant by repetitively squeezing a
handgrip dynamometer 15 times with maximal force for each repetition. Participants also
completed 15 maximal force knee extensions at a joint angular velocity of 60 deg∙s-1 and
a quadriceps fatigue index (QFI) was computed. Each fatigue index was computed as the
72
difference between the average of the first two cycles and the average of the last two
cycles divided by the average of the first two cycles and expressed as a percentage.
Following testing, participants completed 24 weeks of supervised exercise training.
Fatigue testing was performed following 12 and 24 weeks of the exercise intervention.
RESULTS: Significant main effects were found for PFST and all four subscales (p <
.05). No significant main effects were found for either muscular fatigue measures or peak
force. Results indicate significant decreases in PFST (p = .001), PFSB (p = .015), PFSA
(p = .001), PFSS (p = .001), and PFSC (p = .004) following 12 weeks of the exercise
intervention. In addition, there were no statistically significant changes observed in either
measures of objective fatigue HFI (p = .606), QFI (p = .455), peak handgrip force (PHF)
(p = .621) or peak quadriceps force (PQF) (p = .091). Testing following 24 weeks of the
intervention resulted in significant decreases in PFST (p = .031), PFSA (p = .023), and
PFSS (p = .016). CONCLUSION: Following exercise training there was a significant
decrease in subjective fatigue scores (PFST) but not muscular fatigue measures (HFI and
QFI). Exercise was shown to decreases subjective fatigue more significantly than
objective measures of fatigue possibly indicating that exercise may modulate dimensions
of fatigue other than the physical dimensions.
73
Introduction
An estimated 1.6 million new cases of cancer will have been diagnosed in the
United States in 2015 (Siegel et al., 2015). Treating cancer is often challenging and
involves techniques including surgery, radiation, chemotherapy, immunotherapy,
hormone therapy, or various combinations of treatments. Type of treatment is dependent
on a wide variety of factors including cancer type, stage, and location. Cancer treatments
are generally known to negatively affect many dimensions of an individual’s life and may
include decreased endurance, decreased muscular strength, and increased fatigue. In
addition, side effects may include decreased bone density, cardiotoxicity, cognitive
defects, and pulmonary dysfunction (J. C. Brown, Winters‐Stone, et al., 2012). The
majority of cancer patients experience one or more side effects or symptoms during and
following treatment, with the most common being pain, emotional distress, and fatigue.
The management of side effects from cancer treatment is an important aspect of patient
care, and can positively influence quality of life in addition to psychological and physical
functioning (Siegel et al., 2012).
Cancer-related fatigue (CRF) is the most common symptom reported by cancer
survivors and it is estimated that as many as 96% of cancer survivors report CRF as a
side effect of cancer treatment (Mock et al., 2000; Morrow et al., 2002). CRF is
characterized by extreme fatigue and exhaustion and has a considerable negative effect
on quality of life (Mock et al., 2000; Wagner & Cella, 2004). The impact of CRF on a
patient’s functional capacity can be significant, and is one of the most distressing of
reported symptoms (Hofman et al., 2007). CRF has been reported among wide ranges of
cancer types, stages, and treatment protocols. Therefore, CRF does not appear to be
74
initiated by a specific cancer type or treatment, suggesting that unknown physiological
mechanisms may be responsible for the physical manifestations observed among patients
with CRF (Hofman et al., 2007).
Muscular fatigue is commonly associated with exercise but is often times
experienced as a secondary outcome to many health conditions, disease states, and cancer
(Bogdanis, 2012). Several studies have indicated that a commonly observed reduction in
muscle mass among cancer survivors and decreased functional capacity may result from
cancer and its treatments (Christensen et al., 2014; Kilgour et al., 2010; Weber et al.,
2009). Inactivity can be a contributing factor and may lead to decreased muscle mass and
strength as well as increased fatigability of patients (Bogdanis, 2012). Physical activity in
these populations has been shown to increase muscular function and strength in addition
to enhancing the ability of muscles to resist fatigue (Bogdanis, 2012; Hurley, Hanson, &
Sheaff, 2011).
Cancer and its side effects on skeletal muscle have been a topic of recent study.
Overall, cancer and its treatments are known to cause skeletal muscle atrophy and
weakness (Christensen et al., 2014). The prevalence of muscle atrophy and impaired
functioning in the cancer population, makes it difficult to discern whether impairment is
due to impaired contractility or a loss of the contractile components themselves (M. S.
Miller et al., 2014). In addition, skeletal muscle atrophy is a significant side effect of
cancer that greatly depends on the tumor type and stage of cancer. Cachexia is the term
used to describe muscle and fat loss that occurs with various chronic disease states. This
condition, due to cancer and/or its treatment, is termed cancer-related cachexia, and,
unlike muscle wasting due to starvation, it cannot be remedied by nutritional
75
interventions (Fearon et al., 2012; Fearon et al., 2011; Skipworth et al., 2007). Decreases
in skeletal muscle mass have been shown to reduce contractile function, increase muscle
weakness, and decrease aerobic capacity (Bogdanis, 2012). Because of the debilitating
effects of cancer-related cachexia, interventions to combat muscle loss in cancer patients
should be prioritized during the rehabilitation process (Der-Torossian et al., 2013). In
addition to whole muscle contractile dysfunction, investigations into cellular and
molecular mechanisms suggest intrinsic skeletal muscle dysfunction at the level of the
myofilament in cancer patients. While the research is limited, at least a few investigations
show that cancer-induced skeletal muscle contractile dysfunction is independent of
muscle atrophy (Der-Torossian et al., 2013; Toth et al., 2013).
Cancer survivors are frequently instructed by physicians and clinicians to limit
physical activity as a management strategy to conserve energy expenditure. A growing
body of evidence, however, indicates that cancer survivors who engage in regular
physical activity during and following treatment experience a number of health benefits
including increased functional capacity and reductions in fatigue (J. C. Brown et al.,
2011). In the cancer population, physical activity can attenuate multiple side effects of
treatment, potentially reverse functional losses that occurred during treatment, aid in the
prevention of long-term effects, reduce rates of recurrence, and increase survival rates (J.
C. Brown, Winters‐Stone, et al., 2012; Siegel et al., 2012). Both aerobic and resistance
exercise training have been reported to be beneficial in cancer survivors both during and
after treatment and have been shown to reduce CRF (Adamsen et al., 2009; Arnold &
Taylor, 2011; J. C. Brown et al., 2011; J. C. Brown, Huedo-Medina, et al., 2012; Dimeo,
2001; Haas, 2011; Keogh & MacLeod, 2012; Kuchinski et al., 2009; Litterini & Jette,
76
2011; Puetz & Herring, 2012; M. E. Schmidt et al., 2012; Schneider et al., 2007a, 2007b;
van Waart et al., 2015; Velthuis et al., 2010; Wyrick & Davis, 2009), improve functional
capacity (L. W. Jones et al., 2012; Macvicar et al., 1989; Vardar Yagli et al., 2015), and
increase muscular strength (Courneya et al., 2007; Fong et al., 2012; A. L. Schwartz &
Winters-Stone, 2009; Segal et al., 2003; R. L. Siegel et al., 2014; Speck et al., 2010; van
Waart et al., 2015; van Weert et al., 2006)
There is a large body of literature on aerobic exercise and its effects on CRF;
however, there remains substantial variability in the outcomes. Overall, aerobic exercise
appears to have a small but statistically significant positive effect, suggesting that aerobic
exercise could be beneficial in reducing CRF (Tian et al., 2016; Velthuis et al., 2010).
Resistance exercise is also known to improve muscular mass, strength, and function in
cancer survivors (Al-Majid & Waters, 2008). Despite this knowledge, compared to the
research on aerobic training and CRF, there are fewer studies that include only resistance
training with CRF as an outcome. A recent meta-analysis by J. C. Brown, Huedo-Medina,
et al. (2012) found that the greatest reductions in CRF occurred in patients who
participated in moderate or higher intensity resistance exercise. Resistance training has
shown to have a positive effect on CRF; however, as with aerobic exercise not all studies
have shown significant results (J. C. Brown et al., 2011; Courneya et al., 2007; M. E.
Schmidt et al., 2015; Segal et al., 2009). Guidelines for exercise in cancer patients as set
forth by the American College of Sports Medicine (ACSM), include both aerobic and
resistance exercise as part of a well-rounded exercise program (Schmitz et al., 2010).
While not completely elucidated, a majority of investigations have shown a positive
effect of both aerobic and resistance exercise on CRF. Considering the evidence and
77
recommended guidelines, a rehabilitation program that includes a combination of aerobic
and resistance exercise seems most efficacious in reducing CRF (Schmitz et al., 2010).
While exploring the differences in psychological and physiological fatigue among
cancer survivors is not completely novel, the relationship between muscle function and
perceptions of fatigue in cancer survivors remains mechanistically unclear (Kilgour et al.,
2010). Considering the evidence that exercise reduces both CRF and muscular fatigue, it
appears efficacious to evaluate both dimensions when examining fatigue outcomes
following an exercise intervention in is population. Furthermore, the effect of exercise on
objectively measured muscular fatigue has yet to be studied in cancer patients. Evaluation
of how exercise modulates psychological and physiological fatigue dimensions either
similarly, or differently, could aid in our understanding of how exercise affects fatigue in
cancer patients. Therefore the purpose of this study was to evaluate the effect of exercise
on physiologically measured muscular fatigue and psychological fatigue in cancer
survivors following a 24 week exercise intervention.
Methods
Study procedures were approved by the University of Northern Colorado’s (UNC)
Institutional Review Board. Subjects underwent comprehensive screening prior to
inclusion in the study. Participants were males and females over the age of 18 who had
been previously diagnosed with cancer. Participants were referred to the University of
Northern Colorado Cancer Rehabilitation Institute (UNCCRI) from local oncologists.
Individuals were either undergoing or had undergone chemotherapy, radiation, surgery,
immunotherapy or a combination of treatments. Prior to participation, individuals were
apprised of the study procedures and signed an informed consent specific to this study. A
78
total of 21 cancer survivors (60 ± 13 years of age) completed pre, mid (12 weeks), and
post (24 weeks) intervention assessments of fatigue.
Procedures
Medical history was obtained prior to the initial assessment which included
cancer type, stage, medications, and all treatments. Anthropometric data were also
collected including height, weight, and body composition. Cancer survivors completed
three different initial assessments of fatigue including measurements of self-reported and
physiological fatigue. Scores of subjective fatigue were established via the revised Piper
Fatigue Scale (PFS) which evaluates total CRF (PFST), as well as subscales of fatigue
including sensory, affective, behavior, cognitive and mood. The individual subscales
together consisted of 22 questions with the average score representing total CRF. The
PFS has been shown to be a valid and reliable measure of CRF in cancer patients (Piper
et al., 1998). The behavioral/severity subscale (PFSB) assesses the impact of fatigue on
school/work, social interaction, and the overall interference with enjoyable activities. The
affective (PFSA) assesses the extent to which fatigue affects emotional meaning. The
sensory (PFSS) measures mental, physical, and emotional symptoms of fatigue. Finally,
the cognitive/mood subscale (PFSC) assesses the impact of fatigue on concentration,
memory, and mental clarity (Piper et al., 1998).
Following completion of the PFS, assessment of hand grip fatigue was conducted
through the use of a hand dynamometer. The use of a hand dynamometer has been shown
to be a valid and reliable method to measure handgrip strength in cancer patients (D. J.
Brown et al., 2005; Innes, 1999; Trutschnigg et al., 2008). The dynamometer
(Layfayette/TEC, Layfayette IN) handle was first sized to correctly fit the hand of the
79
participant. Fatigue was measured using a protocol of 15 maximum contractions at a rate
of one contraction every two seconds. A metronome in addition to verbal cues and
encouragement was used to keep participants on pace. Both left and right hands were
recorded as well as a note of which is the dominant hand. Values in kilograms (kg) were
recorded for each contraction and a fatigue index (FI) was calculated using the averages
of the two highest and two lowest recorded values. Once the averages were calculated
they were inserted into the following equation to determine fatigue index: FI (%) =
[(highest – lowest)/highest]*100 (Beam & Adams, 2011).
Following hand dynamometry assessment, participants were asked to complete
lower body muscular fatigue testing. Isokinetic torque (N.m) of the knee extensor
muscles was measured using a Biodex© dynamometer (Biodex Medical Inc., Shirley,
NY). Use of isokinetic dynamometers has been shown to be valid and reliable (Drouin et
al., 2004; Innes, 1999) and has previously been used to measure lower body strength
measurements in patients with cancer (Kilgour et al., 2010; Weber et al., 2009; Wilcock
et al., 2008). Subjects were asked to sit upright and while the dynamometer was adjusted
to fit each participant. To prevent additional body movement, straps were used to secure
the testing leg and trunk to the dynamometer chair. The testing leg was then secured to
the leg attachment above the ankle. Range of motion was determined by having the
participant extend and flex their leg as far as possible without discomfort. Correction for
limb weight was obtained by measuring torque exerted on the dynamometer with the
knee fully extended and relaxed. Subjects were instructed on the protocol and were asked
to give maximum effort for each repetition during each set of exercises. The first two sets
consisted of five warm-up repetitions at speeds of 180°/s and 120°/s, respectively. Each
80
of the warm-up sets were followed by 90 seconds of rest. The third set served as the
fatigue protocol which consisted of 15 maximal repetitions at 60°/s. The dynamometer
was then repositioned and the same procedures were performed on the opposite leg.
Throughout the test, visual and verbal encouragement was given by the test administrator.
A familiarization session was conducted prior to the testing session to allow the
participant to become familiar with the protocol. A minimum of two rest days were given
between the familiarization protocol and the testing protocol. MATLAB® R2011a
(Mathworks Inc., Natick, MA) was used to export the data output from the Biodex© and
identify peak torque from each repetition. The same method of determining FI for upper
body (HFI) was used for the lower body (QFI).
After completing the above pre-assessments, participants completed an
individualized, prescriptive exercise intervention that took place at UNCCRI. The
exercise interventions were conducted by a trained Cancer Exercise Specialists for 24
weeks within the standard UNCCRI Phase program. Participants were asked to complete
the aforementioned battery of assessments following 12 and 24 weeks of the exercise
intervention to determine whether exercise had any effect on measurements of functional
performance and fatigue.
