al-majid-et-al-2014-effects-of-exercise-on-biobehavioral-outcomes-of-fatigue-during-cancer-treatment-results-of-a

Article
Effects of Exercise on Biobehavioral
Outcomes of Fatigue During Cancer
Treatment: Results of a Feasibility Study
Biological Research for Nursing
2015, Vol. 17(1) 40-48
ª The Author(s) 2014
Reprints and permission:
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DOI: 10.1177/1099800414523489
brn.sagepub.com
Sadeeka Al-Majid, RN, PhD1, Lori D. Wilson, PhD2,
Cyril Rakovski, PhD3, and Jared W. Coburn, PhD4
Abstract
Cancer treatment is associated with decreased hemoglobin (Hb) concentration and aerobic fitness (VO2 max), which may contribute
to cancer-related fatigue (CRF) and decreased quality of life (QoL). Endurance exercise may attenuate CRF and improve QoL, but
the mechanisms have not been thoroughly investigated. Objectives. To (a) determine the feasibility of conducting an exercise intervention among women receiving treatment for breast cancer; (b) examine the effects of exercise on Hb and VO2 max and determine
their association with changes in CRF and QoL; and (c) investigate changes in selected inflammatory markers. Methods. Fourteen
women receiving chemotherapy for Stages I–II breast cancer were randomly assigned to exercise (n ¼ 7) or usual care (n ¼ 7).
Women in the exercise group performed supervised, individualized treadmill exercise 2–3 times/week for the duration of chemotherapy (9–12 weeks). Data were collected 4 times over 15–16 weeks. Results. Recruitment rate was 45.7%. Sixteen women
consented and 14 completed the trial, for a retention rate of 87.5%. Adherence to exercise protocol was 95–97%, and completion
of data collection was 87.5–100%. Exercise was well tolerated. VO2 max was maintained at prechemotherapy levels in exercisers but
declined in the usual-care group (p < .05). Hb decreased (p < .001) in all participants as they progressed through chemotherapy.
Exercise did not have significant effects on CRF or QoL. Changes in inflammatory markers favored the exercise group. Conclusions.
Exercise during chemotherapy may protect against chemotherapy-induced decline in VO2 max but not Hb concentration.
Keywords
exercise, chemotherapy, biobehavioral, breast cancer
Cancer-related fatigue (CRF) is the most frequently reported
symptom by persons with cancer (Cheng & Yeung, 2013; Siefert, 2010), afflicting up to 94% of women receiving treatment
for breast cancer (Li & Yuan, 2011). CRF interferes with a
patient’s ability to fully engage in leisure and normal daily
activities, leading to poor quality of life (QoL; Gupta, Lis, &
Grutsch, 2007). Researchers have suggested the use of endurance exercise to decrease CRF and improve QoL in women
undergoing chemotherapy for breast cancer (Ligibel et al.,
2010). However, studies about the specific mechanisms
through which exercise may mitigate CRF are scarce. Such
studies might lead to the development of specific exercise programs that target these mechanisms.
Although the mechanisms underlying CRF remain to be elucidated (McMillan & Newhouse, 2011), evidence suggests that
CRF is a complex multifactorial phenomenon caused by a multitude of biobehavioral mechanisms (Al-Majid & Gray, 2009;
McMillan & Newhouse, 2011; Ryan et al., 2007). Some of
these mechanisms include decreased hemoglobin (Hb) concentration (Dolan et al., 2010), decreased aerobic fitness (VO2 max;
Davis & Walsh, 2010), and upregulation of inflammatory mediators (Wang et al., 2012).
Research has documented low Hb in patients receiving chemotherapy and revealed an association with CRF (Romito,
Montanaro, Corvasce, Di Bisceglie, & Mattioli, 2008): higher
Hb levels are associated with lower CRF and higher energy
level and QoL (Boccia, Lillie, Tomita, & Balducci, 2007). Evidence about the effect of endurance exercise on Hb level during
chemotherapy is inconclusive: some authors have reported a
positive relationship (Drouin et al., 2006), while others have
reported no relationship (Dolan et al., 2010).
