IJC

International Journal of Cancer

Effects of resistance exercise on fatigue and quality of life in

breast cancer patients undergoing adjuvant chemotherapy: A
randomized controlled trial
Martina E. Schmidt1, Joachim Wiskemann2, Petra Armbrust2, Andreas Schneeweiss2, Cornelia M. Ulrich1
and Karen Steindorf1
1
Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany
2
Division of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg, Heidelberg, Germany

Multiple exercise interventions have shown beneficial effects on fatigue and quality of life (QoL) in cancer patients, but various
psychosocial interventions as well. It is unclear to what extent the observed effects of exercise interventions are based on physi-
cal adaptations or rather on psychosocial factors associated with supervised, group-based programs. It needs to be determined
which aspects of exercise programs are truly effective. Therefore, we aimed to investigate whether resistance exercise during
chemotherapy provides benefits on fatigue and QoL beyond potential psychosocial effects of group-based interventions. One-
hundred-one breast cancer patients starting chemotherapy were randomly assigned to resistance exercise (EX) or a relaxation
control (RC) group. Both interventions were supervised, group-based, 2/week over 12 weeks. The primary endpoint fatigue was
assessed with a 20-item multidimensional questionnaire, QoL with the EORTC QLQ-C30/BR23. Analyses of covariance for individ-
ual changes from baseline to Week 13 were calculated. In RC, total and physical fatigue worsened during chemotherapy,
whereas EX showed no such impairments (between-group p 5 0.098 and 0.052 overall, and p 5 0.038 and 0.034 among patients
without severe baseline depression). Differences regarding affective or cognitive fatigue were not significant. Benefits of EX were
also seen to affect role and social function. Effect sizes were between 0.43 and 0.48. Explorative analyses indicated significant
effect modification by thyroxin use (p-interaction 5 0.044). In conclusion, resistance exercise appeared to mitigate physical
fatigue and maintain QoL during chemotherapy beyond psychosocial effects inherent to supervised group-based settings. Thus,
resistance exercise could be an integral part of supportive care for breast cancer patients undergoing chemotherapy.

Cancer-related fatigue is among the most common and dis-
tressing symptoms in breast cancer patients during and after
chemotherapy, with severe impact on quality of life (QoL).1–3
Key words: exercise, resistance training, fatigue, breast cancer,
randomized trial
Abbreviations: ANCOVA: analysis of covariance; BMI: body mass
index; CI: confidence interval; CES-D: Center for Epidemiological
Various exercise interventions and, in particular, resistance
exercise, have shown beneficial effects on fatigue and QoL for
different cancer types and treatment settings.4–7 However,
psychosocial and behavioral interventions without exercise
have shown benefits in combating fatigue as well.8,9 As
fatigue is associated with psychological and depressive symp-
toms,10,11 social support and personal contact with other
patients, attention from a trainer, or regaining a structured

Studies—depression scale; EORTC: European Organisation for
Research and Treatment of Cancer; ES: effect size; EX: exercise
group; FAQ: Fatigue Assessment Questionnaire; ITT: intent-to-
treat; NCT: National Center for Tumor Diseases; QoL: quality of
life; RC: resistance control group; VO2peak: peak oxygen
consumption
Additional Supporting Information may be found in the online
version of this article.
DOI: 10.1002/ijc.29383
History: Received 22 Sep 2014; Accepted 24 Nov 2014; Online 00
Month 2014
Correspondence to: Dr. Martina Schmidt, Unit of Physical Activity
and Cancer, Division of Preventive Oncology (G110), National
Center for Tumour Diseases (NCT) and German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg,
Germany, Tel.: 149-6221-42-2220, Fax: 149-6221-42-2229,
E-mail: m.schmidt@dkfz.de
Cancer Therapy
daily routine through a group-based program may affect the
perception of fatigue. Yet most previous randomized exercise
trials used a “usual care” condition as comparison.4,7,12 Thus
it is unclear to what extent the observed intervention effects
are based on the physical adaptations of exercise itself or
rather on psychosocial factors associated with group-based
programs. A clearer distinction between the psychological
and the physiological effects of an exercise intervention seems
to be important in providing concrete evidence-based recom-
mendations with respect to therapies combating fatigue.
Moreover, exercise recommendations may need to be
more specific regarding the different periods within the can-
cer continuum. In breast cancer patients during chemother-
apy, however, exercise training has scarcely been investigated,
although chemotherapy is a major determinant for the occur-
rence and intensity of fatigue.3,13 To our knowledge, only
Courneya et al.14 has specifically investigated exercise

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 2 Effects of resistance exercise on fatigue