Intervention
The exercise intervention consisted of a one-hour period that included aerobic
training, resistance strength training, balance, and flexibility training. Each participant
took part in the intervention no more than three times per week and on non-consecutive
days. Each session included 20 minutes of aerobic training, 30 minutes of resistance
training, and 10 minutes set aside for flexibility. Aerobic and resistance training was
81
progressive and intensity was dependent on the treatment status of the participant. An
initial assessment to estimate maximal strength or one repetition maximum (1RM) was
performed on the following resistance machines: chest press, shoulder press, seated row,
lat pull down, leg extension, leg curl, and leg press. A percentage of the individual’s heart
rate reserve (HRR) and estimated 1RM was used to prescribe exercise intensity for the
first 12 weeks of the program. Heart rate reserve is the difference between an individual’s
maximum heart rate and their resting heart rate and the formula for calculating HRR is as
follows: HRR = HRmax – HRrest. The formula for calculating exercise heart rate for a
specific percentage of HRR was as follows: Exercise HR = % of target intensity (HRmax –
HRrest) + HRrest. Using a percentage of HRR is a common method of determining exercise
intensity for prescriptive exercise (Karvonen et al., 1957). Individuals still undergoing
radiation or chemotherapy treatment began the program at an intensity of 30-45% HRR
and 1RM. Individuals beginning the intervention that were not currently in treatment
began exercise at 40-60% of their HRR and 1RM. For the first 12 weeks, progression for
those individuals in treatment was 5% for cardiovascular fitness and 10-15% for
muscular strength.
Progression of individuals beginning exercise following treatment was 10-20%
for cardiovascular fitness and 30-50% for muscular strength. Following 12 weeks of
training, participant’s maximal strength was re-assessed and training intensity was
increased to continue to progress the individuals from 12 to 24 weeks. Training intensity
for the second 12 week session was 40-60% of HRR and 1RM for individuals who
started the program in treatment with a progression intensity of 10-20% for
cardiovascular training and 30-50% of muscular strength. Training intensity for the
82
second session for individuals who started the program out of treatment began at an
intensity of 60-85% of HRR and 1RM with a progression of 5-15% for cardiovascular
training and 30-50% for muscular strength.
Modes of aerobic exercise included a variety of activities including the following:
treadmill walking and running, walking outside, stationary bikes, recumbent stepper,
AquaCiser, and arm ergometer. Modes of resistance training included the following:
weight machines, free weights, bands, and body weight exercises. Flexibility training
included static stretching, wall mounted range of motion wheel, and wall mounted
stretching ropes. Detailed records of heart rate, blood pressure, and oxygen saturation
responses for each participant were documented by the Cancer Exercise Specialist for
each exercise session. Safety of the participants during the exercise intervention was a
priority. All exercise was supervised and vitals were continuously monitored by Cancer
Exercise Specialists and UNCCRI staff. SAS version 9.4 (Cary, NC) was used for all
analyses.
Results
Data are presented as means ± SD. While both limbs were tested, dominant limbs
were used for all analyses. Initial characteristics of participants are presented in Table 6.
Treatment history and treatment status at time of testing is presented in Table 7. Cancer
stage and cancer type are presented in Tables 8 and 9, respectively.
83
Table 6
Subject Characteristics
Age in years (mean ± SD)
62 ± 14
Mass in kg (mean ± SD)
68 ± 12
Height in cm (mean ± SD)
163 ± 18
Female (n)
13
Male (n)
8
Total (N)
21
Table 7
Treatment History
Surgery (%)
67
Chemotherapy (%)
67
Radiation (%)
42
Treatment Status
In-treatment (n)
2
Out of treatment (n)
19
Table 8
Cancer Stage
I
7
II
7
III
3
IV
4
Total (N)
21
84
Table 9
Cancer Type
Breast
12
Lymphoma
3
Prostate
1
Carcinoma
1
Leukemia
1
Lung
1
Myeloma
1
Tongue
1
A series of repeated measures analysis of variance (RMANOVA) were utilized to
evalute athe effects of exercise on total CRF (PFST), PFS subscales, HFI, QFI, peak hand
force (PHF), and peak quadriceps force (PQF). Significant main effects were observed
for PFST and all four subscales (p < .05). No significant main effects were found for
either muscular fatigue measures or peak force. Additionally, there was no significant
difference between genders for any of the dependent variables (p > .05). Where a main
effect was observed, planned contrasts were used to compare pairs of time points to
identify which testing sessions differed. These results are reperesented in Table 10.
85
Table 10
Means ± SD for each dependent measure by testing session
24 weeks
Pre
12 weeks
2.2 ± 1.4
PFST†‡
4.1 ± 2.4
2.7 ± 2.0
1.6 ± 1.6
PFSB†
3.7 ± 2.5
2.3 ± 2.3
2.1 ± 1.8
PFSA†‡
4.2 ± 2.8
2.6 ± 2.4
2.4 ± 1.4
PFSS†‡
4.4 ± 2.3
2.9 ± 2.1
2.5 ± 1.5
PFSC†
4.1 ± 2.5
3.0 ± 1.9
29.1 ± 13.0
HFI (%)
30.4 ± 17.1
29.2 ± 10.3
QFI (%)
PHF (kg)
34.3 ± 9.6
17.7 ± 5.6
30.9 ± 12.9
17.7 ± 5.6
PQF (N.m)
139.5 ± 50.4
151.3 ± 50.4
† p-value < .05 pre to 12 weeks
‡ p-value < .05 pre to 24 weeks
29.2 ± 10.0
18.9 ± 6.6
143.3 ± 44.9
P values for all contrasts are presented in Table 11. Results show significant
decreases in PFST (p = .001), PFSB (p = .015), PFSA (p = .001), PFSS (p = .001), and
PFSC (p = .004) following 12 weeks of the exercise intervention. Following 12 weeks of
training there were no statistically significant changes in either measures of objective
fatigue HFI (p = .606) and QFI (p = .455), or peak force PHF (p = .621) and PQF (p =
.091). Testing following 24 weeks of the intervention resulted in significant decreases in
PFST (p = .031), PFSA (p = .023), and PFSS (p = .016). While there were further
decreases in both HFI and QFI following 12 and 24 weeks of training these changes were
not significant.
86
Table 11
Contrast Analysis
Contrast
PFST
Pre vs 12 weeks .001
12 vs 24 weeks .899
Pre vs 24 weeks .031
PFSB
.015
.652
.054
PFSA
.001
.991
.023
PFSS
.001
.897
.016
PFSC
.004
.913
.059
Figure 3 represents changes in PFS scores from baseline pre-intervention to 12
weeks and 24 weeks of exercise. Figure 4 summarizes changes in HFI and QFI scores
following training.
Piper Fatigue Scale (score)
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Pre
12 weeks
24 weeks
Time
PFST
PFSB
PFSA
PFSS
PFSC
Figure 3. Changes in total Piper Fatigue Scale scores and PFS subscale scores following
12 and 24 weeks of exercise. PFST = revised Piper Fatigue Scale total score. PFSB =
behavioral subscale, PFSA = affective subscale, PFSS = sensory subscale, and PFSC =
cognitive and mood subscale.
87
35
34
Fatigue Index (%)
33
32
31
30
29
28
27
26
25
Pre
12 weeks
24 weeks
Time
HFI
QFI
Figure 4. Changes in muscular fatigue following 12 and 24 weeks of exercise. HFI
represents the hand fatigue index and QFI represents the quadriceps fatigue index
Discussion
Investigations into physical activity in cancer survivors suggest that the majority
of side effects from cancer and treatments appear to be ameliorated by exercise. Several
review studies in addition to those done in our lab show strong evidence that exercise is
an effective tool for rehabilitation after cancer (Burnham & Wilcox, 2002; Courneya,
2003; Fong et al., 2012; Schneider et al., 2007a, 2007b; Speck et al., 2010; Sprod, Hsieh,
Hayward, & Schneider, 2010; Stevinson et al., 2004). Studies measuring objective fatigue
are minimal compared to the amount of literature using surveys to assess CRF.
Considering that many factors can contribute to muscle fatigue, the lack of an objective
measurement of CRF further hinders our understanding (Yavuzsen et al., 2009). In
addition to the underlying factors associated with CRF, decreased physical activity as
often seen in cancer patients can also be a contributing factor to increased fatigability
(Bogdanis, 2012). Exercise has been shown to have beneficial physiological effects and it
88
can be considered as a therapeutic intervention for cancer survivors (Wolin et al., 2012).
Specifically, exercise has the capacity to positively modify skeletal muscle and
potentially reverse dysfunction. The repeated muscular contractions that take place
during both aerobic and resistance exercise stimulate physiological adaptations such as
increased protein synthesis, muscular hypertrophy, changes in contractile and
mitochondrial function, metabolic changes, and modifications to signaling pathways
(Christensen et al., 2014). Therefore, physical activity could be of particular importance
to advanced stage and cachectic patients due to the potential to offset or increase muscle
mass and strength (Stene et al., 2013).
Results from this study showed significant decreases in subjective fatigue scores
of total CRF in addition to all four subscales following 12 weeks of combined aerobic
and resistance exercise. These results are similar to other exercise intervention studies
that showed significant decreases in subjective scores of CRF in cancer patients
(Adamsen et al., 2009; Arnold & Taylor, 2011; J. C. Brown et al., 2011; J. C. Brown,
Huedo-Medina, et al., 2012; Dimeo, 2001; Haas, 2011; Keogh & MacLeod, 2012;
Kuchinski et al., 2009; Litterini & Jette, 2011; Puetz & Herring, 2012; M. E. Schmidt et
al., 2012; Schneider et al., 2007a, 2007b; van Waart et al., 2015; Velthuis et al., 2010;
Wyrick & Davis, 2009). While there were further decreases in PFS scores from 12 to 24
weeks, PFSB and PFSC were not found to be significant after 24 weeks of training.
These results indicate while continued exercise is beneficial in reducing fatigue, the
greatest changes were observed at the 12 week measurement point.
The present study is in contrast to a study by Frontera, Meredith, O'Reilly,
Knuttgen, and Evans (1988) which found a significant increase in isokinetic peak torque
89
of the quadriceps following a 12 week resistance exercise session in older men.
Differences between the present study from that of Frontera et al. (1988) is the addition
of an aerobic component which may have offset some of the gains in muscle mass that
may have resulted in a resistance only program. Also in contrast to the present study, J. S.
Lee, Kim, Seo, Kim, and Yoon (2015) found significant increases in isokinetic
quadriceps strength following an eight week combined aerobic and resistance training
intervention in older women. An important distinction between the present study and the
aforementioned studies is that they were not conducted in the cancer population. Several
other studies conducted in the cancer population mention testing isokinetic knee strength
prior to an exercise intervention, however, isokinetic strength outcomes were not
mentioned in the results (Daley et al., 2007; M. E. Schmidt et al., 2015; M. E. Schmidt et
al., 2013). It is difficult to discern if the outcomes were left out of results due to nonsignificance or for another purpose.
Results from the present study are also in contrast to other studies which have
seen improvements in maximal strength following exercise training in cancer survivors
(Adamsen et al., 2009; Courneya et al., 2007; Fong et al., 2012; Jarden et al., 2009; A. L.
Schwartz & Winters-Stone, 2009; Segal et al., 2003; R. L. Siegel et al., 2014; Speck et
al., 2010; van Waart et al., 2015; van Weert et al., 2006). Differences in outcome
measures of strength could account for the non-significant change seen in the present
study. Our study used torque (N.m) as outcome measures of strength where the
aforementioned studies used increases in 1RM as an outcome of strength.
The present study did not observe significant increases in handgrip strength
following either 12 or 24 weeks post intervention. Results of the present study are similar
90
to that of Monga et al. (1997) who did not observe increases in handgrip strength in
cancer survivors following an exercise intervention. Present study results are however in
contrast to a number of studies which have observed increased handgrip strength
following an exercise intervention in cancer survivors (Oldervoll et al., 2011; K. M.
Winters-Stone et al., 2012). Theoretically maximal force measurements should not have
been different for our study; however, it is possible that participants did not give maximal
effort, despite verbal encouragement, on the initial repetitions knowing the task involved
completing 15 repetitions rather than one.
Physical activity has been shown to decrease muscle fatigue in both healthy and
diseased populations. The degree of decreases in fatigue depends largely on the prior
training status of the individual as well as they type of exercise performed. A majority of
the evidence citing reductions in muscle fatigue have been in the healthy population
following a high intensity training program (Bogdanis, 2012). Intensity of exercise in this
intervention was low to moderate and may not have been a large enough stimulus to
result in significant decreases. Despite the lack of significance, reductions in muscular
fatigue are important to improve survivor’s ability to carry out daily activities.
Additionally, muscle fatigue may result in a higher risk of falls in this population and has
been shown to be linked to premature death. Reductions in muscular fatigue may prolong
survivorship for individuals experiencing fatigue (Bogdanis, 2012).
Limitations to the present study include the absence of a control group.
Reductions in subjective fatigue would likely be seen in absence of an exercise
intervention due to time elapsed from treatment. Without a control group we cannot
compare whether the reductions in fatigue seen in this population were greater than that
91
following usual care. While this cannot be stated for the present study, there is a
substantial amount of literature that indicates exercise improves CRF when compared to a
control group (Courneya, Friedenreich, et al., 2003; Courneya, Mackey, et al., 2003;
Mock et al., 1997; Segal et al., 2003). This same limitation exists for the reductions seen
in the present study regarding muscle fatigue outcomes. While decreases were seen in
muscle fatigue, they were not found to be statistically significant, and without the
presence of a control group we cannot accurately discern if there would not have been
reductions in muscular fatigue following a usual care program. While the lack of a
control group is generally seen as a limitation, exercise is a recommended practice for
cancer survivors (Schmitz et al., 2010). Our clinic is in agreement with other researchers
in that it seems unethical to withhold exercise from participants (K. M. Winters-Stone et
al., 2012).
A detailed characterization of CRF in addition to a more complete understanding
of its etiology is necessary to develop targeted treatment mechanisms. It has been
suggested that a more complete fatigue assessment would include both a subjective and
physiological assessment (Portenoy & Itri, 1999). Considering the wide variety of
questionnaires currently used to assess CRF it is difficult to compare outcomes. With
more than 22 CRF scales in use, it is hard to clinically define the severity when
investigations and interventions use different scales. Furthermore, considering the
subjective nature of the fatigue dimension, a large amount of variability is possible in this
type of outcome measurement. It is difficult to discern the effect of interventions to
reduce CRF with the lack of a standard assessment tool. A more objective assessment of
fatigue in this population could provide a more universal assessment of CRF. Future
92
investigations should continue to evaluate the objective measures of fatigue in this
population as well as the best mode and intensity of exercise to reduce muscular fatigue
in cancer survivors.
Subjective fatigue is a complex construct but has a connection to physiological
capacity. The relationship between these dimensions currently remains unclear. It is
difficult to discern whether the reductions in subjective fatigue are due to the reductions
in muscular fatigue, or if the opposite is true. Despite the well-known effects of cancer
and its treatments on skeletal muscle mass, the effects of cancer and its effects on
muscular fatigue is less clear. To our knowledge, this is the first study to evaluate
objectively measured muscular fatigue in cancer patients following an exercise
intervention. Results from this study show that cancer rehabilitation is effective in
reducing both psychological outcomes of fatigue and should be included in interventions
aimed at reducing CRF.
In summary, CRF is understood to be largely a subjective symptom resulting from
cancer and its treatment. Investigations into the etiology and mechanisms of CRF;
however, suggest physiological and biological mechanisms to be the underlying cause.