1
School of Nursing, California State University, Fullerton, CA, USA
Department of Kinesiology, California State University, Long Beach, Long
Beach, CA, USA
3
Schmid College of Science & Technology, Chapman University, Orange,
CA, USA
4
Kinesiology Department, California State University, Fullerton, Fullerton,
CA, USA
2
Corresponding Author:
Sadeeka Al-Majid, RN, PhD, School of Nursing, California State University, 800
N State College Blvd, Fullerton, CA 92831, USA.
Email: [email protected]
Al-Majid et al.
41
Table 1. Exercise Protocol.
Program stage
Week
Exercise frequency (sessions/week)
Exercise intensity (% HRR)
Exercise duration (min)
Initial
1
2–3
4–12
2
2–3
2–3
40–50
50–70
70–80
20
30
30–40
Improvement
Note. % HRR ¼ percent heart rate reserve.
VO2 max, an excellent indicator of aerobic capacity, is approximately 30% lower in cancer patients than in age- and sex-matched
sedentary individuals who do not have a history of cancer
(Haykowski, Mackey, Thompson, Jones, & Paterson, 2009; Jones
et al., 2011). Decreased VO2 max reflects reduced exercise capacity,
which may contribute to CRF (Vincent et al., 2013). Endurance
exercise during chemotherapy may increase VO2 max (Dolan
et al., 2010; Vincent et al., 2013). However, it is not clear if this
increase in VO2 max is attributable to improvement in Hb level.
Levels of the proinflammatory cytokine interleukin-6 (IL-6)
increase during cancer treatment. Researchers have suggested
that this increase contributes to CRF (Liu et al., 2012; Wang
et al., 2012). In individuals without cancer, endurance exercise
training lowers resting levels of IL-6 (Reyes-Gibby et al.,
2013), possibly by increasing the level of the anti-inflammatory
cytokine IL-10 (Walsh et al., 2011). It is not known whether
endurance training has similar effects on IL-6 and IL-10 in
patients receiving treatment for breast cancer.
Additionally, the stress hormone cortisol is associated with
chronic inflammatory diseases including cancer (Edwards,
2012). Compared to healthy individuals, patients receiving
chemotherapy have higher levels of cortisol and lower levels
of myeloperoxidase (MPO), a marker of oxidative stress (Limberaki et al., 2011). These findings suggest that chemotherapy
might decrease antioxidant capacity. Endurance exercise training is thought to improve antioxidant status in healthy individuals (Finaud, Lac, & Filaire, 2006). Whether this response to
endurance exercise occurs during chemotherapy is not known.
Few studies have examined the effect of exercise on the
mechanisms underlying CRF in patients receiving chemotherapy. Many of those who have focused on cancer survivors used
home-based exercise protocols and/or did not use comparison
groups. In the present study, we examined the feasibility and
efficacy of a structured, supervised endurance exercise program in women undergoing chemotherapy for early-stage
breast cancer. Our specific aims were to (a) determine the feasibility of the exercise intervention in terms of recruitment,
retention, adherence to the exercise protocol, tolerance of exercise testing and completion of data collection; (b) examine the
effects of the exercise program on Hb and VO2 max and
determine their association with changes in CRF and QoL; and
(c) investigate changes in selected inflammatory markers.
Method
Design, Sample, and Setting
We used a prospective, repeated measures, randomized design.
We recruited participants from two cancer centers in Central
Virginia and Southern California, whose institutional review
boards both approved the study. Patients eligible to participate
included women aged 21 years or older diagnosed with Stage I
or II breast cancer who were scheduled to receive chemotherapy, spoke and read English, and were willing to be randomly
assigned to either group. Consistent with the exclusion criteria
stipulated by the American College of Sports Medicine
(Saxton, 2011), patients who had recent or uncontrolled cardiac
conditions were excluded. Other exclusion criteria included
self-reported history of unstable or severe clinical depression,
activity-limiting arthritis, having had joint surgery within the
previous 3 months, and having been engaged in regular exercise (5 days per week) in the past 3 months.
Eligible patients were informed about the study by referring
oncologists and were approached by study staff who invited them
to participate. Women who consented were scheduled for baseline data collection (T1). Following T1, women were randomly
assigned to the exercise (n ¼ 7) or usual care (n ¼ 7) group.