What’s new?
For cancer patients, exercise can help fight fatigue and improve quality of life, but whether those benefits stem more from
physiological adaptations or psychosocial factors is unclear. Likewise, chemotherapy is a significant source of fatigue, but lit-
tle is known about the effects of exercise during courses of treatment. In the case of breast cancer, the present study sug-
gests that resistance exercise performed over the course of adjuvant chemotherapy can mitigate physical fatigue and lead to
gains in quality of life. The benefits of resistance exercise exceeded those associated with the psychosocial effects provided
by a supervised, group-based muscle-relaxation program.

interventions during adjuvant chemotherapy in breast cancer
patients. Additionally, four randomized exercise trials15–18
included breast cancer patients during any adjuvant treat-
ment, and one trial included 269 patients during adjuvant
chemotherapy with mixed cancer types.19 Results of these tri-
als on fatigue were heterogeneous.
Most randomized exercise trials to date have investigated
aerobic training.7 However, a recent comprehensive meta-
analysis including 44 exercise studies with endpoint fatigue
noted larger effect sizes (ESs) for resistance exercise than for
aerobic exercise.4 Potential biological pathways may involve
countering of muscle atrophy and disruption in muscle
metabolism caused by several cytostatics. Mitochondrial dys-
function and cytokine dysregulations, which are related to
muscle dysfunction, may contribute to fatigue.20,21
Therefore, the BEATE study aimed to investigate whether
progressive resistance training in breast cancer patients dur-
ing chemotherapy provides beneficial effects on fatigue and
QoL beyond the potential psychosocial effects of a supervised,
group-based training.
Patients and Methods
Study design
The BEATE study22 is a prospective, randomized, controlled
intervention trial evaluating a 12-week resistance training
intervention in breast cancer patients during adjuvant chem-
otherapy. To determine the physiological adaptions through
Cancer Therapy
facilities. Patients with contraindications for resistance train-
ing, with other concurrent malignant diseases (except carci-
noma in situ of skin or cervix), or already participating in
systematic intensive resistance or aerobic training (at least 1
hr twice/week) were excluded.
Recruitment and randomization
Breast cancer patients scheduled for adjuvant chemotherapy
at the National Center for Tumor Diseases (NCT), Heidel-
berg, between April 2010 and August 2013 were notified
about the study during their therapy counselling visit and, if
interested, thereafter informed in detail. Breast cancer
patients in the greater Heidelberg area were notified by flyer,
poster or their attending physicians. If baseline cardiopulmo-
nary exercise testing did not indicate contraindications for
resistance training, participants were randomly allocated 1:1
to the exercise group (EX) or relaxation control group (RC).
Allocation was performed by a biostatistician uninvolved in
recruitment, based on predetermined lists with random block
size, stratified by age and baseline physical fatigue level.
Other study personnel did not have access to the randomiza-
tion lists.
Interventions
Both interventions were performed for 60 min twice weekly
over 12 weeks together with other cancer patients under the
supervision and guidance of experienced therapists in specific

exercise per se over and above the psychosocial training ben-
efits, the control group received a supervised, group-based
muscle-relaxation program with comparable time schedule.
Endpoints were assessed during the first or second chemo-
therapy cycle preintervention (baseline) and postintervention
(Week 13). Follow-up data were also collected but not con-
sidered in the primary analyses here. The study was approved
by the ethics committee of the University of Heidelberg and
registered at ClinicalTrials.gov (NCT01106820). All patients
gave written informed consent.
Patient eligibility
Eligibility criteria were: histologically confirmed primary
breast cancer after lumpectomy or mastectomy; scheduled for
adjuvant chemotherapy; age 18 years; body mass index
(BMI) 18 kg/m2; ability to understand and follow the study
protocol and willingness to come to the Heidelberg exercise
training facilities. EX comprised 8 different machine-based
progressive resistance exercises (three sets, 8–12 repetitions at
60–80% of one repetition maximum) without any specific
aerobic exercise.22 RC encompassed progressive muscle relax-
ation according to Jacobson23 without any aerobic or muscle
strengthening exercise.
Outcome measures
Fatigue. Fatigue was self-assessed using the validated 20-
item multidimensional Fatigue Assessment Questionnaire
(FAQ),24 which covers the dimensions physical, affective and
cognitive fatigue. Scores were derived by adding the answers
(0 5 not at all, 1 5 a little, 2 5 quite a bit and 3 5 very
much) of the appropriate items and linearly rescaling to a 0–
100 scale, with higher scores indicating worse fatigue.
Quality of life. QoL was self-assessed using the validated 30-
item EORTC QLQ-C30 (version 3.0).25 Scores were derived