Therefore it is important to investigate interventions of a physiological nature such as
exercise as a form of treatment. Results from this investigation show that a supervised
combined aerobic and resistance cancer rehabilitation program is effective for reducing
subjective CRF but not muscular fatigue in cancer survivors during and following
treatment.
93
References
Adamsen, L., Quist, M., Andersen, C., Moller, T., Herrstedt, J., Kronborg, D., . . . Rorth,
M. (2009). Effect of a multimodal high intensity exercise intervention in cancer
patients undergoing chemotherapy: A randomised controlled trial. British Journal
of Medicine, 339, b3410. doi:10.1136/bmj.b3410
Al-Majid, S., & Waters, H. (2008). The biological mechanisms of cancer-related skeletal
muscle wasting: The role of progressive resistance exercise. Biological Research
for Nursing, 10(1), 7-20.
Arnold, M. E., & Taylor, N. F. (2011). Exercise for patients with cancer: Reducing
disease-related fatigue. Future Oncology, 7(2), 165-167. doi:Doi
10.2217/Fon.10.188
Beam, W. C., & Adams, G. M. (2011). Exercise Physiology Laboratory Manual (6 ed.):
McGraw-Hill.
Bogdanis, G. C. (2012). Effects of physical activity and inactivity on muscle fatigue.
Frontiers in Physiology, 3, 142.
Brown, D. J., McMillan, D. C., & Milroy, R. (2005). The correlation between fatigue,
physical function, the systemic inflammatory response, and psychological distress
in patients with advanced lung cancer. Cancer, 103(2), 377-382.
Brown, J. C., Huedo-Medina, T. B., Pescatello, L. S., Pescatello, S. M., Ferrer, R. A., &
Johnson, B. T. (2011). Efficacy of exercise interventions in modulating cancerrelated fatigue among adult cancer survivors: A meta-analysis. Cancer
Epidemiology Biomarkers & Prevention, 20(1), 123-133. doi:10.1158/10559965.epi-10-0988
94
Brown, J. C., Huedo-Medina, T. B., Pescatello, L. S., Ryan, S. M., Pescatello, S. M.,
Moker, E., . . . Johnson, B. T. (2012). The efficacy of exercise in reducing
depressive symptoms among cancer survivors: A meta-analysis. Public Library of
Science One, 7(1), e30955. doi:10.1371/journal.pone.0030955
Brown, J. C., Winters‐Stone, K., Lee, A., & Schmitz, K. H. (2012). Cancer, physical
activity, and exercise. Comprehensive Physiology.
Burnham, T. R., & Wilcox, A. (2002). Effects of exercise on physiological and
psychological variables in cancer survivors. Medicine & Science in Sports &
Exercise, 34(12), 1863-1867.
Christensen, J., Jones, L., Andersen, J., Daugaard, G., Rorth, M., & Hojman, P. (2014).
Muscle dysfunction in cancer patients. Annals of Oncology, 25(5), 947-958.
Courneya, K. S. (2003). Exercise in cancer survivors: An overview of research. Medicine
& Science in Sports & Exercise, 35(11), 1846-1852.
Courneya, K. S., Friedenreich, C. M., Sela, R. A., Quinney, H. A., Rhodes, R., &
Handman, M. (2003). The group psychotherapy and home‐based physical
exercise (group‐hope) trial in cancer survivors: Physical fitness and quality of life
outcomes. Psycho‐Oncology, 12(4), 357-374.
Courneya, K. S., Mackey, J. R., Bell, G. J., Jones, L. W., Field, C. J., & Fairey, A. S.
(2003). Randomized controlled trial of exercise training in postmenopausal breast
cancer survivors: cardiopulmonary and quality of life outcomes. Journal of
Clinical Oncology, 21(9), 1660-1668.
Courneya, K. S., Segal, R. J., Mackey, J. R., Gelmon, K., Reid, R. D., Friedenreich, C.
M., . . . McKenzie, D. C. (2007). Effects of aerobic and resistance exercise in
95
breast cancer patients receiving adjuvant chemotherapy: A multicenter
randomized controlled trial. Journal of Clinical Oncology, 25(28), 4396-4404.
doi:10.1200/jco.2006.08.2024
Daley, A. J., Crank, H., Saxton, J. M., Mutrie, N., Coleman, R., & Roalfe, A. (2007).
Randomized trial of exercise therapy in women treated for breast cancer. Journal
of Clinical Oncology, 25(13), 1713-1721. doi:10.1200/jco.2006.09.5083
Der-Torossian, H., Couch, M. E., Dittus, K., & Toth, M. J. (2013). Skeletal muscle
adaptations to cancer and its treatment: Their fundamental basis and contribution
to functional disability. Critical Reviews in Eukaryotic Gene Expression, 23(4),
283-297.
Dimeo, F. C. (2001). Effects of exercise on cancer‐related fatigue. Cancer, 92(S6), 16891693.
Drouin, J. M., Valovich-mcLeod, T. C., Shultz, S. J., Gansneder, B. M., & Perrin, D. H.
(2004). Reliability and validity of the Biodex system 3 pro isokinetic
dynamometer velocity, torque and position measurements. European Journal of
Applied Physiology, 91(1), 22-29.
Fearon, K. C., Glass, D. J., & Guttridge, D. C. (2012). Cancer cachexia: mediators,
signaling, and metabolic pathways. Cell Metabolism, 16(2), 153-166.
Fearon, K. C., Strasser, F., Anker, S. D., Bosaeus, I., Bruera, E., Fainsinger, R. L., . . .
Baracos, V. E. (2011). Definition and classification of cancer cachexia: an
international consensus. The Lancet Oncology, 12(5), 489-495.
Fong, D. Y., Ho, J. W., Hui, B. P., Lee, A. M., Macfarlane, D. J., Leung, S. S., . . .
Cheng, K. K. (2012). Physical activity for cancer survivors: Meta-analysis of
96
randomised controlled trials. British Medical Journal, 344, e70.
doi:10.1136/bmj.e70
Frontera, W. R., Meredith, C. N., O'Reilly, K. P., Knuttgen, H. G., & Evans, W. J.
(1988). Strength conditioning in older men: skeletal muscle hypertrophy and
improved function. Journal of Applied Physiology, 64(3), 1038-1044.
Haas, B. K. (2011). Fatigue, self-efficacy, physical activity, and quality of life in women
with breast cancer. Cancer Nursing, 34(4), 322-334.
Hofman, M., Ryan, J. L., Figueroa-Moseley, C. D., Jean-Pierre, P., & Morrow, G. R.
(2007). Cancer-related fatigue: The scale of the problem. The Oncologist, 12(1),
4-10.
Hurley, B. F., Hanson, E. D., & Sheaff, A. K. (2011). Strength training as a
countermeasure to aging muscle and chronic disease. Sports Medicine, 41(4),
289-306.
Innes, E. (1999). Handgrip strength testing: A review of the literature. Australian
Occupational Therapy Journal, 46(3), 120-140.
Jarden, M., Baadsgaard, M. T., Hovgaard, D. J., Boesen, E., & Adamsen, L. (2009). A
randomized trial on the effect of a multimodal intervention on physical capacity,
functional performance and quality of life in adult patients undergoing allogeneic
SCT. Bone Marrow Transplant, 43(9), 725-737. doi:10.1038/bmt.2009.27
Jones, L. W., Hornsby, W. E., Goetzinger, A., Forbes, L. M., Sherrard, E. L., Quist, M., .
. . Abernethy, A. P. (2012). Prognostic significance of functional capacity and
exercise behavior in patients with metastatic non-small cell lung cancer. Lung
Cancer, 76(2), 248-252. doi:10.1016/j.lungcan.2011.10.009
97
Karvonen, M. J., Kentala, E., & Mustala, O. (1957). The effects of training on heart rate;
a longitudinal study. Annales Medicinae Experimentalis et Biologiae Fenniae,
35(3), 307-315.
Keogh, J. W., & MacLeod, R. D. (2012). Body composition, physical fitness, functional
performance, quality of life, and fatigue benefits of exercise for prostate cancer
patients: A systematic review. Journal of Pain and Symptom Management, 43(1),
96-110. doi:10.1016/j.jpainsymman.2011.03.006
Kilgour, R. D., Vigano, A., Trutschnigg, B., Hornby, L., Lucar, E., Bacon, S. L., &
Morais, J. A. (2010). Cancer-related fatigue: The impact of skeletal muscle mass
and strength in patients with advanced cancer. Journal of Cachexia: Sarcopenia
and Muscle, 1(2), 177-185. doi:10.1007/s13539-010-0016-0
Kuchinski, A. M., Reading, M., & Lash, A. A. (2009). Treatment-related fatigue and
exercise in patients with cancer: A systematic review. Medical Surgical Nursing,
18(3), 174-180.
Lee, J. S., Kim, C. G., Seo, T. B., Kim, H. G., & Yoon, S. J. (2015). Effects of 8-week
combined training on body composition, isokinetic strength, and cardiovascular
disease risk factors in older women. Aging Clinical and Experimental Research,
27(2), 179-186.
Litterini, A. J., & Jette, D. U. (2011). Exercise for managing cancer-related fatigue.
Physical Therapy, 91(3), 301-304. doi:10.2522/ptj.20100273
Macvicar, M. G., Winningham, M. L., & Nickel, J. L. (1989). Effects of aerobic interval
training on cancer patients' functional capacity. Nursing Research, 38(6), 348353.
98
Miller, M. S., Callahan, D. M., & Toth, M. J. (2014). Skeletal muscle myofilament
adaptations to aging, disease and disuse and their effects on whole muscle
performance in older adult humans. Frontiers in Physiology, 5(369).
Mock, V., Atkinson, A., Barsevick, A., Cella, D., Cimprich, B., Cleeland, C., . . . Hinds,
P. (2000). NCCN practice guidelines for cancer-related fatigue. Oncology,
14(11A), 151-161.
Mock, V., Dow, K. H., Meares, C. J., Grimm, P. M., Dienemann, J. A., Haisfield-Wolfe,
M. E., . . . Gage, I. (1997). Effects of exercise on fatigue, physical functioning,
and emotional distress during radiation therapy for breast cancer. Paper
presented at the Oncology Nursing Forum.
Monga, U., Jaweed, M., Kerrigan, A. J., Lawhon, L., Johnson, J., Vallbona, C., &
Monga, T. N. (1997). Neuromuscular fatigue in prostate cancer patients
undergoing radiation therapy. Archives of Physical Medicine and Rehabilitation,
78(9), 961-966.
Morrow, G. R., Andrews, P. L., Hickok, J. T., Roscoe, J. A., & Matteson, S. (2002).
Fatigue associated with cancer and its treatment. Supportive Care in Cancer,
10(5), 389-398.
Oldervoll, L. M., Loge, J. H., Lydersen, S., Paltiel, H., Asp, M. B., Nygaard, U. V., . . .
Kaasa, S. (2011). Physical exercise for cancer patients with advanced disease: A
randomized controlled trial. The Oncologist, 16(11), 1649-1657.
doi:10.1634/theoncologist.2011-0133
99
Piper, B. F., Dibble, S. L., Dodd, M. J., Weiss, M. C., Slaughter, R. E., & Paul, S. M.
(1998). The revised Piper Fatigue Scale: Psychometric evaluation in women with
breast cancer. Paper presented at the Oncology Nursing Forum.
Portenoy, R. K., & Itri, L. M. (1999). Cancer-related fatigue: guidelines for evaluation
and management. The Oncologist, 4(1), 1-10.
Puetz, T. W., & Herring, M. P. (2012). Differential effects of exercise on cancer-related
fatigue during and following treatment: A meta-analysis. American Journal of
Preventive Medicine, 43(2), e1-24. doi:10.1016/j.amepre.2012.04.027
Schmidt, M. E., Chang-Claude, J., Vrieling, A., Heinz, J., Flesch-Janys, D., & Steindorf,
K. (2012). Fatigue and quality of life in breast cancer survivors: Temporal courses
and long-term pattern. Journal of Cancer Survivorship, 6(1), 11-19.
Schmidt, M. E., Wiskemann, J., Armbrust, P., Schneeweiss, A., Ulrich, C. M., &
Steindorf, K. (2015). Effects of resistance exercise on fatigue and quality of life in
breast cancer patients undergoing adjuvant chemotherapy: A randomized
controlled trial. International Journal of Cancer, 137(2), 471-480.
Schmidt, M. E., Wiskemann, J., Krakowski-Roosen, H., Knicker, A. J., Habermann, N.,
Schneeweiss, A., . . . Steindorf, K. (2013). Progressive resistance versus
relaxation training for breast cancer patients during adjuvant chemotherapy:
Design and rationale of a randomized controlled trial (BEATE study).
Contemporary Clinical Trials, 34(1), 117-125.
doi:http://dx.doi.org/10.1016/j.cct.2012.10.006
Schmitz, K. H., Courneya, K. S., Matthews, C., Demark-Wahnefried, W., Galvao, D. A.,
Pinto, B. M., . . . American College of Sports, M. (2010). American College of
100
Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine
& Science in Sports & Exercise, 42(7), 1409-1426.
doi:10.1249/MSS.0b013e3181e0c112
Schneider, C. M., Hsieh, C. C., Sprod, L. K., Carter, S. D., & Hayward, R. (2007a).
Effects of supervised exercise training on cardiopulmonary function and fatigue in
breast cancer survivors during and after treatment. Cancer, 110(4), 918-925.
Schneider, C. M., Hsieh, C. C., Sprod, L. K., Carter, S. D., & Hayward, R. (2007b).
Exercise training manages cardiopulmonary function and fatigue during and
following cancer treatment in male cancer survivors. Integrative Cancer
Therapies, 6(3), 235-241.
Schwartz, A. L., & Winters-Stone, K. (2009). Effects of a 12-month randomized
controlled trial of aerobic or resistance exercise during and following cancer
treatment in women. Physician and Sports Medicine, 37(3), 62-67.
doi:10.3810/psm.2009.10.1730
Segal, R. J., Reid, R. D., Courneya, K. S., Malone, S. C., Parliament, M. B., Scott, C. G.,
. . . D’Angelo, M. E. S. (2003). Resistance exercise in men receiving androgen
deprivation therapy for prostate cancer. Journal of Clinical Oncology, 21(9),
1653-1659.
Segal, R. J., Reid, R. D., Courneya, K. S., Sigal, R. J., Kenny, G. P., Prud'Homme, D. G.,
. . . Slovinec D'Angelo, M. E. (2009). Randomized controlled trial of resistance or
aerobic exercise in men receiving radiation therapy for prostate cancer. Journal of
Clinical Oncology, 27(3), 344-351. doi:10.1200/jco.2007.15.4963
101
Siegel, R. L., DeSantis, C., Virgo, K., Stein, K., Mariotto, A., Smith, T., . . . Fedewa, S.
(2012). Cancer treatment and survivorship statistics, 2012. CA: A Cancer Journal
for Clinicians, 62(4), 220-241.