The exercise sessions took place in the rehabilitation facility
within the cancer center and were supervised by a qualified
exercise physiologist or physical therapist familiarized with the
exercise protocol. There was flexibility in scheduling exercise
sessions to accommodate participant availability. Participants
were allowed to make up missed exercise sessions.
Exercise Protocol
The exercise protocol (Table 1) consisted of supervised treadmill exercise with an individualized progressive increase in
workload (speed, incline, and duration). All participants underwent baseline exercise testing to determine their initial
VO2 max. Exercise started within 1 week of the first cycle of
chemotherapy and ended with the completion of chemotherapy
(9–12 weeks). During the first week, participants exercised for
20 min per session at a heart rate that corresponded to an intensity of 50–60% of maximal heart rate, which was determined
via VO2 max measurement. As shown in Table 1, workload was
increased progressively during subsequent weeks until participants achieved a heart rate that corresponded to an intensity of
70–80% of maximal heart rate. All exercisers were able to
achieve target intensity by Week 5 (range 4–5 weeks). Each
exercise session started with a 5-min warm-up and ended with
a 5-min cooldown. While there were occasional fluctuations in
the frequency, intensity, and duration of the exercise over the
course of the study, all exercisers were able to exercise per protocol. Participants completed an average of 32 sessions (range
26–39) at an average incline of 7% (range 5–12%) and average
speed of 3.4 mph (range 2.5–3.7).
42
Biological Research for Nursing 17(1)
Table 2. Data Collection Timeline.
Group
Exercise
T1
Exercise and chemo
!
4.5–6 weeks
T2
Exercise and chemo
!
4.5–6 weeks
T3
Chemo
!
4.5–6 weeks
T2
chemo
!
4.5–6 weeks
T3
!
3–4 weeks
T4
R
Usual care
T1
!
3–4 weeks
T4
Note. N ¼ 14. chemo ¼ chemotherapy; R ¼ randomization; T1 ¼ Time 1, baseline before chemotherapy and exercise; T2 ¼ Time 2, after second cycle of chemotherapy; T3 ¼ Time 3, at the completion of chemotherapy and exercise program; T4 ¼ Time 4, 3–4 weeks after completion of chemotherapy and exercise.
Participants in the usual-care group received usual care,
which did not involve exercise, and were instructed to document and report any exercise activities they engaged in while
on the study. Similarly, we asked exercise-group participants
to report engagement in nonprotocol exercise activities during
the study.
Outcome Measures and Data Collection
Feasibility outcomes included recruitment, retention, adherence to exercise protocol, tolerance of exercise testing and
completion of data collection. Recruitment rate was defined
as the number of women consented divided by the number of
those eligible to participate. Retention was defined as the number of women who completed the trial out of those consented.
Adherence to exercise protocol was calculated as the number of
exercise sessions completed as per protocol out of the total
number of scheduled sessions. Tolerance of exercise testing
was defined as ability to complete VO2 max testing. Completion
of data collection was defined as the number of completed data
collection time points divided by the total number of scheduled
data collection time points.
Efficacy outcomes included Hb concentration, VO2 max,
CRF, QoL, and select inflammatory markers. We assessed all
outcome measures, except inflammatory markers, in all participants (exercise and usual care) four times during the study
(Table 2). Time 1 (T1) data (baseline) were collected at the
time of enrollment in the study, prior to randomization and first
chemotherapy cycle. Time 2 (T2) data were collected after
patients completed two chemotherapy cycles. Time 3 (T3) data
were collected within 1 week after patients completed chemotherapy. Postintervention data (T4) were collected 3–4
weeks following completion of the exercise program, which
coincided with the completion of chemotherapy. Inflammatory
markers were assessed in a subsample of six participants (three
exercisers and three usual care) at baseline and within 1 week
after the last cycle of chemotherapy.