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Schmidt et al.
Figure 1. CONSORT diagram. FAQ 5 Fatigue Assessment Questionnaire.
and scaled from 0 to 100 according to the EORTC scoring
manual,26 i.e., a global QoL score and five multi-item func-
tional scales (physical, emotional, role, cognitive and social
function), with higher scores indicating better QoL, and three
multi-item and six single-item symptom scores, with higher
scores indicating poorer QoL. In addition, the 23-item breast
cancer specific module (EORTC QLQ-BR23) was applied.
Depression. Depressive symptoms were self-assessed using
the 20-item Center for Epidemiologic Studies Depression
scale (CES-D), which is a widely used, validated instrument
for the general population and cancer patients.27 Scores were
linearly rescaled to the 0–100 scale, with higher scores indi-
cating higher depression. Scores above 38 on the 0–100 scale
(referring to a sum score of 23) indicate potential, serious
depressive disorders.28
Cognitive function. Cognitive function (concentration, cog-
nitive flexibility) was estimated using the trail-making-test.
This is a standardized, reliable and valid measurement used
as a neuropsychological diagnostic tool.29,30 It measures the
time needed by the participant to connect numbers and let-
Int. J. Cancer: 00, 00–00 (2014) V
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3
ters in a logical sequence, with higher values indicating worse
cognitive function.
Clinical parameters. Dates and types of cancer therapy were
extracted from medical charts. Concomitant medication was
Cancer Therapy
assessed in personal interviews, and weight, BMI and physical
fitness was measured, i.e., upper and lower body isometric
and isokinetic muscle capacity (IsoMed 2000V R ) and endur-
ance performance (VO2peak, spiroergometry).
Safety issues
Potential adverse effects (e.g., lymphedema, pain, muscle
soreness, nausea, dyspnea and tachycardia) were recorded by
the participants at each training session using standardized
questionnaires.
Sample size calculations
The primary endpoint was change in total fatigue from pre-
to postintervention. The study was designed to detect a mean
standardized ES of 0.5 with an analysis of covariance
(ANCOVA), adjusted for the preintervention fatigue levels
with a power of 80% and a significance level of 5%. Thus,
 4 Effects of resistance exercise on fatigue

Table 1. Baseline characteristics of the study population

Total (N 5 95) Exercise (N 5 49) Control (N 5 46)
Characteristics N % N % N % p
Age, years 0.58
Mean 52.7 52.2 53.3
SD 10.0 9.9 10.2
BMI 0.62
Mean 26.0 25.7 26.3
SD 4.8 4.6 4.9
Baseline depression score 0.025
Mean 25.5 22.2 29.3
SD 14.9 12.2 16.8
Baseline depression 0.0098
No (score  38) 76 80.0 45 91.8 31 67.4
Yes (score > 38) 17 17.9 4 8.2 13 28.3
Missing 2 2.1 0 0.0 2 4.3
Smoking year before diagnosis 18 18.9 12 24.5 6 13.0 0.19
Still smoking at baseline 7 7.4 4 8.2 3 6.5 1.00
Thyroxin user 24 25.3 11 22.4 13 28.3 0.64
Tumor Stage 0.31
1 37 38.9 22 44.9 15 32.6
2 41 43.2 21 42.9 20 43.5
3 15 15.8 6 12.2 9 19.6
4 2 2.1 0 0.0 2 4.3
Days since surgery 0.35
Mean 56.0 58.2 53.7
SD 23.4 27.3 18.5
Days since first chemotherapy 0.30
Mean 18.8 20.1 17.3
SD 13.2 14.6 11.4
Herceptine therapy
Baseline 3 3.2 2 4.1 1 2.2 1.00
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Postintervention 23 24.2 12 24.5 11 23.9 1.00

Taxane-containing therapy
Baseline 31 32.6 13 26.5 18 39.1 0.27
Postintervention 82 86.3 39 79.6 43 93.5 0.072
Anthracycline therapy
Baseline 83 87.4 45 91.8 38 82.6 0.22
Postintervention 85 89.5 46 93.9 39 84.8 0.19
Hormone therapy
Baseline 0 0.0 0 0.0 0 0.0 –
Postintervention 14 14.7 8 8.4 6 12.2 0.27

Abbreviations: BMI 5 body mass index; SD 5 standard deviation.