Siegel, R. L., Ma, J., Zou, Z., & Jemal, A. (2014). Cancer statistics, 2014. CA: A Cancer
Journal for Clinicians, 64(1), 9-29.
Siegel, R. L., Miller, K. D., & Jemal, A. (2015). Cancer statistics, 2016. CA: A Cancer
Journal for Clinicians.
Skipworth, R. J., Stewart, G. D., Dejong, C. H., Preston, T., & Fearon, K. C. (2007).
Pathophysiology of cancer cachexia: Much more than host–tumour interaction?
Clinical Nutrition, 26(6), 667-676.
Speck, R. M., Courneya, K. S., Masse, L. C., Duval, S., & Schmitz, K. H. (2010). An
update of controlled physical activity trials in cancer survivors: A systematic
review and meta-analysis. Journal of Cancer Survivorship, 4(2), 87-100.
doi:10.1007/s11764-009-0110-5
Sprod, L. K., Hsieh, C. C., Hayward, R., & Schneider, C. M. (2010). Three versus six
months of exercise training in breast cancer survivors. Breast Cancer Research
and Treatment, 121(2), 413-419. doi:10.1007/s10549-010-0913-0
Stene, G., Helbostad, J., Balstad, T., Riphagen, I., Kaasa, S., & Oldervoll, L. (2013).
Effect of physical exercise on muscle mass and strength in cancer patients during
treatment—a systematic review. Critical Reviews in Oncology/Hematology,
88(3), 573-593.
102
Stevinson, C., Lawlor, D. A., & Fox, K. R. (2004). Exercise interventions for cancer
patients: systematic review of controlled trials. Cancer Causes & Control, 15(10),
1035-1056.
Tian, L., Lu, H. J., Lin, L., & Hu, Y. (2016). Effects of aerobic exercise on cancer-related
fatigue: A meta-analysis of randomized controlled trials. Supportive Care in
Cancer, 24(2), 969-983.
Toth, M. J., Miller, M. S., Callahan, D. M., Sweeny, A. P., Nunez, I., Grunberg, S. M., . .
. Dittus, K. (2013). Molecular mechanisms underlying skeletal muscle weakness
in human cancer: Reduced myosin-actin cross-bridge formation and kinetics.
Journal of Applied Physiology, 114(7), 858-868.
doi:10.1152/japplphysiol.01474.2012
Trutschnigg, B., Kilgour, R. D., Reinglas, J., Rosenthall, L., Hornby, L., Morais, J. A., &
Vigano, A. (2008). Precision and reliability of strength (Jamar vs. Biodex
handgrip) and body composition (dual-energy X-ray absorptiometry vs.
bioimpedance analysis) measurements in advanced cancer patients. Applied
Physiology, Nutrition, and Metabolism, 33(6), 1232-1239.
van Waart, H., Stuiver, M. M., van Harten, W. H., Geleijn, E., Kieffer, J. M., Buffart, L.
M., . . . Aaronson, N. K. (2015). Effect of low-intensity physical activity and
moderate to high-intensity physical exercise during adjuvant chemotherapy on
physical fitness, fatigue, and chemotherapy completion rates: Results of the
PACES Randomized Clinical Trial. Journal of Clinical Oncology, 33(17), 19181927. doi:10.1200/jco.2014.59.1081
103
van Weert, E., Hoekstra-Weebers, J., Otter, R., Postema, K., Sanderman, R., & van der
Schans, C. (2006). Cancer-related fatigue: Predictors and effects of rehabilitation.
The Oncologist, 11(2), 184-196.
Vardar Yagli, N., Sener, G., Arikan, H., Saglam, M., Inal Ince, D., Savci, S., . . . Ozisik,
Y. (2015). Do yoga and aerobic exercise training have impact on functional
capacity, fatigue, peripheral muscle strength, and quality of life in breast cancer
survivors? Integrative Cancer Therapies, 14(2), 125-132.
doi:10.1177/1534735414565699
Velthuis, M. J., Agasi-Idenburg, S. C., Aufdemkampe, G., & Wittink, H. M. (2010). The
effect of physical exercise on cancer-related fatigue during cancer treatment: A
meta-analysis of randomised controlled trials. Clinical Oncology, 22(3), 208-221.
doi:10.1016/j.clon.2009.12.005
Wagner, L., & Cella, D. (2004). Fatigue and cancer: Causes, prevalence and treatment
approaches. British Journal of Cancer, 91(5), 822-828.
Weber, M. A., Krakowski-Roosen, H., Schröder, L., Kinscherf, R., Krix, M., KoppSchneider, A., . . . Hildebrandt, W. (2009). Morphology, metabolism,
microcirculation, and strength of skeletal muscles in cancer-related cachexia. Acta
Oncologica, 48(1), 116-124.
Wilcock, A., Maddocks, M., Lewis, M., Howard, P., Frisby, J., Bell, S., . . . Mockett, S.
(2008). Use of a Cybex NORM dynamometer to assess muscle function in
patients with thoracic cancer. BMC Palliative Care, 7(1), 3.
Winters-Stone, K. M., Dobek, J., Bennett, J. A., Nail, L. M., Leo, M. C., & Schwartz, A.
(2012). The effect of resistance training on muscle strength and physical function
104
in older, postmenopausal breast cancer survivors: a randomized controlled trial.
Journal of Cancer Survivorship, 6(2), 189-199. doi:10.1007/s11764-011-0210-x
Wolin, K. Y., Schwartz, A. L., Matthews, C. E., Courneya, K. S., & Schmitz, K. H.
(2012). Implementing the exercise guidelines for cancer survivors. Journal of
Supportive Oncology, 10(5), 171-177. doi:10.1016/j.suponc.2012.02.001
Wyrick, K., & Davis, A. (2009). Exercise for the management of cancer-related fatigue.
American Family Physician, 80(7), 689.
Yavuzsen, T., Davis, M. P., Ranganathan, V. K., Walsh, D., Siemionow, V., Kirkova, J., .
. . Yue, G. H. (2009). Cancer-related fatigue: Central or peripheral? Journal of
Pain and Symptom Management, 38(4), 587-596.
doi:10.1016/j.jpainsymman.2008.12.003
105
CHAPTER VI
GENERAL CONCLUSIONS
Results from this study show that objective measures of upper body levels of
fatigue, as measured though a hand dynamometer, are significantly related to subjective
feelings of cancer-related fatigue (CRF). Additionally, handgrip strength was shown to be
associated with lower levels of CRF. This objective fatigue measure is quick,
inexpensive, and easily administered by clinical staff. Incorporating a measure of
muscular fatigue in addition to subjective measures may give clinicians a better
understanding of fatigue and how it affects an individual’s ability to participate in
specific rehabilitation exercises. In contrast, lower body fatigue was not related to
subjective feelings of fatigue indicating that muscles of the lower body may be less
affected by CRF.
A supervised aerobic and resistance exercise program was shown to be effective
in reducing subjective CRF in as few as 12 weeks. Continued physical activity further
reduced subjective feelings of fatigue following 24 weeks of exercise indicating cancer
rehabilitation is an effective tool for reducing CRF. Currently the optimal mode and
intensity of exercise to reduce muscular fatigue in the cancer population is unclear. The
effect of exercise on muscular fatigue in cancer survivors remains unclear and should
continue to be a topic for future study.
106
REFERENCES
Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., . . .
Takeda, F. (1993). The European Organization for Research and Treatment of
Cancer QLQ-C30: A quality-of-life instrument for use in International Clinical
Trials in Oncology. Journal of the National Cancer Institute, 85(5), 365-376.
doi:10.1093/jnci/85.5.365
Acharyya, S., Ladner, K. J., Nelsen, L. L., Damrauer, J., Reiser, P. J., Swoap, S., &
Guttridge, D. C. (2004). Cancer cachexia is regulated by selective targeting of
skeletal muscle gene products. The Journal of Clinical Investigation, 114(3), 370378.
Adams, G. R., Harris, R. T., Woodard, D., & Dudley, G. A. (1993). Mapping of electrical
muscle stimulation using MRI. Journal of Applied Physiology, 74(2), 532-537.
Adamsen, L., Quist, M., Andersen, C., Moller, T., Herrstedt, J., Kronborg, D., . . . Rorth,
M. (2009). Effect of a multimodal high intensity exercise intervention in cancer
patients undergoing chemotherapy: A randomised controlled trial. British Journal
of Medicine, 339, b3410. doi:10.1136/bmj.b3410
Agteresch, H. J., Dagnelie, P. C., van der Gaast, A., Stijnen, T., & Wilson, J. H. P.
(2000). Randomized clinical trial of adenosine 5′-triphosphate in patients with
advanced non-small-cell lung cancer. Journal of the National Cancer Institute,
92(4), 321-328. doi:10.1093/jnci/92.4.321
107
Ahlberg, K., Ekman, T., Gaston-Johansson, F., & Mock, V. (2003). Assessment and
management of cancer-related fatigue in adults. The Lancet, 362(9384), 640-650.
Al-Majid, S., & Waters, H. (2008). The biological mechanisms of cancer-related skeletal
muscle wasting: The role of progressive resistance exercise. Biological Research
for Nursing, 10(1), 7-20.
Andrews, P., Morrow, G., Hickok, J., Roscoe, J., & Stone, P. (2004). Mechanisms and
models of fatigue associated with cancer and its treatment: Evidence of preclinical and clinical studies. Fatigue in Cancer, 51-87.
Arena, R., Myers, J., Williams, M. A., Gulati, M., Kligfield, P., Balady, G. J., . . .
Fletcher, G. (2007). Assessment of functional capacity in clinical and research
settings: a scientific statement from the American Heart Association Committee
on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology
and the Council on Cardiovascular Nursing. Circulation, 116(3), 329-343.
doi:10.1161/circulationaha.106.184461
Arnold, M. E., & Taylor, N. F. (2011). Exercise for patients with cancer: Reducing
disease-related fatigue. Future Oncology, 7(2), 165-167. doi:Doi
10.2217/Fon.10.188
Baechle, T. R., & Earle, R. W. (2008). Essentials of strength training and conditioning:
Human Kinetics.
Baldwin, K., Brooks, G., Fahey, T., & White, T. (2005). Exercise physiology: Human
bioenergetics and its applications: McGraw-Hill.
Battaglini, C., Bottaro, M., Dennehy, C., Rae, L., Shields, E., Kirk, D., & Hackney, A. C.
(2007). The effects of an individualized exercise intervention on body
108
composition in breast cancer patients undergoing treatment. Sao Paulo Medical
Journal, 125(1), 22-28.
Baumann, F. T., Kraut, L., Schule, K., Bloch, W., & Fauser, A. A. (2009). A controlled
randomized study examining the effects of exercise therapy on patients
undergoing haematopoietic stem cell transplantation. Bone Marrow Transplant,
45(2), 355-362.
Beam, W. C., & Adams, G. M. (2011). Exercise Physiology Laboratory Manual (6 ed.):
McGraw-Hill.
Belza, B. L. (1995). Comparison of self-reported fatigue in rheumatord-arthritis and
controls. Journal of Rheumatology, 22(4), 639-643.
Berger, A. M. (1997). Patterns of fatigue and activity and rest during adjuvant breast
cancer chemotherapy. Paper presented at the Oncology Nursing Forum.
Bigland-Ritchie, B., & Woods, J. J. (1984). Changes in muscle contractile properties and
neural control during human muscular fatigue. Muscle & Nerve, 7(9), 691-699.
doi:10.1002/mus.880070902
Blakely, A. A., Howard, R. C., Sosich, R. M., Murdoch, J. C., Menkes, D. B., & Spears,
G. F. (1991). Psychiatric symptoms, personality and ways of coping in chronic
fatigue syndrome. Psychological Medicine, 21(02), 347-362.
Bogdanis, G. C. (2012). Effects of physical activity and inactivity on muscle fatigue.
Frontiers in Physiology, 3, 142.
Bonifati, D. M., Ori, C., Rossi, C. R., Caira, S., Fanin, M., & Angelini, C. (2000).
Neuromuscular damage after hyperthermic isolated limb perfusion in patients
109
with melanoma or sarcoma treated with chemotherapeutic agents. Cancer
Chemotherapy and Pharmacology, 46(6), 517-522.
Bossola, M., Muscaritoli, M., Costelli, P., Grieco, G., Bonelli, G., Pacelli, F., . . .
Baccino, F. M. (2003). Increased muscle proteasome activity correlates with
disease severity in gastric cancer patients. Annals of Surgery, 237(3), 384-389.
Bower, J. E., Ganz, P. A., Dickerson, S. S., Petersen, L., Aziz, N., & Fahey, J. L. (2005).
Diurnal cortisol rhythm and fatigue in breast cancer survivors.
Psychoneuroendocrinology, 30(1), 92-100.
Brown, D. J., McMillan, D. C., & Milroy, R. (2005). The correlation between fatigue,
physical function, the systemic inflammatory response, and psychological distress
in patients with advanced lung cancer. Cancer, 103(2), 377-382.
Brown, J. C., Huedo-Medina, T. B., Pescatello, L. S., Pescatello, S. M., Ferrer, R. A., &
Johnson, B. T. (2011). Efficacy of exercise interventions in modulating cancerrelated fatigue among adult cancer survivors: A meta-analysis. Cancer
Epidemiology Biomarkers & Prevention, 20(1), 123-133. doi:10.1158/10559965.epi-10-0988
Brown, J. C., Huedo-Medina, T. B., Pescatello, L. S., Ryan, S. M., Pescatello, S. M.,
Moker, E., . . . Johnson, B. T. (2012). The efficacy of exercise in reducing
depressive symptoms among cancer survivors: A meta-analysis. PLoS One, 7(1),
e30955. doi:10.1371/journal.pone.0030955
Brown, J. C., Winters‐Stone, K., Lee, A., & Schmitz, K. H. (2012). Cancer, physical
activity, and exercise. Comprehensive Physiology.
110
Brown, L. F., & Kroenke, K. (2009). Cancer-related fatigue and its associations with
depression and anxiety: a systematic review. Psychosomatics, 50(5), 440-447.
doi:10.1176/appi.psy.50.5.440
Bruera, E., Brenneis, C., Michaud, M., Rafter, J., Magnan, A., Tennant, A., . . .
Macdonald, R. N. (1989). Association between asthenia and nutritional status,
lean body mass, anemia, psychological status, and tumor mass in patients with
advanced breast cancer. Journal of Pain and Symptom Management, 4(2), 59-63.
Burnham, T. R., & Wilcox, A. (2002). Effects of exercise on physiological and
psychological variables in cancer survivors. Medicine & Science in Sports &
Exercise, 34(12), 1863-1867.
Campos, G. E., Luecke, T. J., Wendeln, H. K., Toma, K., Hagerman, F. C., Murray, T. F.,
. . . Staron, R. S. (2002). Muscular adaptations in response to three different
resistance-training regimens: Specificity of repetition maximum training zones.
