Journal of Cancer Research and Clinical Oncology

https://doi.org/10.1007/s00432-017-2573-5

ORIGINAL ARTICLE – CLINICAL ONCOLOGY

Influence of physical activity on the immune system in breast cancer

patients during chemotherapy
Thorsten Schmidt1   · Walter Jonat2 · Daniela Wesch3 · Hans‑Heinrich Oberg3 · Sabine Adam‑Klages3 · Lisa Keller2 ·
Christoph Röcken1 · Christoph Mundhenke2

Received: 20 November 2017 / Accepted: 27 December 2017

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose  Physical activity can impact the immune system in different ways, e.g. by alteration of the humoral and cellular
immune response. Physical activity at medium intensity enhances numbers of cytotoxic T cells, NK cells and macrophages
in healthy people. The aim of this study was to compare the effects of endurance and resistance training on the immune
system in breast cancer patients during adjuvant chemotherapy.
Methods  In a prospective, controlled and randomized intervention exploratory trial, 12-week supervised endurance or resist-
ance training were compared with usual care twice a week. Endpoints were the absolute numbers of the immune cells such
as ­CD3+ T lymphocytes including ­CD4+- and ­CD8+, αβ T cells, γδT cells, ­CD3−/CD16+/56+ NK cells and ­CD19+ B cells,
before and after 12 weeks of treatment. Cell numbers were analyzed using fluorescence-activated cell sorting.
Results  Despite different physical interventions in all groups immune cell count decreased in CD3 T cells including TCR αβ
and CD4 T cells, NK cells and CD19 B cells 12 weeks after initiation of chemotherapy and start of the physical intervention
program, while the reduction of γδ T cells and CD8 T cells is less prominent in the RT and UC group.
Conclusion  Chemotherapy led to a decrease in nearly all measured immune cells. In this study, physical intervention with
endurance or resistance training did not suppress cellular immunity any further. Larger multicenter trials are needed to evalu-
ate the exact impact of sports intervention on immune cell subpopulations.

Keywords  Physical activity · Breast cancer · Immune system · Chemotherapy

Introduction evaluated. It has been suggested that physical activity can

For primary prevention and the prevention of breast can-
cer recurrence it is important to assess the potential of new
approaches to supportive care. Nowadays, physical activ-
ity is often used as adjunctive therapy during chemo‑ and
radiotherapy to relieve disease and therapy related symp-
toms. In several randomized controlled trials the influence
of physical activity of breast cancer patients during medical
treatment on psychological and physical parameters has been
* Thorsten Schmidt
Thorsten.schmidt@uksh.de
1
Comprehensive Cancer Center North, University of Kiel,
Arnold‑Heller Straße 3, Haus 14, 24105 Kiel, Germany
2
OB/GYN, University of Kiel, Arnold‑Heller Straße 3, Haus
24, 24105 Kiel, Germany
3
Institute of Immunology, University of Kiel, Arnold‑Heller
Straße 3, 24105 Kiel, Germany
not only improve physical performance, but also influences
factors as quality of life, depression and fatigue (Baumann
et al. 2013; Courneya et al. 2013, 2014; Hayes et al. 2013;
Markes et al. 2006).
The effector function of the immune system is impaired
with advanced age and by exogenous agents. For instance,
immunological reactions can be diminished by inactivating
antigen‑specific B and T cells through, e.g. altered presenta-
tion and costimulation by dendritic cells or macrophages as
well as through influencing innate immune functions of nat-
ural killer (NK) cells and neutrophils (Brolinson and Elliott
2007; Pawelec et al. 2001). This appears to be important for
the increased incidence of malignant diseases in the elderly
persons (Senchina and Kohut 2007). Risk factors such as
advanced age, hereditary factors, obesity, lifestyle, environ-
mental pollution, nicotine and physical activity influence
the immune system and play a role in carcinogenesis. While
the influence of physical activity on the immune system in