Aerobic fitness. Maximal oxygen (O2) consumption (VO2 max)
was measured using a motorized treadmill (Trackmaster,
TM500/S; JAS Fitness Systems, Carrollton, TX). Each participant wore a nose clip and breathed through a two-way valve
(2700; Hans Rudolph, Kansas City, MO). Expired gas samples
were continuously collected throughout the test and were analyzed using a calibrated TrueMax 2400 metabolic cart (Parvo
Medics, Sandy, UT) with O2, carbon dioxide, and ventilatory
parameters expressed as 20-s averages. Heart rate was monitored throughout the test with the Polar Heart Watch system
(Polar Electro Inc., Lake Success, NY). A Bruce protocol was
used for testing, with occasional modifications based on exercise tolerance. VO2 max was defined as the highest value
recorded during the last 30 s of the test. The test was terminated
if the participant met at least two of the following three criteria:
(a) 90% of age-predicted heart rate (220—age); (b) Borg rating
of 18; or (c) inability to maintain the exercise intensity despite
verbal encouragement.
Hb concentration. Hb concentration was measured in venous
blood using a clinically performed complete blood count,
which was conducted at the cancer center where chemotherapy
treatment was administered. Blood samples were drawn in the
morning of each data-collection visit.
CRF. CRF was measured using the revised Piper Fatigue Scale
(PFS). The PFS is a 22-item scale that measures four dimensions
(behavioral/severity, sensory, cognitive, and affective meaning)
of subjective fatigue on a scale of 0 (no fatigue) to10 (extreme
fatigue), where participants circle the number that best describes
their current fatigue experience. The PFS was validated in breast
cancer patients with internal consistency (Cronbach’s a coefficients) ranging from .92 to .98 (Piper et al., 1998).
QoL. QoL was measured using the Functional Assessment of
Cancer Therapy–Breast (FACT-B) questionnaire-Version 4
(Brady et al. 1997). This 37-item self-reporting instrument consists of five subscales including 27 general QoL questions and
10 breast-cancer–specific questions. The general QoL questions are divided into four subscales: physical well-being,
social well-being, emotional well-being, and functional wellbeing. The breast-cancer–specific scale asks how bothered participants are by symptoms such as pain, hair loss, weight
change, and shortness of breath. Using a 5-point scale, participants rate how true each statement has been for them during the
past 7 days. The FACT-B total score ranges from 0 to 144, with
higher numbers indicating better QoL. Total score is calculated
by summing all subscale scores. The a coefficient is .90 for the
Al-Majid et al.
43
Table 3. Baseline Demographic Characteristics of Study Participants.
Variable
Age, years
Cancer stage
Ethnicity
Hispanic
Non-Hispanic
Marital status
Married
Unmarried
Education
<High school
High school
Technical school
College
Postcollege
Employment
Employed
Unemployed
Exercise group (n ¼ 7)
n (%) or M + SD
Control group (n ¼ 7)
n (%) or M + SD
47.9 + 10.4
2.0 + 0.5
52.7 + 10.7
1.6 + 0.6
2 (28.6)
5 (71.4)
2 (28.6)
5 (71.4)
5 (71.4)
2 (28.6)
3 (42.9)
4 (57.1)
1 (14.3)
1 (14.3)
0 (0.0)
2 (28.6)
3 (42.9)
0 (0.0)
3 (42.9)
3 (42.9)
0 (0.0)
1 (14.3)
4 (57.1)
3 (42.9)
t
p
0.9
1.2
—
.41
.26
1.00a
—
.59a
—
.37a
—
.91a
5 (71.4)
2 (28.6)
a
p-values based on exact two-sample multinomial test.
entire instrument and ranges from .63 to .86 for the subscales
(Brady et al., 1997).
Select inflammatory markers. Inflammatory markers were measured in plasma samples obtained at baseline (T1) and within a
week of patients having completed chemotherapy (T3). Highsensitivity immunoassay quantification kits were used as follows:
IL-6 and IL-10 were measured using kits by R&D Technologies
(North Kingstown, Rhode Island, USA), cortisol was measured
using IBL International (Toronto, Ontario, Canada), and MPO
was measured using Northwest Life (Toronto, Ontario, Canada).
The sensitivity of the tests were as follows: IL-6 (0.016 pg/ml),
IL-10 (0.5 pg/ml), cortisol (2.5 ng/ml) and MPO (0.4 ng/ml).