European Journal of Applied Physiology, 88(1-2), 50-60.
Can, G., Durna, Z., & Aydiner, A. (2004). Assessment of fatigue in and care needs of
Turkish women with breast cancer. Cancer Nursing, 27(2), 153-161.
Cannon, T., Couch, M., Yin, X., Guttridge, D., Lai, V., & Shores, C. (2007). Comparison
of animal models for head and neck cancer cachexia. The Laryngoscope, 117(12),
2152-2158.
Cantarero-Villanueva, I., Fernández-Lao, C., Díaz-Rodríguez, L., Fernández-de-lasPeñas, C., Ruiz, J. R., & Arroyo-Morales, M. (2012). The handgrip strength test
as a measure of function in breast cancer survivors: relationship to cancer-related
111
symptoms and physical and physiologic parameters. American Journal of
Physical Medicine & Rehabilitation, 91(9), 774-782.
Cao, D.-x., Wu, G.-h., Zhang, B., Quan, Y.-j., Wei, J., Jin, H., . . . Yang, Z.-a. (2010).
Resting energy expenditure and body composition in patients with newly detected
cancer. Clinical Nutrition, 29(1), 72-77.
Chalder, T., Berelowitz, G., Pawlikowska, T., Watts, L., Wessely, S., Wright, D., &
Wallace, E. P. (1993). Development of a fatigue scale Journal of Psychosomatic
Research, 37(2), 147-153. doi:10.1016/0022-3999(93)90081-p
Chodzko-Zajko, W. J., Proctor, D. N., Fiatarone Singh, M. A., Minson, C. T., Nigg, C.
R., Salem, G. J., & Skinner, J. S. (2009). Exercise and physical activity for older
adults. Medicine & Science in Sports & Exercise, 41(7), 1510-1530.
doi:10.1249/MSS.0b013e3181a0c95c
Christensen, J., Jones, L., Andersen, J., Daugaard, G., Rorth, M., & Hojman, P. (2014).
Muscle dysfunction in cancer patients. Annals of Oncology, 25(5), 947-958.
Christie, A., Snook, E. M., & Kent-Braun, J. A. (2011). Systematic Review and MetaAnalysis of Skeletal Muscle Fatigue in Old Age. Medicine & Science in Sports &
Exercise, 43(4), 568-577. doi:10.1249/MSS.0b013e3181f9b1c4
Coleman, E. A., Coon, S., Hall-Barrow, J., Richards, K., Gaylor, D., & Stewart, B.
(2003). Feasibility of exercise during treatment for multiple myeloma. Cancer
Nursing, 26(5), 410-419.
Collins, P., Bing, C., McCulloch, P., & Williams, G. (2002). Muscle UCP-3 mRNA
levels are elevated in weight loss associated with gastrointestinal adenocarcinoma
in humans. British Journal of Cancer, 86(3), 372-375.
112
Committee, P. A. G. A. (2008). Physical activity guidelines advisory committee report,
2008. Washington, DC: US Department of Health and Human Services, 2008,
A1-H14.
Copeland, G., Leinster, S., Davis, J., & Hipkin, L. (1987). Insulin resistance in patients
with colorectal cancer. British Journal of Surgery, 74(11), 1031-1035.
Costelli, P., Carbo, N., Tessitore, L., Bagby, G. J., Lopezsoriano, F. J., Argiles, J. M., &
Baccino, F. M. (1993). Tumor-necrosis-factor-alpha mediates changes in tissue
protein-turnover in a rat cancer cachexia model. Journal of Clinical Investigation,
92(6), 2783-2789. doi:10.1172/jci116897
Costill, D. L. (1972). Physiology of marathon running. Journal of the American Medical
Association, 221(9), 1024-1029.
Courneya, K. S. (2003). Exercise in cancer survivors: An overview of research. Medicine
& Science in Sports & Exercise, 35(11), 1846-1852.
Courneya, K. S., Friedenreich, C. M., Sela, R. A., Quinney, H. A., Rhodes, R., &
Handman, M. (2003). The group psychotherapy and home‐based physical
exercise (group‐hope) trial in cancer survivors: Physical fitness and quality of life
outcomes. Psycho‐Oncology, 12(4), 357-374.
Courneya, K. S., Mackey, J. R., Bell, G. J., Jones, L. W., Field, C. J., & Fairey, A. S.
(2003). Randomized controlled trial of exercise training in postmenopausal breast
cancer survivors: cardiopulmonary and quality of life outcomes. Journal of
Clinical Oncology, 21(9), 1660-1668.
Courneya, K. S., Segal, R. J., Mackey, J. R., Gelmon, K., Reid, R. D., Friedenreich, C.
M., . . . McKenzie, D. C. (2007). Effects of aerobic and resistance exercise in
113
breast cancer patients receiving adjuvant chemotherapy: A multicenter
randomized controlled trial. Journal of Clinical Oncology, 25(28), 4396-4404.
doi:10.1200/jco.2006.08.2024
Cramer, H., Lauche, R., Klose, P., Dobos, G., & Langhorst, J. (2014). A systematic
review and meta‐analysis of exercise interventions for colorectal cancer patients.
European Journal of Cancer Care, 23(1), 3-14.
Cramp, F., & Byron-Daniel, J. (2012). Exercise for the management of cancer-related
fatigue in adults. Cochrane Database System Review, 11(11).
Cunningham, B. A., Morris, G., Cheney, C. L., Buergel, N., Aker, S. N., & Lenssen, P.
(1986). Effects of resistive exercise on skeletal muscle in marrow transplant
recipients receiving total parenteral nutrition. Journal of Parenteral and Enteral
Nutrition, 10(6), 558-563.
Daley, A. J., Crank, H., Saxton, J. M., Mutrie, N., Coleman, R., & Roalfe, A. (2007).
Randomized trial of exercise therapy in women treated for breast cancer. Journal
of Clinical Oncology, 25(13), 1713-1721. doi:10.1200/jco.2006.09.5083
Demark-Wahnefried, W., Case, L. D., Blackwell, K., Marcom, P. K., Kraus, W., Aziz,
N., . . . Shaw, E. (2008). Results of a diet/exercise feasibility trial to prevent
adverse body composition change in breast cancer patients on adjuvant
chemotherapy. Clinical Breast Cancer, 8(1), 70-79. doi:10.3816/CBC.2008.n.005
Der-Torossian, H., Couch, M. E., Dittus, K., & Toth, M. J. (2013). Skeletal muscle
adaptations to cancer and its treatment: Their fundamental basis and contribution
to functional disability. Critical Reviews in Eukaryotic Gene Expression, 23(4),
283-297.
114
Derogatis, L. R., Morrow, G. R., Fetting, J., Penman, D., Piasetsky, S., Schmale, A. M., .
. . Carnicke, C. L. (1983). The prevalence of psychiatric disorders among cancer
patients. Journal of the American Medical Association, 249(6), 751-757.
Dillon, E. L., Volpi, E., Wolfe, R. R., Sinha, S., Sanford, A. P., Arrastia, C. D., . . .
Sheffield-Moore, M. (2007). Amino acid metabolism and inflammatory burden in
ovarian cancer patients undergoing intense oncological therapy. Clinical
Nutrition, 26(6), 736-743. doi:10.1016/j.clnu.2007.07.004
Dimeo, F. C. (2001). Effects of exercise on cancer‐related fatigue. Cancer, 92(S6), 16891693.
Dimeo, F. C., Thomas, F., Raabe-Menssen, C., Pröpper, F., & Mathias, M. (2004). Effect
of aerobic exercise and relaxation training on fatigue and physical performance of
cancer patients after surgery. A randomised controlled trial. Supportive Care in
Cancer, 12(11), 774-779.
Dittus, K. L., Lakoski, S. G., Savage, P. D., Kokinda, N., Toth, M., Stevens, D., . . .
Ades, P. A. (2015). Exercise-based oncology rehabilitation: leveraging the cardiac
rehabilitation model. Journal of Cardiopulmonary Rehabilitation and Prevention,
35(2), 130-139. doi:10.1097/hcr.0000000000000091
Doyle, C., Kushi, L. H., Byers, T., Courneya, K. S., Demark‐Wahnefried, W., Grant, B., .
. . Gansler, T. (2006). Nutrition and physical activity during and after cancer
treatment: An American Cancer Society guide for informed choices. CA: A
Cancer Journal for Clinicians, 56(6), 323-353.
Drouin, J. M., Valovich-mcLeod, T. C., Shultz, S. J., Gansneder, B. M., & Perrin, D. H.
(2004). Reliability and validity of the Biodex system 3 pro isokinetic
115
dynamometer velocity, torque and position measurements. European Journal of
Applied Physiology, 91(1), 22-29.
Edwards, R. H. (1981). Human muscle function and fatigue. Ciba Foundation
Symposium, 82, 1-18.
Edwards, R. H., Hill, D. K., Jones, D. A., & Merton, P. A. (1977). Fatigue of long
duration in human skeletal muscle after exercise. The Journal of Physiology,
272(3), 769-778.
Egan, B., & Zierath, J. R. (2013). Exercise metabolism and the molecular regulation of
skeletal muscle adaptation. Cell Metabolism, 17(2), 162-184.
Eley, H. L., Russell, S. T., Baxter, J. H., Mukerji, P., & Tisdale, M. J. (2007). Signaling
pathways initiated by β-hydroxy-β-methylbutyrate to attenuate the depression of
protein synthesis in skeletal muscle in response to cachectic stimuli. American
Journal of Physiology-Endocrinology and Metabolism, 293(4), E923-E931.
Enomoto, A., Rho, M. C., Fukami, A., Hiraku, O., Komiyama, K., & Hayashi, M. (2004).
Suppression of cancer cachexia by 20S,21-epoxy-resibufogenin-3-acetate - a
novel nonpeptide IL-6 receptor antagonist. Biochemical and Biophysical
Research Communications, 323(3), 1096-1102. doi:10.1016/j.bbrc.2004.08.196
Falkenberg, J. H., Iaizzo, P. A., & McLoon, L. K. (2002). Muscle strength following
direct injection of doxorubicin into rabbit sternocleidomastoid muscle in situ.
Muscle & Nerve, 25(5), 735-741.
Fearon, K. C., Glass, D. J., & Guttridge, D. C. (2012). Cancer cachexia: mediators,
signaling, and metabolic pathways. Cell Metabolism, 16(2), 153-166.
116
Fearon, K. C., Strasser, F., Anker, S. D., Bosaeus, I., Bruera, E., Fainsinger, R. L., . . .
Baracos, V. E. (2011). Definition and classification of cancer cachexia: an
international consensus. The Lancet Oncology, 12(5), 489-495.
Fong, D. Y., Ho, J. W., Hui, B. P., Lee, A. M., Macfarlane, D. J., Leung, S. S., . . .
Cheng, K. K. (2012). Physical activity for cancer survivors: Meta-analysis of
randomised controlled trials. British Medical Journal, 344, e70.
doi:10.1136/bmj.e70
Freedman, R., Aziz, N., Albanes, D., Hartman, T., Danforth, D., Hill, S., . . . Yanovski, J.
(2004). Weight and body composition changes during and after adjuvant
chemotherapy in women with breast cancer. The Journal of Clinical
Endocrinology & Metabolism, 89(5), 2248-2253.
Friedman, H. S., Colvin, O. M., Aisaka, K., Popp, J., Bossen, E. H., Reimer, K. A., . . .
Levi, R. (1990). Glutathione protects cardiac and skeletal muscle from
cyclophosphamide-induced toxicity. Cancer Research, 50(8), 2455-2462.
Frontera, W. R., Meredith, C. N., O'Reilly, K. P., Knuttgen, H. G., & Evans, W. J.
(1988). Strength conditioning in older men: skeletal muscle hypertrophy and
improved function. Journal of Applied Physiology, 64(3), 1038-1044.
Gallagher, I. J., Stephens, N. A., MacDonald, A. J., Skipworth, R. J., Husi, H., Greig, C.
A., . . . Fearon, K. C. (2012). Suppression of skeletal muscle turnover in cancer
cachexia: evidence from the transcriptome in sequential human muscle biopsies.
Clinical Cancer Research, 18(10), 2817-2827.
Garber, C. E., Blissmer, B., Deschenes, M. R., Franklin, B. A., Lamonte, M. J., Lee, I.M., . . . Swain, D. P. (2011). American College of Sports Medicine position stand.
117
Quantity and quality of exercise for developing and maintaining cardiorespiratory,
musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance
for prescribing exercise. Medicine & Science in Sports & Exercise, 43(7), 13341359.
Gillette, E., Mahler, P., Powers, B., Gillette, S., & Vujaskovic, Z. (1995). Late radiation
injury to muscle and peripheral nerves. International Journal of Radiation
Oncology* Biology* Physics, 31(5), 1309-1318.
Gilliam, L. A., Moylan, J. S., Ferreira, L. F., & Reid, M. B. (2011). TNF/TNFR1
signaling mediates doxorubicin-induced diaphragm weakness. American Journal
of Physiology-Lung Cellular and Molecular Physiology, 300(2), L225-L231.
Gilliam, L. A., Moylan, J. S., Patterson, E. W., Smith, J. D., Wilson, A. S., Rabbani, Z.,
& Reid, M. B. (2012). Doxorubicin acts via mitochondrial ROS to stimulate
catabolism in C2C12 myotubes. American Journal of Physiology-Cell Physiology,
302(1), C195-C202.
Gilliam, L. A., & St. Clair, D. K. (2011). Chemotherapy-induced weakness and fatigue in
skeletal muscle: The role of oxidative stress. Antioxidants & Redox Signaling,
15(9), 2543-2563.
Giordano, A., Calvani, M., Petillo, O., Carteni, M., Melone, M. R. A., & Peluso, G.
(2003). Skeletal muscle metabolism in physiology and in cancer disease. Journal
of Cellular Biochemistry, 90(1), 170-186.
Glaus, A., Crow, R., & Hammond, S. (1996). A qualitative study to explore the concept
of fatigue/tiredness in cancer patients and in healthy individuals. Supportive Care
in Cancer, 4(2), 82-96.
118
Gollnick, P. D., Armstrong, R., Saltin, B., Saubert, C., Sembrowich, W. L., & Shepherd,
R. E. (1973). Effect of training on enzyme activity and fiber composition of
human skeletal muscle. Journal of Applied Physiology, 34(1), 107-111.
Greenspan, S. L., Coates, P., Sereika, S. M., Nelson, J. B., Trump, D. L., & Resnick, N.
M. (2005). Bone loss after initiation of androgen deprivation therapy in patients
with prostate cancer. The Journal of Clinical Endocrinology & Metabolism,
90(12), 6410-6417.
Guttridge, D. C., Mayo, M. W., Madrid, L. V., Wang, C.-Y., & Baldwin Jr, A. S. (2000).
NF-κB-induced loss of MyoD messenger RNA: Possible role in muscle decay and
cachexia. Science, 289(5488), 2363-2366.