13
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healthy athletes and older adults has already been studied
well for many years (Brolinson and Elliott 2007; Gleeson
and Walsh 2012; Pedersen 1991; Pedersen and Bruunsgaard
1995; Phillips et al. 2010), the impact on the immune system
of cancer patients and on disease progression has not been
adequately investigated. Initial findings on the immunologi-
cal impact of physical activity in cancer patients have been
made in the 1990s. (Nieman et al. 1995; Peters et al. 1994;
Uhlenbruck and Order 1991).
Currently, only a small number of studies evaluated the
effects on the immune system of breast cancer patients. Sev-
eral authors described an enhanced immune function and a
low susceptibility to cancer which occur with regular mod-
erate exercise, whereas inactivity and/ or exhaustive exer-
cise suppress immune function, and elevate susceptibility
to infections (Fairey et al. 2005, 2002; Hagstrom et al. 2016;
Hutnick et al. 2005; McTiernan 2008; Peters et al. 1994).
Most of these studies focus on the period after adjuvant ther-
apy and investigated endurance training as the intervention
method, whereas resistance training as intervention and the
influence of physical activity during chemotherapy on the
immune system are underrepresented (Fairey et al. 2002;
Hagstrom et al. 2016; Hutnick et al. 2005; Mohamady et al.
2013; Nieman et al. 1995; Peters et al. 1995, 1994; Saxton
et al. 2014; Zimmer et al. 2016).
The aim of the study was to compare the effects of resist-
ance and endurance training with standard care on the
immune system of women with primary breast cancer dur-
ing adjuvant chemotherapy.
Materials and methods
Design and procedures
In this prospective, controlled and randomized intervention
exploratory trial 12-week supervised resistance training
(RT) or endurance training (ET) were compared with usual
care (UC) in women with primary moderate or high risk
breast cancer during adjuvant chemotherapy. An overview
of the study flow is shown in Fig. 1. Patients were recruited
at an academical breast unit in Germany. Inclusion criteria
were: primary moderate or high risk breast cancer, planned
adjuvant or neoadjuvant chemotherapy with epirubicine/
cyclophosphamide (EC) (4×, q3w) followed by paclitaxel
(12×, q1w), fluorouracil/epirubicine/cyclophosphamide
(3×, q3w) followed by doxetaxel (3×, q3w) or further
chemotherapy regimen 18–70 years old women and fitness
to exercise. Exclusion criteria comprised, acute infectious
disease, severe cardiac disease (New York Heart Associa-
tion functional class III; myocardial infarction < 3 months),
severe pulmonary or renal insufficiency (glomerular filtra-
tion rate < 30%), serious neurological disorders, less than
13
Journal of Cancer Research and Clinical Oncology
• Screening
• Determination of the immune parameter
T1 Baseline • Randomization
• Arm 1: Resistance training
• Arm 2: Endurance training
Chemotherapy • Arm 3: Usual care
• Determination of the immune parameter
T2 End of study
• Collection of all data
Chemotherapy
Fig. 1  Study flow
10,000 platelets per ml, hemoglobin < 8 g/dl and a planned
radiotherapy during the study. The active study period was
from the initiation of chemotherapy to the end of EC appli-
cation. The study was approved by the local review board
(registration number: AZ A 157/11). All participants were
included in the study after providing written informed con-
sent, as required by the Declaration of Helsinki (1975).
Randomization
After baseline assessments the patients were assigned ran-
domly (1:1:1) to RT, ET UC using a computer-generated
program. The allocation sequence was executed by the clini-
cal research unit and concealed from the project team. To
prevent possible bias, the investigators and study nurses did
not have access to the randomization files.
Statistical analysis
The analyses included data of patients who attended a mini-
mum of 70% of the training sessions according to the proto-
col. Immunological profiles were assessed at baseline on the
day when chemotherapy (T1) was initiated, 12 week after
initiation of chemotherapy and physical intervention (T2).
Primary endpoints of this trial were the absolute number
count of T cell receptor (TCR) αβ and TCR γδ ­CD3+ T cells
­(CD3+), ­CD3+ TCR γδ T cells alone (γδ T cells), ­CD3+
TCR αβ T cells (αβ T cells), αβ T helper cells ­(CD4+), αβ-
and γδ cytotoxic T cells ­(CD8+), ­CD8− γδ T cells, NK cells
­(CD3−/CD16+/56+) and B cells (CD19). Obtained results
at baseline were compared across the treatment and control
groups using an independent t test for continuous outcomes.
Statistical significance for the t test at T1 and T2 was set at
the probability level of p < 0.05. The effects are expressed
with mean and standard deviations. The analyses were per-
formed using the SPSS system for windows (Version: PASW
18).
Journal of Cancer Research and Clinical Oncology