N 5 50 patients per arm were needed, assuming a maximal Statistical analyses

drop-out rate of 15% and a correlation between pre- and ANCOVA on the intent-to-treat-basis (ITT) was conducted
postintervention fatigue levels of 0.6.31 with change pre- to postintervention as dependent variable,

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Schmidt et al. 5

Table 2. Fatigue pre-/postintervention, adjusted mean changes and between-group differences

Adjusted2 mean Adjusted2
Preintervention, Postintervention, change (95% CI) difference (95% CI)
Outcome Arm N1 mean (SD) mean (SD) pre to post between-groups p
Overall
Total fatigue Exercise 49 36.4 (19.2) 36.1 (20.6) 21.1 (25.9, 3.6) 25.8 (212.6, 1.1) 0.098
Relaxation 46 41.0 (21.1) 44.8 (21.0) 4.6 (20.3, 9.6)
Physical fatigue Exercise 49 40.4 (24.5) 39.9 (25.0) 21.0 (26.7, 4.7) 28.1 (216.3, 0.1) 0.052
Relaxation 46 42.9 (23.8) 49.4 (22.7) 7.1 (1.2, 13.0)
Affective fatigue Exercise 49 29.2 (21.9) 26.8 (23.5) 23.7 (28.6, 1.2) 23.0 (210.2, 4.2) 0.41
Relaxation 46 40.0 (28.0) 37.9 (27.1) 20.7 (25.8, 4.4)
Cognitive fatigue Exercise 49 30.2 (25.3) 34.9 (25.1) 3.5 (23.2, 10.2) 0.0 (29.7, 9.7) >.99
Relaxation 46 34.8 (28.1) 37.0 (27.6) 3.5 (23.4, 10.5)
Without baseline depression
Total fatigue Exercise 45 33.8 (17.4) 33.7 (18.8) 0.1 (24.9, 5.0) 28.1 (215.7, 20.4) 0.038
Relaxation 33 32.7 (16.5) 41.0 (21.2) 8.1 (2.3, 13.9)
Physical fatigue Exercise 45 36.9 (21.7) 37.3 (23.3) 0.6 (25.5, 6.8) 210.2 (219.7, 20.8) 0.034
Relaxation 33 35.6 (20.9) 46.8 (23.8) 10.9 (3.7, 18.0)
Affective fatigue Exercise 45 27.0 (21.4) 24.0 (21.6) 23.1 (27.7, 1.6) 26.4 (213.6, 0.7) 0.078
Relaxation 33 27.5 (19.1) 30.8 (23.3) 3.3 (22.1, 8.8)
Cognitive fatigue Exercise 45 29.4 (25.5) 33.6 (25.1) 3.9 (23.2, 11.0) 20.9 (211.8, 10.0) 0.87
Relaxation 33 30.6 (27.6) 35.0 (28.1) 4.8 (23.5, 13.1)
With baseline depression
Total fatigue Exercise 4 65.8 (14.0) 63.3 (23.0) 21.4 (220.0, 17.2) 7.0 (214.3, 28.3) 0.49
Relaxation 13 62.2 (16.0) 54.2 (18.0) 28.3 (218.6, 2.0)
Physical fatigue Exercise 4 79.5 (21.6) 69.7 (27.2) 24.0 (223.6, 15.7) 3.3 (219.6, 26.2) 0.76
Relaxation 13 61.3 (21.3) 55.9 (18.9) 27.2 (217.8, 3.3)
Affective fatigue Exercise 4 53.3 (9.4) 58.3 (24.0) 3.2 (222.8, 29.2) 18.5 (211.7, 48.8) 0.21
Relaxation 13 71.8 (21.1) 55.9 (28.5) 215.3 (229.1, 21.6)
Cognitive fatigue Exercise 4 38.9 (23.1) 50.0 (21.3) 8.3 (217.5, 34.2) 10.9 (218.7, 40.5) 0.44
Relaxation 13 45.3 (27.4) 41.9 (26.9) 22.6 (216.8, 11.7)
1
Number of patients with measures at both timepoints.
2
Regression models are adjusted for baseline value.

Cancer Therapy
Abbreviations: CI 5 confidence interval; SD 5 standard deviation.

intervention group as independent variable and the baseline
measure as covariate. There was no evidence of a departure
from normality assumptions. As very few fatigue values were
missing (3%), we performed complete-case analyses. Sensitiv-
ity analyses using multiple imputation algorithms (SAS
PROC MI and MIANALYSE) or ANCOVA models adjusted
for randomization strata yielded no substantial changes in
the results. Besides the primary endpoint total fatigue, we
conducted a priori planned analyses on the three different
fatigue dimensions. We also calculated ANCOVA models,
excluding 17 patients with baseline depression scores above
the cut-off point for serious depression, as for those patients
cancer-related fatigue development cannot be distinguished
from fatigue related to the depression.
The secondary analyses on QoL, depression and cognitive
function were exploratory, without adjustment for multiple
comparisons. Further, we explored effect modification by age,
BMI, smoking status, cancer treatment, concomitant diseases
(osteoarthritis, allergies and cardiovascular diseases) and thy-
roxin use by including a multiplicative interaction term in
the ANCOVA model.
Standardized ESs were calculated by dividing the between-
group difference of the postintervention means (adjusted for base-
line values) by the pooled baseline standard deviation. For ease of
presentation, ES in favor of EX received a positive sign and in
favor of RC a negative sign. SAS Version 9.3 was used. Statistical
significance was set at p < 0.05, and all tests were two-sided.
Results
Participants
Of 101 randomized breast cancer patients, 97 (96%) reached
the postintervention assessment of the primary outcome