Haas, B. K. (2011). Fatigue, self-efficacy, physical activity, and quality of life in women
with breast cancer. Cancer Nursing, 34(4), 322-334.
Hagstrom, A. D., Marshall, P. W., Lonsdale, C., Papalia, S., Cheema, B. S., Toben, C., . .
. Green, S. (2016). The effect of resistance training on markers of immune
function and inflammation in previously sedentary women recovering from breast
cancer: A randomized controlled trial. Breast Cancer Research and Treatment.
doi:10.1007/s10549-016-3688-0
Häkkinen, K., & Keskinen, K. (1989). Muscle cross-sectional area and voluntary force
production characteristics in elite strength-and endurance-trained athletes and
sprinters. European Journal of Applied Physiology and Occupational Physiology,
59(3), 215-220.
Hann, D. M., Jacobsen, P. B., Azzarello, L. M., Martin, S. C., Curran, S. L., Fields, K.
K., . . . Lyman, G. (1998). Measurement of fatigue in cancer patients:
119
development and validation of the Fatigue Symptom Inventory. Quality of Life
Research, 7(4), 301-310. doi:10.1023/a:1008842517972
Hanson, E. D., Sheaff, A. K., Sood, S., Ma, L., Francis, J. D., Goldberg, A. P., & Hurley,
B. F. (2012). Strength training induces muscle hypertrophy and functional gains
in black prostate cancer patients despite androgen deprivation therapy. The
Journals of Gerontology Series A: Biological Sciences and Medical Sciences,
gls206.
Harber, M. P., Konopka, A. R., Douglass, M. D., Minchev, K., Kaminsky, L. A., Trappe,
T. A., & Trappe, S. (2009). Aerobic exercise training improves whole muscle and
single myofiber size and function in older women. American Journal of
Physiology - Regulatory, Integrative and Comparative Physiology, 297(5),
R1452-R1459. doi:10.1152/ajpregu.00354.2009
Harber, M. P., Konopka, A. R., Jemiolo, B., Trappe, S. W., Trappe, T. A., & Reidy, P. T.
(2010). Muscle protein synthesis and gene expression during recovery from
aerobic exercise in the fasted and fed states. American Journal of PhysiologyRegulatory, Integrative and Comparative Physiology, 299(5), R1254-R1262.
Harber, M. P., Konopka, A. R., Undem, M. K., Hinkley, J. M., Minchev, K., Kaminsky,
L. A., . . . Trappe, S. (2012). Aerobic exercise training induces skeletal muscle
hypertrophy and age-dependent adaptations in myofiber function in young and
older men. Journal of Applied Physiology, 113(9), 1495-1504.
doi:10.1152/japplphysiol.00786.2012
Hardin, B. J., Campbell, K. S., Smith, J. D., Arbogast, S., Smith, J., Moylan, J. S., &
Reid, M. B. (2008). TNF-α acts via TNFR1 and muscle-derived oxidants to
120
depress myofibrillar force in murine skeletal muscle. Journal of Applied
Physiology, 104(3), 694-699.
Haskell, W. L., Lee, I.-M., Pate, R. R., Powell, K. E., Blair, S. N., Franklin, B. A., . . .
Bauman, A. (2007). Physical activity and public health: updated recommendation
for adults from the American College of Sports Medicine and the American Heart
Association. Circulation, 116(9), 1081.
Hather, B., Tesch, P., Buchanan, P., & Dudley, G. (1991). Influence of eccentric actions
on skeletal muscle adaptations to resistance training. Acta Physiologica
Scandinavica, 143(2), 177-185.
Hayward, R., Hydock, D., Gibson, N., Greufe, S., Bredahl, E., & Parry, T. (2013). Tissue
retention of doxorubicin and its effects on cardiac, smooth, and skeletal muscle
function. Journal of Physiology and Biochemistry, 69(2), 177-187.
Hermansen, L., & Wachtlova, M. (1971). Capillary density of skeletal muscle in welltrained and untrained men. Journal of Applied Physiology, 30(6), 860-863.
Hofman, M., Ryan, J. L., Figueroa-Moseley, C. D., Jean-Pierre, P., & Morrow, G. R.
(2007). Cancer-related fatigue: The scale of the problem. The Oncologist, 12(1),
4-10.
Holloszy, J. O. (1967). Biochemical adaptations in muscle effects of exercise on
mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle.
Journal of Biological Chemistry, 242(9), 2278-2282.
Howald, H., Hoppeler, H., Claassen, H., Mathieu, O., & Straub, R. (1985). Influences of
endurance training on the ultrastructural composition of the different muscle fiber
types in humans. Pflügers Archiv, 403(4), 369-376.
121
Hurley, B. F., Hanson, E. D., & Sheaff, A. K. (2011). Strength training as a
countermeasure to aging muscle and chronic disease. Sports Medicine, 41(4),
289-306.
Hydock, D. S., Lien, C. Y., Jensen, B. T., Schneider, C. M., & Hayward, R. (2011).
Exercise preconditioning provides long-term protection against early chronic
doxorubicin cardiotoxicity. Integrative Cancer Therapies, 10(1), 47-57.
doi:10.1177/1534735410392577
Innes, E. (1999). Handgrip strength testing: A review of the literature. Australian
Occupational Therapy Journal, 46(3), 120-140.
Jarden, M., Baadsgaard, M. T., Hovgaard, D. J., Boesen, E., & Adamsen, L. (2009). A
randomized trial on the effect of a multimodal intervention on physical capacity,
functional performance and quality of life in adult patients undergoing allogeneic
SCT. Bone Marrow Transplant, 43(9), 725-737. doi:10.1038/bmt.2009.27
Jereczek-Fossa, B. A., Marsiglia, H. R., & Orecchia, R. (2002). Radiotherapy-related
fatigue. Critical Reviews in Oncology/Hematology, 41(3), 317-325.
Jones, D. A., Rutherford, O. M., & Parker, D. F. (1989). Physiological changes in skeletal
muscle as a result of strength training. Quarterly Jounal of Experimental
Physiology, 74(3), 233-256.
Jones, L. W., Douglas, P. S., Eves, N. D., Marcom, P. K., Kraus, W. E., Herndon, J. E.,
2nd, . . . Peppercorn, J. (2010). Rationale and design of the Exercise Intensity
Trial (EXCITE): A randomized trial comparing the effects of moderate versus
moderate to high-intensity aerobic training in women with operable breast cancer.
BMC Cancer, 10, 531. doi:10.1186/1471-2407-10-531
122
Jones, L. W., Eves, N. D., Haykowsky, M., Freedland, S. J., & Mackey, J. R. (2009).
Exercise intolerance in cancer and the role of exercise therapy to reverse
dysfunction. The Lancet Oncology, 10(6), 598-605. doi:10.1016/s14702045(09)70031-2
Jones, L. W., Eves, N. D., Kraus, W. E., Potti, A., Crawford, J., Blumenthal, J. A., . . .
Douglas, P. S. (2010). The lung cancer exercise training study: A randomized trial
of aerobic training, resistance training, or both in postsurgical lung cancer
patients: Rationale and design. BMC Cancer, 10, 155. doi:10.1186/1471-2407-10155
Jones, L. W., Hornsby, W. E., Goetzinger, A., Forbes, L. M., Sherrard, E. L., Quist, M., .
. . Abernethy, A. P. (2012). Prognostic significance of functional capacity and
exercise behavior in patients with metastatic non-small cell lung cancer. Lung
Cancer, 76(2), 248-252. doi:10.1016/j.lungcan.2011.10.009
Jones, L. W., Liang, Y., Pituskin, E. N., Battaglini, C. L., Scott, J. M., Hornsby, W. E., &
Haykowsky, M. (2011). Effect of exercise training on peak oxygen consumption
in patients with cancer: A meta-analysis. The Oncologist, 16(1), 112-120.
Jubrias, S. A., Esselman, P. C., Price, L. B., Cress, M. E., & Conley, K. E. (2001). Large
energetic adaptations of elderly muscle to resistance and endurance training.
Journal of Applied Physiology, 90(5), 1663-1670.
Karayiannakis, A. J., Syrigos, K. N., Polychronidis, A., Pitiakoudis, M., Bounovas, A., &
Simopoulos, K. (2001). Serum levels of tumor necrosis factor-alpha and
nutritional status in pancreatic cancer patients. Anticancer Research, 21(2B),
1355-1358.
123
Karvonen, M. J., Kentala, E., & Mustala, O. (1957). The effects of training on heart rate;
a longitudinal study. Annales Medicinae Experimentalis Biologiae Fenniae,
35(3), 307-315.
Kasper, C. E., & Sarna, L. P. (2000). Influence of adjuvant chemotherapy on skeletal
muscle and fatigue in women with breast cancer. Biological Research for
Nursing, 2(2), 133-139.
Keogh, J. W., & MacLeod, R. D. (2012). Body composition, physical fitness, functional
performance, quality of life, and fatigue benefits of exercise for prostate cancer
patients: A systematic review. Journal of Pain and Symptom Management, 43(1),
96-110. doi:10.1016/j.jpainsymman.2011.03.006
Kilgour, R. D., Vigano, A., Trutschnigg, B., Hornby, L., Lucar, E., Bacon, S. L., &
Morais, J. A. (2010). Cancer-related fatigue: The impact of skeletal muscle mass
and strength in patients with advanced cancer. Journal of Cachexia: Sarcopenia
and Muscle, 1(2), 177-185. doi:10.1007/s13539-010-0016-0
Kisiel-Sajewicz, K., Davis, M. P., Siemionow, V., Seyidova-Khoshknabi, D., Wyant, A.,
Walsh, D., . . . Yue, G. H. (2012). Lack of muscle contractile property changes at
the time of perceived physical exhaustion suggests central mechanisms
contributing to early motor task failure in patients with cancer-related fatigue.
Journal of Pain and Symptom Management, 44(3), 351-361.
doi:10.1016/j.jpainsymman.2011.08.007
Kohler, B. A., Sherman, R. L., Howlader, N., Jemal, A., Ryerson, A. B., Henry, K. A., . .
. Penberthy, L. (2015). Annual report to the nation on the status of cancer, 19752011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and
124
state. Journal of the National Cancer Institute, 107(6), djv048.
doi:10.1093/jnci/djv048
Konopka, A. R., Douglass, M. D., Kaminsky, L. A., Jemiolo, B., Trappe, T. A., Trappe,
S., & Harber, M. P. (2010). Molecular adaptations to aerobic exercise training in
skeletal muscle of older women. Journals of Gerontology Series a-Biological
Sciences and Medical Sciences, 65(11), 1201-1207. doi:10.1093/gerona/glq109
Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011). Otto Warburg's contributions to
current concepts of cancer metabolism. Nature Reviews Cancer, 11(5), 325-337.
Krupp, L. B., Larocca, N. G., Muirnash, J., & Steinberg, A. D. (1989). The fatigue
severity scale - application to patients with multiple-scleerosis and systemic lupiserythematosus. Archives of Neurology, 46(10), 1121-1123.
Krzystek-Korpacka, M., Matusiewicz, M., Diakowska, D., Grabowski, K., Blachut, K.,
Kustrzeba-Wojcicka, I., & Banas, T. (2007). Impact of weight loss on circulating
IL-1, IL-6, IL-8, TNF-α, VEGF-A, VEGF–C and midkine in gastroesophageal
cancer patients. Clinical Biochemistry, 40(18), 1353-1360.
Kuchinski, A. M., Reading, M., & Lash, A. A. (2009). Treatment-related fatigue and
exercise in patients with cancer: A systematic review. Medical Surgical Nursing,
18(3), 174-180.
Lane, R. J., Barrett, M. C., Taylor, D. J., Kemp, G. J., & Lodi, R. (1998). Heterogeneity
in chronic fatigue syndrome: Evidence from magnetic resonance spectroscopy of
muscle. Neuromuscular Disorders, 8(3), 204-209.
Lee, J. S., Kim, C. G., Seo, T. B., Kim, H. G., & Yoon, S. J. (2015). Effects of 8-week
combined training on body composition, isokinetic strength, and cardiovascular
125
disease risk factors in older women. Aging Clinical and Experimental Research,
27(2), 179-186.
Lee, K. A., Hicks, G., & Ninomurcia, G. (1991). Validity and reliability of a scale to
measure fatigue. Psychiatry Research, 36(3), 291-298. doi:10.1016/01651781(91)90027-m
Litterini, A. J., & Jette, D. U. (2011). Exercise for managing cancer-related fatigue.
Physical Therapy, 91(3), 301-304. doi:10.2522/ptj.20100273
Lorite, M., Cariuk, P., & Tisdale, M. (1997). Induction of muscle protein degradation by
a tumour factor. British Journal of Cancer, 76(8), 1035.
Lorite, M., Smith, H. J., Arnold, J., Morris, A., Thompson, M., & Tisdale, M. J. (2001).
Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and
murine myoblasts in vitro by a proteolysis-inducing factor (PIF). British Journal
of Cancer, 85(2), 297.
Lorite, M., Thompson, M., Drake, J., Carling, G., & Tisdale, M. (1998). Mechanism of
muscle protein degradation induced by a cancer cachectic factor. British Journal
of Cancer, 78(7), 850.
Lovell, D. I., Cuneo, R., & Gass, G. C. (2010). Can aerobic training improve muscle
strength and power in older men? Journal of Aging and Physical Activity, 18(1),
14-26.
Lundholm, K., Holm, G., & Scherstén, T. (1978). Insulin resistance in patients with
cancer. Cancer Research, 38(12), 4665-4670.
MacDougall, J. D., Gibala, M. J., Tarnopolsky, M. A., MacDonald, J. R., Interisano, S.
A., & Yarasheski, K. E. (1995). The time course for elevated muscle protein
126
synthesis following heavy resistance exercise. Canadian Journal of Applied
Physiology, 20(4), 480-486. doi:10.1139/h95-038
MacDougall, J. D., Sale, D., Elder, G., & Sutton, J. (1976). Ultrastructural properties of
human skeletal muscle following heavy resistance training & immobilization.
Medicine & Science in Sports & Exercise, 8(1), 72.
MacDougall, J. D., Sale, D., Moroz, J., Elder, G., Sutton, J., & Howald, H. (1978).
Mitochondrial volume density in human skeletal muscle following heavy
resistance training. Medicine & Science in Sports & Exercise, 11(2), 164-166.
MacDougall, J. D., Ward, G., Sale, D., & Sutton, J. (1977). Biochemical adaptation of
human skeletal muscle to heavy resistance training and immobilization. Journal
of Applied Physiology, 43(4), 700-703.
Macvicar, M. G., Winningham, M. L., & Nickel, J. L. (1989). Effects of aerobic interval
training on cancer patients' functional capacity. Nursing Research, 38(6), 348353.
Makino, T., Noguchi, Y., Yoshikawa, T., & Nomura, K. (1998). Circulating interleukin 6
concentrations and insulin resistance in patients with cancer. British Journal of
Surgery, 85(12), 1658-1662.