Setting and participants completed one training set of 20 repetitions with a hypo-

Out of 100 patients screened between February 2012 and
October 2013, 81 patients were enrolled in the study and
randomized before the start of chemotherapy into the inter-
vention groups ET and RT or usual care (UC). Nineteen
patients did not enroll due to timing problems. Due to chem-
otherapy related side effects or withdrawal of consent 14 out
of 81 patients dropped out: three withdrew from the RT, nine
from the ET and two from the UC. The data of 67 patients
were fully evaluable (21 patients in the RT, 20 in the ET and
26 in the SC). An overview of the patient cohort is shown
in Tables 1, 2.
Exercise training intervention
RT and ET were performed during the period of chemo-
therapy. After the initiation of chemotherapy, both physi-
cal interventions took place for 60 min twice a week for
12 weeks. The training sessions of the RT and ET were
supervised and documented by experienced exercise ther-
apists. Before each resistance and endurance training the
individual intensity levels were checked according to the
exercise guidelines for cancer survivors of the American
College of Sports Medicine (36).
To define the individual resistance for each exercise the
therapist carried out the hypothetic one-repetition maximum
(h1RM) according to the Brzycki Method (Brzycki 1993)
in the first training session of the RT group. The h1RM is
a dynamic maximum force test and was performed accord-
ing to the repetition method. Hereby, the therapist chose
the weight to avoid that the patient carry out more than 20
repeats (Gießing 2003). The h1RM test took place on all
workout machines. At the beginning, patients of the RT
thetical 50% of the maximum weight. The training took
place on the following devices: squat, chest press, leg curl,
rowing, leg extension, upper arm curl, upper arm extensors,
shoulder press, abdominal bench and lats pull down. Any
further increase in intensity was based on the Borg scale
(Borg 1998; Wahlund 1948).
The endurance training took place on an indoor bike
(Tomahawk, Indoorcycling group, Nürnberg, Germany).
The Borg-scale was used as a subjective reference point for
the performance during the training. During the training,
patients exercise for 45 min. After a 10-min warm-up, the
patients exercise for 25–30 min followed by a 5 min cool
down. The patients were encouraged to be active at Borg
level 11–14 (Borg 1998; Wahlund 1948).
The training intervention took place on Monday and
Wednesday, while the chemotherapy took place on Thursday.
Usual care
Participants in the usual care group were informed about
the feasibility of physical activity and the impact of physi-
cal activity during chemotherapy. Patients did not receive a
supervised training.
Determination of the immune parameter
The determination of the absolute cell number as immune
parameters was made by flow cytometry (Fulwyler 1965)
using a FACS Canto and the DIVA software. The BD Mul-
titest 6-color TBNK (M6T) Reagent with BD Trucount™
Beads (http://www.bd.com/resource.aspx?IDX=17743
DX = 17,742, BD Biosciences, San Jose, CA, USA)
was applied to determine the absolute number of αβ T

Table 1  Anamnestic and n Age (years) Height (cm) T1 weight (kg) T2 weight (kg) p value
anthropometric parameters of (mean ± d) (mean ± d) (mean ± d) (mean ± d)
the patients
RT 21 53 ± 12.55 176 ± 5.63 74.8 ± 15.83 75.7 ± 10.28 0.82 (n.s.)
ET 20 56 ± 10.15 175 ± 4.87 72.1 ± 12.35 73.2 ± 9.10 0.75 (n.s.)
UC 26 54 ± 11.19 177 ± 2.57 76.3 ± 15.40 76.1 ± 13.50 0.96 (n.s.)