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 6 Effects of resistance exercise on fatigue

Figure 2. Effect sizes (indicated by a dot) with 95% confidence intervals for the difference between the resistance exercise (EX) and the
relaxation control (RC) group, based on changes from baseline to the end of intervention (Week 13) and adjusted for baseline scores. For
ease of presentation, effects in favor of EX received a positive sign and in favor of RC a negative sign. FAQ 5 Fatigue Assessment Question-
naire; EORTC 5 European Organisation for Research and Treatment of Cancer; QoL 5 quality of life; HRQoL 5 health-related quality of life;
CES-D 5 20-item depression scale. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Cancer Therapy

(Fig. 1). Two patients had to be excluded from analysis, because
they started chemotherapy after baseline. Thus, the analysis
included n 5 95 patients with an average age of 52.7 (range:
30–71) years, BMI 25.6 kg/m2 (range: 18.3–40.6) and 52 days
after breast surgery (range: 22–199) (Table 1). Most patients
had early stage breast cancer. The two study participants with
metastases received chemotherapy comparable to several non-
metastasized participants (i.e., paclitaxel) and had no symptoms
or limitations contraindicating intense fitness testing or training.
Baseline characteristics, fatigue and QoL were similarly distrib-
uted between both intervention groups, except for depression,
which was significantly more common in RC than EX.
Intervention adherence and safety
Median attendance was similar in both groups, with 17 out
of 24 scheduled sessions attended (71%; interquartile range
11–22 in EX and 11–23 in RC). EX resulted in significant
improvements compared to RC regarding isometric and iso-
kinetic muscle strength, but not cardiorespiratory fitness
(VO2max).
No injuries or severe adverse events were reported in
either intervention group. The frequency of self-reported
lymphedema, pain, muscle soreness, nausea, dyspnea or tach-
ycardia did not differ significantly between-groups.
Fatigue
Overall, the between-group difference regarding change in
total fatigue from pre- to postintervention was 25.8 with a
95% confidence interval (CI) of (212.6, 1.1), p 5 0.098, tend-
ing to indicate a beneficial effect of EX vs. RC (Table 2). This
benefit was mainly due to effects on the physical fatigue
dimension (p 5 0.052). There was no overall intervention
effect on the affective or cognitive fatigue dimension.

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Schmidt et al. 7

Table 3. Patient Reported Outcomes pre-/postintervention, adjusted mean changes and between-group differences (Patients without baseline
depression)
Adjusted2 mean Adjusted2
Preintervention, Postintervention, change (95% CI) difference (95% CI)
Outcome Arm N1 mean (SD) mean (SD) pre to post between-groups p
Quality of life—EORTC QLQ30 (scale 0–100)
Global QoL Exercise 45 61.5 (17.5) 61.7 (18.3) 0.4 (24.3, 5.1) 5.1 (22.2, 12.4) 0.17
Relaxation 32 59.4 (16.6) 54.9 (22.9) 24.7 (210.3, 0.8)
Physical function Exercise 45 85.0 (13.5) 79.5 (22.1) 25.5 (211.2, 0.1) 7.6 (21.1, 16.4) 0.087
Relaxation 32 84.4 (14.1) 71.3 (23.3) 213.2 (219.9, 26.5)
Emotional function Exercise 45 70.0 (25.3) 70.4 (24.6) 0.6 (24.7, 5.9) 1.9 (26.4, 10.2) 0.65
Relaxation 32 68.0 (18.9) 67.0 (23.8) 21.3 (27.6, 5.0)
Role function Exercise 45 61.5 (31.5) 65.6 (32.1) 4.6 (24.2, 13.4) 14.7 (1.0, 28.3) 0.035
Relaxation 32 59.4 (29.3) 50.0 (32.2) 210.1 (220.5, 0.3)
Cognitive function Exercise 44 79.2 (21.6) 73.9 (21.1) 24.6 (210.4, 1.3) 23.0 (212.1, 6.0) 0.51
Relaxation 32 76.0 (25.0) 75.5 (22.8) 21.5 (28.4, 5.3)
Social function Exercise 44 70.5 (26.6) 71.2 (30.2) 2.4 (25.5, 10.4) 12.6 (0.2, 24.9) 0.046
Relaxation 32 62.5 (31.1) 54.7 (29.4) 210.1 (219.5, 20.8)
Depression—CES-D (scale 0–100)
Depression score Exercise 45 20.3 (10.7) 20.4 (12.8) 0.1 (22.9, 3.1) 20.8 (25.5, 4.0) 0.75
Relaxation 31 20.3 (9.9) 21.1 (13.2) 0.9 (22.8, 4.5)
Cognitive function—trail-making test (seconds)
Overall Exercise 40 100.4 (31.3) 91.2 (28.6) 210.2 (216.3, 24.2) 26.1 (215.6, 3.4) 0.20
Performance Relaxation 28 114.8 (39.1) 109.3 (41.4) 24.1 (211.3, 3.1)
1
Number of patients with measures at both timepoints.
2
Regression models are adjusted for baseline value.
Abbreviations: CI 5 confidence interval; CES-D 5 Center of Diseases Depression Scale; QoL 5 Quality of Life; SD 5 standard deviation.