McMillan, E. M., & Newhouse, I. J. (2011). Exercise is an effective treatment modality
for reducing cancer-related fatigue and improving physical capacity in cancer
patients and survivors: A meta-analysis. Applied physiology, nutrition, and
metabolism, 36(6), 892-903.
McNair, D. (1971). Manual profile of mood states: Educational & Industrial Testing
Service.
127
Mello, M., Tanaka, C., & Dulley, F. L. (2003). Effects of an exercise program on muscle
performance in patients undergoing allogeneic bone marrow transplantation. Bone
Marrow Transplant, 32(7), 723-728. doi:10.1038/sj.bmt.1704227
Mendoza, T. R., Wang, X. S., Cleeland, C. S., Morrissey, H., Johnson, B. A., Wendt, J.
K., & Huber, S. L. (1999). The rapid assessment of fatigue severity in cancer
patients - use of the brief fatigue inventory. Cancer, 85(5), 1186-1196.
Miller, B. F., Olesen, J. L., Hansen, M., Døssing, S., Crameri, R. M., Welling, R. J., . . .
Babraj, J. A. (2005). Coordinated collagen and muscle protein synthesis in human
patella tendon and quadriceps muscle after exercise. The Journal of Physiology,
567(3), 1021-1033.
Miller, M. S., Callahan, D. M., & Toth, M. J. (2014). Skeletal muscle myofilament
adaptations to aging, disease and disuse and their effects on whole muscle
performance in older adult humans. Frontiers in Physiology, 5(369).
Minton, O., & Stone, P. (2008). A systematic review of the scales used for the
measurement of cancer-related fatigue (CRF). Annals of Oncology, mdn537.
Mock, V., Atkinson, A., Barsevick, A., Cella, D., Cimprich, B., Cleeland, C., . . . Hinds,
P. (2000). NCCN practice guidelines for cancer-related fatigue. Oncology,
14(11A), 151-161.
Mock, V., Dow, K. H., Meares, C. J., Grimm, P. M., Dienemann, J. A., Haisfield-Wolfe,
M. E., . . . Gage, I. (1997). Effects of exercise on fatigue, physical functioning,
and emotional distress during radiation therapy for breast cancer. Paper
presented at the Oncology Nursing Forum.
128
Moldawer, L. L., Rogy, M. A., & Lowry, S. F. (1992). The role of cytokines in cancer
cachexia. Journal of Parenteral and Enteral Nutrition, 16(6), 43S-49S.
Monga, U., Jaweed, M., Kerrigan, A. J., Lawhon, L., Johnson, J., Vallbona, C., &
Monga, T. N. (1997). Neuromuscular fatigue in prostate cancer patients
undergoing radiation therapy. Archives of Physical Medicine and Rehabilitation,
78(9), 961-966.
Mormont, M. C., Hecquet, B., Bogdan, A., Benavides, M., Touitou, Y., & Levi, F.
(1998). Non-invasive estimation of the circadian rhythm in serum cortisol in
patients with ovarian or colorectal cancer. International Journal of Cancer, 78(4),
421-424.
Mormont, M. C., & Waterhouse, J. (2002). Contribution of the rest–activity circadian
rhythm to quality of life in cancer patients. Chronobiology International, 19(1),
313-323.
Morrow, G. R., Andrews, P. L., Hickok, J. T., Roscoe, J. A., & Matteson, S. (2002).
Fatigue associated with cancer and its treatment. Supportive Care in Cancer,
10(5), 389-398.
Mustian, K. M., Peppone, L., Darling, T. V., Palesh, O., Heckler, C. E., & Morrow, G. R.
(2009). A 4-week home-based aerobic and resistance exercise program during
radiation therapy: A pilot randomized clinical trial. The Journal of Supportive
Oncology, 7(5), 158-167.
Nicolay, C. W., & Walker, A. L. (2005). Grip strength and endurance: Influences of
anthropometric variation, hand dominance, and gender. International Journal of
Industrial Ergonomics, 35(7), 605-618.
129
Nordlund, M. M., Thorstensson, A., & Cresswell, A. G. (2004). Central and peripheral
contributions to fatigue in relation to level of activation during repeated maximal
voluntary isometric plantar flexions. Journal of Applied Physiology, 96(1), 218225. doi:10.1152/japplphysiol.00650.2003
Oldervoll, L. M., Loge, J. H., Lydersen, S., Paltiel, H., Asp, M. B., Nygaard, U. V., . . .
Kaasa, S. (2011). Physical exercise for cancer patients with advanced disease: A
randomized controlled trial. The Oncologist, 16(11), 1649-1657.
doi:10.1634/theoncologist.2011-0133
Pastoris, O., Aquilani, R., Foppa, P., Bovio, G., Segagni, S., Baiardi, P., . . . Dossena, M.
(1997). Altered muscle energy metabolism in post-absorptive patients with
chronic renal failure. Scandinavian Journal of Urology and Nephrology, 31(3),
281-287.
Patton, J. F., Kraemer, W., Knuttgen, H., & Harman, E. (1990). Factors in maximal
power production and in exercise endurance relative to maximal power. European
Journal of Applied Physiology and Occupational Physiology, 60(3), 222-227.
Pensini, M., Martin, A., & Maffiuletti, N. (2002). Central versus peripheral adaptations
following eccentric resistance training. International Journal of Sports Medicine,
23(8), 567-574.
Piper, B. F., Dibble, S. L., Dodd, M. J., Weiss, M. C., Slaughter, R. E., & Paul, S. M.
(1998). The revised Piper Fatigue Scale: Psychometric evaluation in women with
breast cancer. Paper presented at the Oncology Nursing Forum.
Portenoy, R. K., & Itri, L. M. (1999). Cancer-related fatigue: guidelines for evaluation
and management. The Oncologist, 4(1), 1-10.
130
Poterucha, T., Burnette, B., & Jatoi, A. (2012). A decline in weight and attrition of
muscle in colorectal cancer patients receiving chemotherapy with bevacizumab.
Medical Oncology, 29(2), 1005-1009.
Puetz, T. W., & Herring, M. P. (2012). Differential effects of exercise on cancer-related
fatigue during and following treatment: A meta-analysis. American Journal of
Preventive Medicine, 43(2), e1-24. doi:10.1016/j.amepre.2012.04.027
Quist, M., Rorth, M., Langer, S., Jones, L. W., Laursen, J. H., Pappot, H., . . . Adamsen,
L. (2012). Safety and feasibility of a combined exercise intervention for
inoperable lung cancer patients undergoing chemotherapy: A pilot study. Lung
Cancer, 75(2), 203-208. doi:10.1016/j.lungcan.2011.07.006
Ream, E., & Richardson, A. (1997). Fatigue in patients with cancer and chronic
obstructive airways disease: a phenomenological enquiry. International Journal
of Nursing Studies, 34(1), 44-53.
Reid, M. B., & Moylan, J. S. (2011). Beyond atrophy: redox mechanisms of muscle
dysfunction in chronic inflammatory disease. The Journal of Physiology, 589(9),
2171-2179.
Reis, C., Liberman, S., Pompeo, A. C., Srougi, M., Halpern, A., & Jacob Filho, W.
(2009). Body composition alterarions, energy expenditure and fat oxidation in
elderly males suffering from prostate cancer, pre and post orchiectomy. Clinics,
64(8), 781-784.
Rubin, P., & Casarett, G. W. (1968). Clinical Radiation Pathology. Volume II.
Ryan, J. L., Carroll, J. K., Ryan, E. P., Mustian, K. M., Fiscella, K., & Morrow, G. R.
(2007). Mechanisms of cancer-related fatigue. The Oncologist, 12(1), 22-34.
131
Sakuma, K., & Yamaguchi, A. (2012). Sarcopenia and cachexia: The adaptations of
negative regulators of skeletal muscle mass. Journal of Cachexia: Sarcopenia and
Muscle, 3(2), 77-94.
Saligan, L. N., Olson, K., Filler, K., Larkin, D., Cramp, F., Sriram, Y., . . . Kamath, J.
(2015). The biology of cancer-related fatigue: A review of the literature.
Supportive Care in Cancer, 23(8), 2461-2478.
Saltin, B., & Gollnick, P. D. (1983). Skeletal muscle adaptability: Significance for
metabolism and performance. Comprehensive Physiology.
Saltin, B., Nazar, K., Costill, D., Stein, E., Jansson, E., Essén, B., & Gollnick, P. (1976).
The nature of the training response; peripheral and central adaptations to one‐
legged exercise. Acta Physiologica Scandinavica, 96(3), 289-305.
Schmidt, M. E., Chang-Claude, J., Vrieling, A., Heinz, J., Flesch-Janys, D., & Steindorf,
K. (2012). Fatigue and quality of life in breast cancer survivors: Temporal courses
and long-term pattern. Journal of Cancer Survivorship, 6(1), 11-19.
Schmidt, M. E., Wiskemann, J., Armbrust, P., Schneeweiss, A., Ulrich, C. M., &
Steindorf, K. (2015). Effects of resistance exercise on fatigue and quality of life in
breast cancer patients undergoing adjuvant chemotherapy: A randomized
controlled trial. International Journal of Cancer, 137(2), 471-480.
Schmidt, M. E., Wiskemann, J., Krakowski-Roosen, H., Knicker, A. J., Habermann, N.,
Schneeweiss, A., . . . Steindorf, K. (2013). Progressive resistance versus
relaxation training for breast cancer patients during adjuvant chemotherapy:
Design and rationale of a randomized controlled trial (BEATE study).
132
Contemporary Clinical Trials, 34(1), 117-125.
doi:http://dx.doi.org/10.1016/j.cct.2012.10.006
Schmitz, K. H., Ahmed, R. L., Troxel, A., Cheville, A., Smith, R., Lewis-Grant, L., . . .
Greene, Q. P. (2009). Weight lifting in women with breast-cancer–related
lymphedema. New England Journal of Medicine, 361(7), 664-673.
Schmitz, K. H., Courneya, K. S., Matthews, C., Demark-Wahnefried, W., Galvao, D. A.,
Pinto, B. M., . . . American College of Sports, M. (2010a). American College of
Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine
& Science in Sports & Exercise, 42(7), 1409-1426.
doi:10.1249/MSS.0b013e3181e0c112
Schneider, C. M., Hsieh, C. C., Sprod, L. K., Carter, S. D., & Hayward, R. (2007a).
Effects of supervised exercise training on cardiopulmonary function and fatigue in
breast cancer survivors during and after treatment. Cancer, 110(4), 918-925.
Schneider, C. M., Hsieh, C. C., Sprod, L. K., Carter, S. D., & Hayward, R. (2007b).
Exercise training manages cardiopulmonary function and fatigue during and
following cancer treatment in male cancer survivors. Integrative Cancer
Therapies, 6(3), 235-241.
Schwartz, A. L. (2003). Schwartz cancer fatigue scale. Measurement of Nursing
Outcomes: Volume 2, Client Outcomes and Quality of Care, 2, 114.
Schwartz, A. L., & Winters-Stone, K. (2009). Effects of a 12-month randomized
controlled trial of aerobic or resistance exercise during and following cancer
treatment in women. Physician and Sports Medicine, 37(3), 62-67.
doi:10.3810/psm.2009.10.1730
133
Schwartz, A. L., Winters-Stone, K., & Gallucci, B. (2007). Exercise effects on bone
mineral density in women with breast cancer receiving adjuvant chemotherapy.
Oncology Nursing Forum, 34(3), 627-633. doi:10.1188/07.onf.627-633
Schwartz, R. S., Shuman, W. P., Larson, V., Cain, K. C., Fellingham, G. W., Beard, J. C.,
. . . Abrass, I. B. (1991). The effect of intensive endurance exercise training on
body-fat distribution in young and older men. Metabolism-Clinical and
Experimental, 40(5), 545-551. doi:10.1016/0026-0495(91)90239-s
Segal, R. J., Reid, R. D., Courneya, K. S., Malone, S. C., Parliament, M. B., Scott, C. G.,
. . . D’Angelo, M. E. S. (2003). Resistance exercise in men receiving androgen
deprivation therapy for prostate cancer. Journal of Clinical Oncology, 21(9),
1653-1659.
Segal, R. J., Reid, R. D., Courneya, K. S., Sigal, R. J., Kenny, G. P., Prud'Homme, D. G.,
. . . Slovinec D'Angelo, M. E. (2009). Randomized controlled trial of resistance or
aerobic exercise in men receiving radiation therapy for prostate cancer. Journal of
Clinical Oncology, 27(3), 344-351. doi:10.1200/jco.2007.15.4963
Seyidova-Khoshknabi, D., Davis, M. P., & Walsh, D. (2010). A systematic review of
cancer-related fatigue measurement questionnaires. American Journal of Hospice
and Palliative Medicine, 1049909110381590.
Short, K. R., Vittone, J. L., Bigelow, M. L., Proctor, D. N., & Nair, K. S. (2004). Age and
aerobic exercise training effects on whole body and muscle protein metabolism.
American Journal of Physiology - Endocrinology and Metabolism, 286(1), E92E101. doi:10.1152/ajpendo.00366.2003
134
Siegel, R., Ma, J., Zou, Z., & Jemal, A. (2014). Cancer statistics, 2014. CA: A Cancer
Journal for Clinicians, 64(1), 9-29.
Siegel, R. L., DeSantis, C., Virgo, K., Stein, K., Mariotto, A., Smith, T., . . . Fedewa, S.
(2012). Cancer treatment and survivorship statistics, 2012. CA: A Cancer Journal
for Clinicians, 62(4), 220-241.
Siegel, R. L., Ma, J., Zou, Z., & Jemal, A. (2014). Cancer statistics, 2014. CA: A Cancer
Journal for Clinicians, 64(1), 9-29.
Siegel, R. L., Miller, K. D., & Jemal, A. (2015). Cancer statistics, 2016. CA: A Cancer
Journal for Clinicians.
Sipila, S., & Suominen, H. (1995). Effects of strength and endurance training on thigh
and leg muscle mass and composition in elderly women. Journal of Applied
Physiology, 78(1), 334-340.
Skipworth, R. J., Stewart, G. D., Dejong, C. H., Preston, T., & Fearon, K. C. (2007).
Pathophysiology of cancer cachexia: Much more than host–tumour interaction?
Clinical Nutrition, 26(6), 667-676.
Smets, E. M. A., Garssen, B., Bonke, B., & Dehaes, J. (1995). The multidimensional
fatigue inventori (MFI) psychometric qualities of an instrument to assess fatigue.
Journal of Psychosomatic Research, 39(3), 315-325. doi:10.1016/00223999(94)00125-o
Smith, H. J., Lorite, M. J., & Tisdale, M. J. (1999). Effect of a cancer cachectic factor on
protein synthesis/degradation in murine C2C12 myoblasts: Modulation by
eicosapentaenoic acid. Cancer Research, 59(21), 5507-5513.