Due to known diurnal variations in some of the biomarkers,
blood samples were collected at 9:00 a.m. via standard phlebotomy procedures. Participants were instructed not to exercise
the morning of blood collection. Blood samples were centrifuged within 2 hr of acquisition and separated plasma was
stored at 80 C for batch analysis. Plasma samples were
thawed only once and run in duplicates.
Data Analysis
Analysis of group differences for demographic characteristics
was performed using a two-sample t-test (for age) and the exact
two-sample multinomial test for all categorical variables (ethnicity, marital status, education, and employment status). Twosample multinomial exact tests based on enumeration of all
possible outcomes under the null and subsequent calculation
of the exact p values were implemented.
Group differences in VO2 max, Hb, CRF, and QoL were analyzed using repeated measures analysis of variance (RMANOVA). The small subsample of six participants (three
exercisers and three usual care) that was used for examination
of inflammatory markers precluded statistical analyses. These
data are reported as percentage changes from baseline (T1) to
end of chemotherapy (T3).
We employed appropriately designed contrasts to test the
global hypotheses of no group differences over all time points.
In the cases of significant p values for the global hypothesis, we
used corresponding contrast to test for differences between the
exercise and the usual-care groups at all time points individually with Bonferonni adjustments for multiple comparisons. All
calculations were carried out using the R statistical software
package (http://www.r-project.org).
Results
Sample Characteristics
Descriptive data on sample demographic characteristics are
reported as frequencies, means, and standard deviations
(Table 3). There were no group differences with respect to age,
stage of cancer, ethnicity, or race. Age ranged between 32 and
67 years for the exercise group and between 37 and 73 years
and for the usual-care group. The majority of participants were
Caucasian and non-Hispanic.
Feasibility Outcomes
Participants’ flow through the trial is presented in Figure 1. We
screened 52 women presenting with breast cancer for eligibility. Of the 35 women who met eligibility criteria, 19 (51%)
declined participation. With 16 women consenting to participate, our recruitment rate was 45.7%. Of these, one withdrew
consent before baseline data collection due to fear of commitment and one decided to discontinue chemotherapy after the
first cycle and was no longer eligible, resulting in a retention
rate of 87.5%. The remaining 14 women completed the trial.
44
Biological Research for Nursing 17(1)
Screened (n = 52)
Ineligible (n = 17)
• Advanced cancer (n = 3)
• Not receiving chemo (n = 10)
• Prior chemo (n = 2)
• Other reasons (n = 2)
Eligible (n = 35)
Declined (n = 19)
Consented (n = 16)
Randomized (N = 14)
Exercise (n = 7)
• Time commitment (n = 6)
• Overwhelmed (n = 1)
• Long commute (n = 7)
• Work schedule (n = 3)
• Too tired (n = 1)
• Refused randomization (n = 1)
Withdrew consent (n = 1)
Discontinued chemotherapy,
thus no longer eligible (n = 1)
Control (n = 7)
Completed T1 data collection (n = 7)
Completed T2 data collection (n = 6)
Completed T3 data collection (n = 6)
Completed T4 data collection (n = 6)
Completed T1 data collection (n = 7)
Completed T2 data collection (n = 6)
Completed T3 data collection (n = 6)
Completed T4 data collection (n = 7)
Figure 1. Participant flow through the study.
Adherence to per-protocol exercise sessions was very high,
ranging between 95% and 97%. Of the seven participants in the
exercise group, two missed one and five missed two of the total
number of scheduled exercise sessions. All participants completed
remaining sessions per protocol. None of the women in either group
reported participating in out-of-study exercise activities.
All but 1 participant (n ¼ 13) tolerated and completed exercise testing (VO2 max measurement) without problems. The participant who did not complete it was from the usual-care group
and was not able to continue exercise testing past the first 2 min
on the second data-collection time point (T2) due to overwhelming tiredness.
Completion of study measurements ranged between 85.7%
and 100%. All participants (100%) completed measurements
at T1, 12 (85.7%) completed them at T2 (85.7%), 3 completed
them at T3 (85.7%), and 13 (92.8%) completed them at T4
data-collection time points.