Table 2  Different Chemotherapies of the intervention groups and the standard care group
4 × epirubicin/cyclo- 4 × epirubicin/cyclo- 3 × fluorouracil/Epiru- 3 ×  fluorouracil/ Further chemo- Further chemo-
phosphamid, q3w, phosphamid, q3w fol- bicin cyclophospha- epirubicin cyclophos- therapy-regimen therapy-regi-
followed by 12 × taxol lowed by 4 × docetaxel, mid, q3w, followed by phamid, q3w, followed men + herceptin
weekly q3w 3 × docetaxel, q3w by 3 × docetaxel,
q3w + herceptin

RT 10 3 1 1 5 1
ET 16 2 0 2 0
UC 13 6 1 5 1

13

lymphocytes including ­CD4+ and ­CD8+ T cell subsets as
well as NK cells and B lymphocytes (Hensley et al. 2012;
Nicholson et al. 1997). Since γδ T cells are not detected by
M6T, we adapted γδ T cell staining and monitoring from the
BD Trucount™ Tube technical data sheet (version 8/2010)
as described elsewhere (Oberg et al. 2014). The blood sam-
ple was taken before the first chemotherapy (T1) and after
12 weeks before the fourth chemotherapy.
Results
As shown in Table 3, the absolute number of ­CD3+ T lym-
phocytes drastically decreased in all groups within 12 weeks
after the initiation of chemotherapy and physical interven-
tion (RT: − 19.32%, p: 046; ET: − 25.78%, p: 0.001; UC:
− 21.54%, p: 0.001). While the decrease of absolute CD3 T
cell number was highly significant in the ET and UC group,
a non-significant reduction was observed in the RT group.
Regarding the different C ­ D3+ T cell subsets, αβ T cells
highly significantly decreased in all groups with less extent
in the RT group (RT: − 19.84%; p: 0.04; ET: − 26.22%; p:
< 0.0001; UC: − 21.86% p: < 0.0001), whereas the absolute
γδ T cell number was nearly stable, in contrast to αβ T cells
within 12 weeks (RT: +0.89%, p: 0.95; ET: 16.16%, p: 0.14;
UC: − 14.93%, p: 0.12). In detail, γδ T cells were stable
within 12 weeks in the RT and only slightly decreased in
the ET- and UC group. Interestingly, similar results as for
γδT cell population were measured for C ­ D8+ T cells which
co-express either the TCR αβ or occasionally TCR γδ(RT:
− 10.93% p: 0.13; ET: − 16.89% p: 0.04; UC: − 4.00% p:
0.41) whereas a significant decrease of the ­CD4+ T cells
was detected in all three groups (RT: − 31.96% p: 0.001; ET:
− 35.14%; p: 0.001; UC: − 29.17% p: 0.001).
In addition, NK cells (CD16/CD56) were slightly reduced
in the RT and UC group and highly significant in the ET
group (RT: − 22.88% p: 0.53; ET: − 40.16% p: 0.001; UC:
− 19.39% p: 0.05). Extremely striking was the highly signifi-
cant reduction of the B cells (CD19) in all three groups (RT:
− 86.60%; p: 0.001; ET: − 92.59%, p: 0.001; UC: − 88.76%,
p: 0.001). The differences of all immune parameters between
the arms are not significant.
Discussion
Meanwhile there is evidence for a benefit of physical activity
during medical treatment and in aftercare of breast cancer
patients. Previous studies documented an improvement in
physical function, fatigue and quality of life after interven-
tional physical activity (Adamsen et al. 2009; Baumann et al.
2013; Courneya et al. 2014a, b; Mishra et al. 2012; Schmidt
et al. 2015).
13
Journal of Cancer Research and Clinical Oncology
Previous studies that investigated the influence of physi-
cal activity on the immune system of breast cancer patients
focused mainly on the time after medical treatment and
described the effect on the cells of the immune system and