Considering only patients without depression at baseline,
the effects were more pronounced, showing statistically sig-
nificant between-group differences of 28.1 (215.7, 20.4) for
total fatigue (p 5 0.039) with an ES of 0.47 (Fig. 2) and of
210.2 (219.7, 20.8) for physical fatigue (p 5 0.034,
ES 5 0.48). Hereby, fatigue increased significantly in RC
whereas there was no increase in EX. There were slight
stantially lower level compared to patients without baseline
depression, and there were no statistically significant inter-
vention effects.
Depression and cognitive performance
There was no between-group difference regarding depression
(ES 5 0.07), which remained unchanged in both groups

effects on affective fatigue in favor of EX (p 5 0.078,
ES 5 0.31), but no significant intervention effect for cognitive
fatigue. The patients with baseline depression started with
substantially higher fatigue, and levels remained high or
decreased over time with no significant between-group
differences.
Quality of life
The exploratory analyses suggest benefits of EX regarding
role function (p 5 0.035, ES 5 0.48) and social function
(p 5 0.046, ES 5 0.44) as well as a beneficial tendency regard-
ing physical function (p 5 0.087, ES 5 0.55; Table 3, Fig. 2).
RC appeared to have a better effect than EX on “dry mouth”
(p 5 0.042, ES 5 20.50, Fig. 2, Supporting Information Table
S1). Effects did not differ substantially when including
patients with baseline depression. Among the 17 patients
with baseline depression, all functional scores were at a sub-
Cancer Therapy
(Table 3, Fig. 2). Cognitive performance improved signifi-
cantly in EX only, but the between-group difference did not
reach statistical significance.
Effect modification
Significant interactions were found for thyroxin use
(p 5 0.020 overall population, p 5 0.044 among patients with-
out baseline depression) and smoking in the year before diag-
nosis (p 5 0.011 or p 5 0.047, respectively). Both interaction
terms remained statistically significant even when included
simultaneously in the model.
Thyroxin was used by 22% of patients in EX and 28% in
RC (p 5 0.64). Stratified analyses showed significant interven-
tion effects on fatigue in the thyroxin users subgroup (Table
4), where fatigue increased significantly in RC but not in EX
regarding the physical dimension (p 5 0.015, ES 5 1.31) and
the affective dimension (p 5 0.027, ES 5 1.12). In thyroxin

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 8 Effects of resistance exercise on fatigue