Efficacy Outcomes
Aerobic fitness (VO2 max). The longitudinal changes in VO2 max
for the exercise and usual-care groups are presented in Table
4. There were no group differences in baseline VO2 max (p ¼
0.26). The exercise-group participants maintained VO2 max at
prechemotherapy levels throughout chemotherapy, whereas the
Table 4. Longitudinal Changes in Aerobic Fitness (VO2 max; ml/kg/min)
and Hemoglobin Concentration (mg/dl) in the Exercise and Usual-Care
Participants.
Outcome
Measure
T1
T2
T3
T4
VO2 max (ml/kg/min)
Exercise
26.1 (2.6)
24.8 (3.0)
24.7 (2.5)
26.0 (2.5)
Usual care 23.8 (2.9)
20.4 (3.3)* 17.6 (2.8)* 17.5 (2.8)*
Hemoglobin (mg/dl)
Exercise
14.11 (1.02) 11.8 (1.32)* 12.4 (0.55)* 11.84 (0.60)*
Usual care 13.23 (2.27) 11.5 (1.36)* 11.3 (0.88)* 11.03 (0.95)*
Note. Data are presented as mean (SD). VO2 max ¼ maximal oxygen consumption; T1 ¼ Time 1 (baseline) data; T2 ¼ Time 2 data (after second cycle of chemotherapy); T3 ¼ Time 3 data (within a week of completion of chemotherapy
and exercise); T4 ¼ Time 4 data (3–4 weeks after completion of chemotherapy
and exercise).
*Significant decrease from T1 (p < 0.5).
usual-care group showed a significant decline of up to 6.3 ml/
kg/min (p < .05) that continued 3–4 weeks following the completion of chemotherapy.
Hb concentration. Hb levels in the exercise and usual-care
groups throughout the trial are also presented in Table 4. There
Al-Majid et al.
45
Table 5. Longitudinal Changes in Cancer-Related Fatigue (CRF), Overall Quality of Life (QoL) and Subscales of QoL in the Exercise and
Usual-Care Groups.
Variable
CRF
Exercise
Usual care
FACT-B total (0–144)
Exercise
Usual care
PWB scale (0–28)
Exercise
Usual care
SWB scale (0–24)
Exercise
Usual care
EWB scale (0–28)
Exercise
Usual care
FWB scale (0–28)
Exercise
Usual care
BCS (0–36)
Exercise
Usual care
T1
Mean (SE)
T2
Mean (SE)
T3
Mean (SE)
T4
Mean (SE)
3.0 (0.7)
0.8 (0.5)
3.9 (1.2)
3.3 (0.9)
3.0 (0.8)
4.6 (0.9)
2.9 (1.0)
4.3 (1.2)
116.4 (6.1)
115.5 (5.4)
110.1 (6.4)
107.0 (5.3)
108.0 (6.7)
96.4 (1.9)
113.3 (6.4)
97.5 (6.1)
23.9 (2.1)
25.3 (1.2)
19.9 (2.2)
19.2 (1.9)
19.3 (2.1)
16.2 (1.7)
21.9 (1.6)
17.3 (2.4)
25.6 (1.8)
24.7 (2.0)
24.1 (1.5)
24.0 (1.5)
23.1 (1.7)
24.8 (1.5)
25.6 (1.9)
24.0 (1.8)
18.4 (1.3)
19.2 (1.3)
18.7 (1.5)
22.2 (1.2)
19.4 (0.9)
17.2 (1.8)
20.3 (0.9)
17.0 (2.0)
22.9 (1.8)
22.7 (1.7)
22.7 (1.0)
18.6 (2.0)
21.4 (2.2)
16.6 (1.5)
22.4 (1.6)
16.8 (2.2)
23.8 (2.0)
23.7 (0.9)
24.9 (1.7)
23.0 (1.9)
24.7 (2.0)
21.6 (1.0)
24.0 (1.6)
22.3 (2.3)
p
.09
.52
.45
.81
.07
.45
.86
Note. SE ¼ standard error. BCS ¼ breast cancer scale; EWB ¼ emotional well-being; FACT-B total ¼ total quality of life; FWB ¼ functional well-being; PWB ¼
physical well-being; SWB ¼ social well-being; T1 ¼ Time 1 (baseline) data; T2 ¼ Time 2 data (after second cycle of chemotherapy); T3 ¼ Time 3 data (within a
week of completion of chemotherapy and exercise); T4 ¼ Time 4 data (3–4 weeks after completion of chemotherapy and exercise).