changes in cytotoxins. In a systematic review (Schmidt et al.
2017a, b) we identify ten studies, who investigate especially
in the effects of physical training on the immune system
(NK cells, monocytes macrophages, lymphocytes or the
tumor-associated macrophages, interleukines and the tumor
necrosis factor (TNF)) of breast cancer patients (Evans et al.
2015; Fairey et al. 2005; Hagstrom et al. 2016; Hutnick et al.
2005; Mohamady et al. 2013; Nieman et al. 1995; Peters
et al. 1995, 1994; Saxton et al. 2014; Zimmer et al. 2016).
The results of these studies show that the NK cell popula-
tions increase or their function improves due to different
sports interventions. Fairey et al. and Peters et al. report in
addition a change in the lymphocyte population. Both the
NK-cells and also the lymphocytes play an important role
in the immune system and the immunoreaction (Fairey et al.
2005; Peters et al. 1995, 1994).
Our study represents a first attempt to obtain informa-
tion about the influence of several training programs on
the immune system of breast cancer patients undergoing
chemotherapy. In contrast to our results, Hagstrom et al.
could determine a positive effect of physical training on
the immune system of breast cancer patients in aftercare.
39 BC patients were randomized to an intervention and a
control group. The 20 participants in the intervention group
completed equipment training over 16 weeks at 80% of the
“one repetition maximum”. The NK-cells, the “natural killer
T-cells” (NKT) and the inflammation markers TNF-α, IL-6,
IL-10 and CRP (C reactive protein) were measured before
and after the intervention. The results showed an altered
TNF-α expression in NK- and NKT cells of the intervention
group compared to the control group (Hagstrom et al. 2016).
This result corresponds to findings obtained in other stud-
ies (Fairey et al. 2002; Hagstrom et al. 2016; Hutnick et al.
2005; Mohamady et al. 2013; Saxton et al. 2014; Zimmer
et al. 2016).
In our study the absolute cell number of NK cells, B cells
and T cells decreased in the intervention groups as well in
the control group with a lowest reduction of the CD3 T cells
to T2 in the resistance group. While in the past, discouraged
from physical activity during chemotherapy on the basis of
a physical activity induced immunosuppression, our data
describe that supervised physical activities has no influence
on chemotherapy induced immunosuppression. Slightly no
significant higher values or lower reduction of the subsets
of immune parameter (γδ T cells and CD8 T cells) from T1
to T2 we observed in the resistance group.
The different results of the studies can be attributed to the
various study designs. While the present study concentrates
on the phase during chemotherapy, previous studies focused
 Table 3  Immune cells at T1, T2, T3 in the RT, EC an UC-group
CD3 CD4 CD8 CD19
T1 vs. T2 p % Change T1 vs. T2 p % Change T1 vs. % Change T1 vs. T2 p % Change
value T1/T2 value T1/T2 T2 p T1/T2 value T1/T2
value

RT
 T1 1252.82 ± 422.86 0.46 − 19.32 827.33 ± 317.86 0.001 − 31.96 359.67 ± 156.92 0.13 − 10.93 191.81 ± 78.78 0.001 − 86.60
 T2 1010.81 ± 484.96 562.86 ± 210.31 320.33 ± 208.24 25.71 ± 33.09
ET
 T1 1153.40 ± 365.05 0.001 − 25.78 753.60 ± 259.90 0.001 − 35.14 339.40 ± 173.98 0.04 − 16.89 172.70 ± 71.93 0.001 − 92.59
 T2 856.00 ± 379.00 488.75 ± 192.85 282.05 ± 152.28 12.80 ± 11.07
UC
Journal of Cancer Research and Clinical Oncology