135
Smith, K., & Tisdale, M. (1993). Increased protein degradation and decreased protein
synthesis in skeletal muscle during cancer cachexia. British Journal of Cancer,
67(4), 680.
Speck, R. M., Courneya, K. S., Masse, L. C., Duval, S., & Schmitz, K. H. (2010). An
update of controlled physical activity trials in cancer survivors: A systematic
review and meta-analysis. Journal of Cancer Survivorship, 4(2), 87-100.
doi:10.1007/s11764-009-0110-5
Sprod, L. K., Hsieh, C. C., Hayward, R., & Schneider, C. M. (2010). Three versus six
months of exercise training in breast cancer survivors. Breast Cancer Research
and Treatment, 121(2), 413-419. doi:10.1007/s10549-010-0913-0
Staron, R., Karapondo, D., Kraemer, W., Fry, A., Gordon, S. E., Falkel, J., . . . Hikida, R.
(1994). Skeletal muscle adaptations during early phase of heavy-resistance
training in men and women. Journal of Applied Physiology, 76(3), 1247-1255.
Stein, K. D., Martin, S. C., Hann, D. M., & Jacobsen, P. B. (1998). A multidimensional
measure of fatigue for use with cancer patients. Cancer Practice, 6(3), 143-152.
doi:10.1046/j.1523-5394.1998.006003143.x
Steindorf, K., Schmidt, M., Klassen, O., Ulrich, C., Oelmann, J., Habermann, N., . . .
Wiskemann, J. (2014). Randomized, controlled trial of resistance training in
breast cancer patients receiving adjuvant radiotherapy: Results on cancer-related
fatigue and quality of life. Annals of Oncology, 25(11), 2237-2243.
Stene, G., Helbostad, J., Balstad, T., Riphagen, I., Kaasa, S., & Oldervoll, L. (2013).
Effect of physical exercise on muscle mass and strength in cancer patients during
136
treatment—a systematic review. Critical Reviews in Oncology/Hematology,
88(3), 573-593.
Stephens, N. A., Gray, C., MacDonald, A. J., Tan, B. H., Gallagher, I. J., Skipworth, R.
J., . . . Greig, C. A. (2012). Sexual dimorphism modulates the impact of cancer
cachexia on lower limb muscle mass and function. Clinical Nutrition, 31(4), 499505.
Stevinson, C., Lawlor, D. A., & Fox, K. R. (2004). Exercise interventions for cancer
patients: systematic review of controlled trials. Cancer Causes & Control, 15(10),
1035-1056.
Stone, P., Hardy, J., Broadley, K., Kurowska, A., & A'Hern, R. (1999). Fatigue in
advanced cancer: a prospective controlled cross-sectional study. British Journal of
Cancer, 79(9-10), 1479.
Stone, P., Richards, M., A'hern, R., & Hardy, J. (2000). A study to investigate the
prevalence, severity and correlates of fatigue among patients with cancer in
comparison with a control group of volunteers without cancer. Annals of
Oncology, 11(5), 561-567.
Stone, P. C., & Minton, O. (2008). Cancer-related fatigue. European Journal of Cancer,
44(8), 1097-1104. doi:10.1016/j.ejca.2008.02.037
Stone, P. C., Richards, M., & Hardy, J. (1998). Fatigue in patients with cancer. European
Journal of Cancer, 34(11), 1670-1676.
Strasser, B., Steindorf, K., Wiskemann, J., & Ulrich, C. M. (2013). Impact of resistance
training in cancer survivors: a meta-analysis. Medicine & Science in Sports &
Exercise, 45(11), 2080-2090.
137
Strelkov, A. B., Fields, A., & Baracos, V. E. (1989). Effects of systemic inhibition of
prostaglandin production on protein metabolism in tumor-bearing rats. American
Journal of Physiology-Cell Physiology, 257(2), C261-C269.
Taylor, A. W., & Bachman, L. (1999). The effects of endurance training on muscle fibre
types and enzyme activities. Canadian Journal of Applied Physiology, 24(1), 4153. doi:10.1139/h99-005
Thorsen, L., Nilsen, T. S., Raastad, T., Courneya, K. S., Skovlund, E., & Fossa, S. D.
(2012). A randomized controlled trial on the effectiveness of strength training on
clinical and muscle cellular outcomes in patients with prostate cancer during
androgen deprivation therapy: Rationale and design. BMC Cancer, 12, 123.
doi:10.1186/1471-2407-12-123
Tian, L., Lu, H. J., Lin, L., & Hu, Y. (2016). Effects of aerobic exercise on cancer-related
fatigue: A meta-analysis of randomized controlled trials. Supportive Care in
Cancer, 24(2), 969-983.
Tisdale, M. J. (1997). Biology of cachexia. Journal of the National Cancer Institute,
89(23), 1763-1773.
Toth, M. J., Miller, M. S., Callahan, D. M., Sweeny, A. P., Nunez, I., Grunberg, S. M., . .
. Dittus, K. (2013). Molecular mechanisms underlying skeletal muscle weakness
in human cancer: Reduced myosin-actin cross-bridge formation and kinetics.
Journal of Applied Physiology, 114(7), 858-868.
doi:10.1152/japplphysiol.01474.2012
Trutschnigg, B., Kilgour, R. D., Reinglas, J., Rosenthall, L., Hornby, L., Morais, J. A., &
Vigano, A. (2008). Precision and reliability of strength (Jamar vs. Biodex
138
handgrip) and body composition (dual-energy X-ray absorptiometry vs.
bioimpedance analysis) measurements in advanced cancer patients. Applied
Physiology, Nutrition, and Metabolism, 33(6), 1232-1239.
van Waart, H., Stuiver, M. M., van Harten, W. H., Geleijn, E., Kieffer, J. M., Buffart, L.
M., . . . Aaronson, N. K. (2015). Effect of low-intensity physical activity and
moderate to high-intensity physical exercise during adjuvant chemotherapy on
physical fitness, fatigue, and chemotherapy completion rates: Results of the
PACES Randomized Clinical Trial. Journal of Clinical Oncology, 33(17), 19181927. doi:10.1200/jco.2014.59.1081
van Weert, E., Hoekstra-Weebers, J., Otter, R., Postema, K., Sanderman, R., & van der
Schans, C. (2006). Cancer-related fatigue: Predictors and effects of rehabilitation.
The Oncologist, 11(2), 184-196.
Vardar Yagli, N., Sener, G., Arikan, H., Saglam, M., Inal Ince, D., Savci, S., . . . Ozisik,
Y. (2015). Do yoga and aerobic exercise training have impact on functional
capacity, fatigue, peripheral muscle strength, and quality of life in breast cancer
survivors? Integrative Cancer Therapies, 14(2), 125-132.
doi:10.1177/1534735414565699
Vaupel, P., Kallinowski, F., & Okunieff, P. (1989). Blood flow, oxygen and nutrient
supply, and metabolic microenvironment of human tumors: a review. Cancer
Research, 49(23), 6449-6465.
Velthuis, M. J., Agasi-Idenburg, S. C., Aufdemkampe, G., & Wittink, H. M. (2010). The
effect of physical exercise on cancer-related fatigue during cancer treatment: A
139
meta-analysis of randomised controlled trials. Clinical Oncology, 22(3), 208-221.
doi:10.1016/j.clon.2009.12.005
Verney, J., Kadi, F., Saafi, M. A., Piehl-Aulin, K., & Denis, C. (2006). Combined lower
body endurance and upper body resistance training improves performance and
health parameters in healthy active elderly. European Journal of Applied
Physiology, 97(3), 288-297. doi:10.1007/s00421-006-0175-z
Visser, M., & Smets, E. (1998). Fatigue, depression and quality of life in cancer patients:
how are they related? Supportive Care in Cancer, 6(2), 101-108.
Vollestad, N. K. (1997). Measurement of human muscle fatigue. Journal of Neuroscience
Methods, 74(2), 219-227.
Von Hoff, D. D., Layard, M. W., Basa, P., Davis, H. L., Von Hoff, A. L., Rozencweig,
M., & Muggia, F. M. (1979). Risk factors for doxorubicin-induced congestive
heart failure. Annals of Internal Medicine, 91(5), 710-717.
Wagner, L., & Cella, D. (2004). Fatigue and cancer: Causes, prevalence and treatment
approaches. British Journal of Cancer, 91(5), 822-828.
Wang, N., Hikida, R. S., Staron, R. S., & Simoneau, J.-A. (1993). Muscle fiber types of
women after resistance training—quantitative ultrastructure and enzyme activity.
Pflügers Archiv, 424(5-6), 494-502.
Wang, X. S. (2008). Pathophysiology of cancer-related fatigue. Clinical Journal of
Oncology Nursing, 12, 11-20.
Warburg, O., Wind, F., & Negelein, E. (1927). The metabolism of tumors in the body.
The Journal of General Physiology, 8(6), 519-530.
140
Weber, M. A., Kinscherf, R., Krakowski-Roosen, H., Aulmann, M., Renk, H., Künkele,
A., . . . Hildebrandt, W. (2007). Myoglobin plasma level related to muscle mass
and fiber composition–a clinical marker of muscle wasting? Journal of Molecular
Medicine, 85(8), 887-896.
Weber, M. A., Krakowski-Roosen, H., Schröder, L., Kinscherf, R., Krix, M., KoppSchneider, A., . . . Hildebrandt, W. (2009). Morphology, metabolism,
microcirculation, and strength of skeletal muscles in cancer-related cachexia. Acta
Oncologica, 48(1), 116-124.
Weis, J., & Horneber, M. (2014). Cancer-Related Fatigue: Springer.
Weis, J., & Horneber, M. (2015). Etiology and Pathogenesis of Cancer-Related Fatigue
Cancer-Related Fatigue (pp. 11-17): Springer.
Wigmore, S. J., Barber, M. D., Ross, J. A., Tisdale, M. J., & Fearon, K. C. (2000). Effect
of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer.
Nutrition and Cancer, 36(2), 177-184.
Wilcock, A., Maddocks, M., Lewis, M., Howard, P., Frisby, J., Bell, S., . . . Mockett, S.
(2008). Use of a Cybex NORM dynamometer to assess muscle function in
patients with thoracic cancer. BMC Palliative Care, 7(1), 3.
Williams, C. A., & Ratel, S. (2009). Definitions of muscle fatigue. Human Muscle
Fatigue, 3-16.
Williams, J. P., Phillips, B. E., Smith, K., Atherton, P. J., Rankin, D., Selby, A. L., . . .
Rennie, M. J. (2012). Effect of tumor burden and subsequent surgical resection on
skeletal muscle mass and protein turnover in colorectal cancer patients. American
Journal of Clinical Nutrition, 96(5), 1064-1070.
141
Winters-Stone, K. M., Bennett, J. A., Nail, L., & Schwartz, A. (2008). Strength, physical
activity, and age predict fatigue in older breast cancer survivors. Paper presented
at the Oncol Nurs Forum.
Winters-Stone, K. M., Dobek, J., Bennett, J. A., Nail, L. M., Leo, M. C., & Schwartz, A.
(2012). The effect of resistance training on muscle strength and physical function
in older, postmenopausal breast cancer survivors: a randomized controlled trial.
Journal of Cancer Survivorship, 6(2), 189-199. doi:10.1007/s11764-011-0210-x
Wiskemann, J., Dreger, P., Schwerdtfeger, R., Bondong, A., Huber, G., Kleindienst, N., .
. . Bohus, M. (2011). Effects of a partly self-administered exercise program
before, during, and after allogeneic stem cell transplantation. Blood, 117(9), 26042613. doi:10.1182/blood-2010-09-306308
Woledge, R. C., Curtin, N. A., & Homsher, E. (1985). Energetic aspects of muscle
contraction. Monographics of the Physiological Society, 41, 1-357.
Wolin, K. Y., Schwartz, A. L., Matthews, C. E., Courneya, K. S., & Schmitz, K. H.
(2012). Implementing the exercise guidelines for cancer survivors. Journal of
Supportive Oncology, 10(5), 171-177. doi:10.1016/j.suponc.2012.02.001
Wu, H. S., & McSweeney, M. (2004). Assessing fatigue in persons with cancer. Cancer,
101(7), 1685-1695.
Wyrick, K., & Davis, A. (2009). Exercise for the management of cancer-related fatigue.
American Family Physician, 80(7), 689.
Yavuzsen, T., Davis, M. P., Ranganathan, V. K., Walsh, D., Siemionow, V., Kirkova, J., .
. . Yue, G. H. (2009). Cancer-related fatigue: Central or peripheral? Journal of
142
Pain and Symptom Management, 38(4), 587-596.
doi:10.1016/j.jpainsymman.2008.12.003
Yellen, S. B., Cella, D. F., Webster, K., Blendowski, C., & Kaplan, E. (1997). Measuring
fatigue and other anemia-related symptoms with the functional assessment of
cancer therapy (FACT) measurement system. Journal of Pain and Symptom
Management, 13(2), 63-74. doi:10.1016/s0885-3924(96)00274-6
Yoshikawa, T., Noguchi, Y., Doi, C., Makino, T., & Nomura, K. (2001). Insulin
resistance in patients with cancer: Relationships with tumor site, tumor stage,
body-weight loss, acute-phase response, and energy expenditure. Nutrition, 17(7),
590-593.
Zampieri, S., Doria, A., Adami, N., Biral, D., Vecchiato, M., Savastano, S., . . .
Merigliano, S. (2010). Subclinical myopathy in patients affected with newly
diagnosed colorectal cancer at clinical onset of disease: Evidence from skeletal
muscle biopsies. Neurological Research, 32(1), 20-25.
Zhang, S., Liu, X., Bawa-Khalfe, T., Lu, L.-S., Lyu, Y. L., Liu, L. F., & Yeh, E. T.
(2012). Identification of the molecular basis of doxorubicin-induced
cardiotoxicity. Nature Medicine, 18(11), 1639-1642.
Zhang, Y.-W., Shi, J., Li, Y.-J., & Wei, L. (2009). Cardiomyocyte death in doxorubicininduced cardiotoxicity. Archivum Immunologiae et Therapiae Experimentalis,
57(6), 435-445.
Zoico, E., & Roubenoff, R. (2002). The role of cytokines in regulating protein
metabolism and muscle function. Nutrition Reviews, 60(2), 39-51.
143
Zou, L.-Y., Yang, L., He, X.-L., Sun, M., & Xu, J.-J. (2014). Effects of aerobic exercise
on cancer-related fatigue in breast cancer patients receiving chemotherapy: A
meta-analysis. Tumor Biology, 35(6), 5659-5667.
144
APPENDIX A
INSTITUTIONAL REVIEW BOARD
DOCUMENTS
145
146
147
148
149
APPENDIX B
UNIVERSITY OF NORTHERN COLORADO CANCER
REHABILITATION INSITUTE INFORMED CONSENT
150
151
152
APPENDIX C
STUDY INFORMED CONSENT
153
154
155
APPENDIX D
REVISED PIPER FATIGUE SCALE
156
157
158