were no group differences in Hb concentration at any of the
four data-collection time points. Hb levels decreased significantly (13.7 + 1.7 mg/dl to 11.0 + 0.9, p < .001) in all participants as they progressed through chemotherapy. In both
groups, Hb decreased significantly by T2 (after the second
cycle of chemotherapy) and remained low through T4 (3–4
weeks following the completion of chemotherapy).
Relative to prechemotherapy, postchemotherapy cortisol levels dropped by 24% (from 92.7 to 70.2 mg/dl) in the exercise group
but did not change in the usual-care group (69.2 and 70.6 mg/dl).
Post-chemotherapy MPO was similar to the pre-chemotherapy
level in the exercisers (11.8 and 11.9 mg/dl) but increased by
25% (from 11.7 to 14.7 mg/dl) in the usual-care group.
CRF and QoL. The longitudinal changes in CRF and QoL in the
exercise and usual-care participants as well as the p values for
the global test for overall difference between the two groups
across all time points are presented in Table 5. Changes in these
variables favored the exercise group but did not reach statistical
significance. Participants in both groups showed significant
decrease in overall QoL as well as in physical and functional
well-being (p ¼ .02, .005, and .01, respectively) as they progressed through chemotherapy.
Discussion
Select inflammatory markers. Prechemotherapy IL-6 level was
higher in the usual-care group than in the exercise group
(4.45 vs. 1.23 mg/dl). By the end of chemotherapy, IL-6 levels
dropped slightly (2.96 mg/dl) in the usual-care group but did
not change in the exercise group. Relative to prechemotherapy,
postchemotherapy levels of IL-10 increased by 64% in the
exercise group (from 0.58 to 1.22 pg/dl) and by only 30% in the
usual-care group (from 0.81 to 1.11 pg/dl).
This study provides information suggesting that a supervised,
individualized treadmill exercise intervention performed during chemotherapy for early-stage breast cancer is both feasible
and efficacious.
Feasibility Outcomes
Our 95–97% adherence to the exercise protocol is slightly
higher than that reported in the literature. A recent metaanalysis of 17 randomized controlled trials that employed various types and doses of exercise during chemotherapy for
breast cancer revealed adherence rates ranging between 26%
and 93.8% (Carayol et al., 2012). However, Knobf, Thompson,
Fennie, and Erdos (2013) reported a higher exercise adherence
rate of up to 98% among cancer survivors. Our high adherence
rate could be attributed to scheduling flexibility and permission
to make up missed exercise sessions.
46
As with other exercise studies, particularly those that
involved patients undergoing chemotherapy, it was difficult
to recruit patients into the present study. Our recruitment rate
of 45.7% is, however, within the range (33–54%) reported in
the literature (Courneya et al., 2007; Dolan et al., 2010;
Griffith et al., 2010; Payne, Held, Thorpe, & Shaw, 2008;
Vincent et al., 2013). Several factors might have contributed
to the low recruitment rate. First, baseline measures had to
be obtained before initiation of chemotherapy, which meant
that women had to make a decision about participating in the
study at about the same time they were making decisions
about their treatment options. Second, offering the exercise
intervention in the cancer center entailed women making several trips per week to the center, which might have discouraged participation. Last, the mode of exercise (walking on a
treadmill) might have deterred women with no prior treadmill
experience from participating. However, this supervised exercise protocol allowed for quantification of exercise dose in
terms of intensity, duration, and frequency.