Table 4. Fatigue pre-/postintervention, adjusted mean changes and between-group differences stratified by thyroxin use (patients without
baseline depression)
Preinterven- Postinterven- Adjusted2 mean Adjusted2 difference
tion, mean tion, mean change (95% CI) pre (95% CI) between-
Outcome Arm N1 (SD) (SD) to post groups p
Thyroxin users
Total fatigue Exercise 10 35.3 (12.4) 32.7 (20.9) 22.8 (213.5, 7.9) 219.3 (234.4, 24.1) 0.016
Relaxation 10 36.3 (18.1) 52.6 (15.6) 16.5 (5.8, 27.2)
Physical fatigue Exercise 10 42.7 (17.9) 37.5 (28.2) 24.7 (219.8, 10.4) 227.3 (248.6, 25.9) 0.015
Relaxation 10 40.6 (23.3) 63.7 (20.0) 22.6 (7.5, 37.6)
Affective fatigue Exercise 10 20.7 (10.2) 18.5 (11.1) 23.5 (211.8, 4.7) 213.7 (225.7, 21.8) 0.027
Relaxation 10 28.0 (14.0) 36.8 (16.5) 10.2 (1.9, 18.4)
Cognitive fatigue Exercise 10 26.7 (22.3) 33.3 (31.9) 4.6 (211.8, 21.0) 23.0 (226.3, 20.3) 0.79
Relaxation 10 34.4 (25.4) 40.0 (19.0) 7.6 (28.8, 24.0)
Thyroxin nonusers
Total fatigue Exercise 35 33.3 (18.8) 34.0 (18.5) 1.0 (24.7, 6.6) 23.4 (212.4, 5.5) 0.45
Relaxation 23 31.1 (16.0) 36.0 (21.6) 4.4 (22.6, 11.4)
Physical fatigue Exercise 35 35.3 (22.7) 37.2 (22.1) 2.3 (24.2, 8.8) 23.2 (213.6, 7.2) 0.54
Relaxation 23 33.5 (19.9) 39.5 (21.8) 5.5 (22.5, 13.6)
Affective fatigue Exercise 35 28.9 (23.5) 25.6 (23.7) 23.2 (28.8, 2.5) 23.8 (212.8, 5.2) 0.40
Relaxation 23 27.2 (21.3) 28.1 (25.6) 0.7 (26.3, 7.7)
Cognitive fatigue Exercise 35 30.2 (26.6) 33.7 (23.4) 3.8 (24.5, 12.0) 0.3 (212.8, 13.4) 0.96
Relaxation 23 29.0 (29.0) 32.9 (31.3) 3.5 (26.7, 13.6)
1
Number of patients with measures at both timepoints.
2
Regression models are adjusted for baseline value.
3
Abbreviations: CI 5 confidence interval; SD 5 standard deviation.

nonusers fatigue levels did not increase significantly over
time.
In the year before diagnosis, 24% of patients in EX and
13% in RC (p 5 0.19) were smokers. Among this group the
intervention effect on physical fatigue was significant
(p 5 0.0023, ES 5 1.67) and stronger than among nonsmokers
(p 5 0.32, ES 5 0.26). However, due to the small numbers in
Cancer Therapy
increase in EX suggests a substantial improvement, as many
breast cancer patients experience fatigue as the most distress-
ing side effect of chemotherapy.1 The observed significant
between-group difference of 10 points on the 0–100 scale
corresponds to the age-related increase in fatigue from
around age 25 to age 70 in the general female population.35
Thus, the benefit of resistance training on fatigue appears to

this subgroup and a large heterogeneity, as most patients quit
smoking after diagnosis, these results must be interpreted
with care.
Discussion
This randomized intervention trial in breast cancer patients
indicated a beneficial impact of resistance exercise during
chemotherapy on physical fatigue and QoL aspects, over and
above the psychosocial benefits related to supervised, group-
based interventions. Whereas in RC, physical fatigue and
physical, role and social function worsened during chemo-
therapy, EX showed no such deterioration. There was no sig-
nificant difference between EX and RC regarding the affective
or the cognitive fatigue dimension.
As in several other studies,32–34 we observed increasing
fatigue levels over the course of chemotherapy in our control
group. Thus, our finding that there is no such fatigue
be not only statistically significant but also clinically relevant.
Likewise, evidence-based guidelines for the interpretation of
changes in EORTC scores36 indicate that the observed effects
of exercise on role and social function are clinically relevant
of small to moderate size. As these function scores indicate
how much the disease impacts day-to-day tasks, leisure-time
activities, family life and relationships to friends, resistance
exercise appears to be a meaningful intervention that may
counteract the decline of these important aspects of QoL dur-
ing chemotherapy.
The comparison of our exercise intervention with a non-
exercise intervention with similar psychosocial conditions
enabled us to investigate the pure training effects, as the
study design controlled for factors associated with supervised,
group-based programs, such as social support from the
group, talking to other cancer patients, attention from a
trainer, travelling to a training facility twice a week and