Efficacy Outcomes
In this feasibility study, we demonstrated that a relatively shortduration endurance exercise program might protect against
chemotherapy-associated decline in VO2 max. Exercise-group
participants maintained their VO2 max, while those in the
usual-care group showed a significant decline as they progressed through chemotherapy. This protective effect of exercise
on VO2 max was independent of changes in Hb, suggesting that
exercise might have improved O2 uptake/extraction at the tissue
level, possibly by protecting against loss of skeletal muscle mitochondria, capillary density, and/or aerobic enzymes. Previous
researchers have reported maintenance of prechemotherapy
VO2 max level in women with breast cancer who exercised during chemotherapy (Dolan et al., 2010; Vincent et al., 2013). Similar to our findings, Dolan et al. (2010) reported no effect of
endurance exercise on Hb during chemotherapy for breast cancer. The ability of these women to maintain their prechemotherapy VO2 max in the face of chemotherapy-induced decline in Hb
provides evidence to support the beneficial role of exercise during chemotherapy.
We found no significant effect of exercise on CRF. However,
the exercise group participants maintained their baseline level of
mild CRF (defined as 1–3 on PFS) throughout the study. Conversely, CRF in the usual-care group increased from less than
mild at baseline to moderate (defined as 4–6 on PFS) by the end
of chemotherapy and remained elevated 3–4 weeks after chemotherapy. Failure of exercise to significantly decrease CRF
in this study could be due to low statistical power and low baseline levels of CRF in our sample. Other researchers also found no
significant effect of exercise on mild to moderate CRF in breast
cancer patients (Dodd et al., 2010; Payne et al., 2008; Vincent
et al., 2013). However, Heim, Malsburg, and Niklas (2007)
found that CRF decreased significantly in response to exercise
in breast cancer patients who had higher levels of fatigue (>4
on an 11-point scale) at baseline. Future studies involving
Biological Research for Nursing 17(1)
interventions for CRF should consider a certain level of baseline
fatigue as one of the inclusion criteria.
Although exercisers maintained relatively higher QoL
throughout the study compared to nonexercisers, there was
no significant effect of exercise on QoL. This finding is consistent with those of Courneya et al. (2007) who found no effect of
resistance or endurance exercise on QoL in women receiving
chemotherapy for breast cancer. Similarly, Adamsen et al.
(2009) found that a multimodal high-intensity exercise program did not have significant effects on QoL in patients undergoing chemotherapy for various cancers. There was a wide
variability in longitudinal changes of QoL in our sample, as
evidenced by the wide range of standard deviation (5–18). This
variability, along with the small sample size, could have contributed to the failure to demonstrate a significant effect of
exercise on overall QoL.
Our preliminary findings regarding the effects of endurance
exercise on IL-6 are consistent with those of Payne, Held,
Thorpe, and Shaw (2008), suggesting that endurance exercise
during chemotherapy for breast cancer does not affect IL-6 levels. However, increased levels of the anti-inflammatory cytokine IL-10 among the exercisers in the present study suggest
that endurance exercise may attenuate some of the proinflammatory effects of chemotherapy.
Our findings also show that MPO levels remained steady in
the exercise group but increased by 25% in the usual-care
group. This finding suggests that exercise during chemotherapy
may contribute to increased antioxidant functioning. Additionally, our exercise group showed a greater drop in cortisol level
compared to the usual-care group, suggesting that exercise may
have positive effects on the stress response.
Limitations
The present study had several limitations. A major limitation is
the small sample size, which reflects the limitations (budget
and time) inherent in pilot and feasibility studies. The small
sample size precludes us from drawing definitive conclusions
regarding the effects of our endurance exercise protocol on the
biobehavioral markers measured in this study. Another limitation is that participants had only mild baseline levels of CRF,
which could have contributed to the failure to demonstrate a
significant effect of exercise on CRF. Major strengths include
the use of randomization, inclusion of a control group, and
exploration of the effect of exercise on biological and behavioral factors concurrently.
Implications
The endurance exercise program used in this study appears to
be feasible and potentially effective. Results from the study,
despite the small sample size, support the role of exercise in
preventing a decline in aerobic fitness during chemotherapy for
breast cancer. Results for all outcome variables favored the
exercise intervention, which supports the need for larger scale
studies. Recruitment of eligible participants into the study was
Al-Majid et al.
challenging; for future studies, researchers should explore strategies to increase participant enrollment in randomized control
trials involving exercise during cancer treatment.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: Funded
by a grant from the Oncology Nursing Society.
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