Int. J. Cancer: 00, 00–00 (2014) V

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Schmidt et al.
gaining a positive attitude by becoming proactive. This aspect
has scarcely been investigated before. One randomized trial
investigating patients of different cancer types, both during
and after treatment, compared the effects of group psycho-
therapy with or without the addition of home-based (mainly
aerobic) exercise. That study also observed the significant
effect of exercise on fatigue and functional well-being beyond
the benefits of group psychotherapy.37 Another study found
that the beneficial effect of group-based exercise on QoL was
partly mediated by general self-efficacy and mastery, i.e.,
patients’ perception of being in control of ongoing
situations.38
Regarding type of exercise, a recent randomized trial in
breast cancer patients receiving chemotherapy found no sig-
nificant differences between a combined aerobic and resist-
ance training and a standard or high-dose aerobic training
with respect to fatigue.39 As our study investigated a resist-
ance training without any aerobic exercise (and consequently
without observed benefits on cardiorespiratory fitness), our
results suggest that resistance training is an effective type of
exercise, likely affecting fatigue via pathways independent
from the cardiovascular system, possibly via muscle mass or
function, inflammatory or metabolic factors. To explore the
biological mechanisms underlying the observed effect of the
resistance training on fatigue, comprehensive analyses of the
intervention effects on various aspects of isometric and isoki-
netic muscle strength, cardiorespiratory fitness, body compo-
sition, inflammatory parameters and other biomarkers and
their potential mediating roles are warranted. In line with
previous trials40,41 we observed no increase in lymphedema,
and resistance training appeared to be safe without causing
an increase in pain or any severe adverse events.
Excluding patients with depression at baseline yielded
clearer effects, likely because the pathophysiology of fatigue
might differ between patients with and without pre-existing
depression. In some randomized trials on cancer-related
fatigue, depression is even an exclusion criterion at recruit-
ment. Yet, this hasn’t been taken into consideration at set-up
of the BEATE study. Depression scores remained relatively
stable over the course of the intervention in both groups, and
there was no significant between-group difference.
The statistically significant interactions with thyroxin use
and smoking could be chance findings. In particular, the sig-
nificance of the smoking interaction is uncertain due to the
small numbers and large heterogeneity in the subgroups.
However, the interaction with thyroxin may be worth further
investigation within other trials. About a quarter of our
breast cancer patients used thyroxin (T4), mainly due to
diagnosed hypothyroidism or following a thyroidectomy. T4
is a potent steroid hormone that is primarily responsible for
the regulation of metabolism, and insufficient levels can cause
fatigue.42 Our data indicated a larger increase in fatigue dur-
ing chemotherapy in thyroxin users than nonusers in RC. In
contrast, thyroxin users in EX showed no increase in fatigue
during chemotherapy. Interestingly, a previous study
Int. J. Cancer: 00, 00–00 (2014) V
C 2014 UICC
9
observed that chemotherapy influenced thyroid function in
breast cancer patients, especially reducing the uptake of the
more bio-active triiodothyronine (T3) which originated from
T4, and it was hypothesized that this could contribute to
fatigue.43
Strengths of the BEATE study include the use of an active
control group, a well-defined and supervised resistance train-
ing, minimal drop-out rate and good intervention adherence.
Limitations include the incomplete information on nonparti-
cipants due to partial recruitment via posters and flyers,
which limits the generalizability of the results. At our major
recruiting center, however, we recorded the reasons for study
refusal, yielding long distances to the training facility or time
constraints as major barriers to participation. Further, due to
the explorative nature of the analyses regarding the different
dimensions of fatigue and QoL aspects, confirmation of the
results by other studies is needed. In fact, a parallel random-
ized trial (BEST-Study) with identical interventions as in
BEATE but in an independent population of breast cancer
patients during radiotherapy also demonstrated significant
benefits on physical fatigue and role function, although ESs
in the BEATE population during chemotherapy were larger.44
This strengthens the evidence that resistance exercise pro-
vides beneficial effects on physical fatigue and QoL. Although
the guidelines of the American College of Sports Medicine
and the American Cancer Society include resistance training,
in practice exercise recommendations and programs for can-
cer patients focus predominantly on aerobic exercise. There-
fore, our results will raise the awareness that resistance
training is effective and important in addition to aerobic
exercise.
Conclusion
While exercise unquestionably is generally good for health,
physicians, patients and their relatives are often still reluc-
tant to begin exercise during the already burdensome chem-
otherapy and uncertain what type of exercise might be
Cancer Therapy
effective. Our study indicates significant and clinically rele-
vant benefits of resistance exercise over and above the psy-
chosocial effects on fatigue and important QoL scales
during chemotherapy. Starting exercise early may prevent
the vicious cycle of impaired muscle strength, low physical
activity, fatigue and further reduction in physical activity,
which could lead to long-term health impairments even
after the successful completion of cancer treatment. Given
the observed safety and feasibility of supervised progressive
resistance training, it should be offered as an integral part
of supportive care for breast cancer patients undergoing
chemotherapy.
Acknowledgements
The study was funded by the German Cancer Research Center (DKFZ),
Division of Preventive Oncology. The interventions were partially supported
by the foundation “Stiftung Leben mit Krebs”. JW’s position was partially
funded by the “Manfred-Lautenschlaeger-Stiftung”. We would like to thank
 10
the patients who participated in this clinical trial; the Institute of Sports and
Sports Science at the University of Heidelberg for providing the training
facilities; H. Krakowski-Roosen, F. Baumann and A. Knicker for helpful dis-
cussions about the intervention program; L. Kempf, M. Bannasch, N. Ungar,
B. Biazeck and I. Pages and her team for performing the interventions; R.
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