 T1 1255.48 ± 340.32 0.001 − 21.54 788.60 ± 199.43 0.001 − 29.17 369.84 ± 150.37 0.41 − 4.00 183.20 ± 79.71 0.001 − 88.76
 T2 985.00 ± 323.98 558.60 ± 159.44 355.00 ± 170.71 20.6 ± 20.08
T2 0.41 0.36 0.40 0.21
between
the
groups
p-value
T2 Δ 0.91 0.8 0.41 0.97
between
the
groups
p-value
CD16/56 γδ αβ
T1 vs. T2 p value % Change T1/T2 T1 vs. T2 p % Change T1/T2 T1 vs. T2 p % Change T1/T2
value value

RT
 T1 230.14 ± 118.26 0.53 − 22.88 42.67 ± 25.96 0.95 + 0.89 1209.76 ± 411.78 0.04 − 19.84
 T2 177.48 ± 118.05 43.05 ± 29.74 969.38 ± 473.59
ET
 T1 182.65 ± 82.44 0.001 − 40.16 41.75 ± 47.66 0.14 − 16.16 1112.35 ± 355.27 0.00 − 26.22
 T2 109.30 ± 42.30 35.00 ± 52.45 820.70 ± 358.57
UC
 T1 188.76 ± 79.30 0.05 − 19.39 53.84 ± 66.48 0.12 − 14.93 1203.64 ± 328.85 0.00 − 21.86
 T2 152.16 ± 99.20 45.80 ± 48.65 940.48 ± 308.83
T2 between 0.07 0.72 0.42
the groups
p-value

13
 Journal of Cancer Research and Clinical Oncology

on the time after the operation, chemotherapy or radiation

% Change T1/T2
therapy. Furthermore, the sport and exercise programs in the
studies cited differ in several points, so that comparability
is limited. The intervention programs differ with respect to
their intensity, duration of the individual training sessions,
their frequency and the overall extent of physical activity.
T1 vs. T2 p

While Hagstrom et al. conducted a resistance training

with an intensity of 80% of the 1RM, Zimmer et al. con-
value

ducted a single intervention as a half-marathon, Evans et al.

an interval training on a cycle ergometer with 60% of the
VO2 max, Saxton et al. a progressive aerobic and strength
training at 65–85% heart rate, Hutnick et al. an endurance
and exercise program at 60–70% of the functional capac-
ity, Niemann et al. a supervised walking training at 75%
0.91

of HFmax and Peters et al. a cycle ergometer training at

αβ

60–80% HF max. Mohamady et al. performed a mobilization

and mobility training, Fairey et al. a cycle training without
% Change T1/T2

specific details about the impact. Other differences can be

observed with respect to the length of the individual train-
ing sessions (30–60 min), the frequency (three times per
week–five times per week) and the overall duration (between
8 weeks and 7 months) (Evans et al. 2015; Fairey et al. 2005;
T1 vs. T2 p

Hagstrom et al. 2016; Hutnick et al. 2005; Mohamady et al.

2013; Saxton et al. 2014; Zimmer et al. 2016).
value

A further common limitation for the comparison of all

the studies is the time at which blood samples were drawn
(directly after training, 24 h after training or at some other
time). The changes in the immune cell numbers are short-
lived and are often determined by the type and duration of
0.44

activity.
γδ

A limitation of this study is the small sample size with

an inhomogeneous collective relating to the chemotherapy
% Change T1/T2

(Table 2) and the lack of attention to additional activity on

the job, in everyday life and leisure during the study. Addi-
tionally, the blood sample were taken before the chemo-
therapy and not immediately after the resistance and endur-
ance training, so that the acute influence of physical activity
could not demonstrated. In the course of our study, we ana-
T1 vs. T2 p value

lyzed the effects of a resistance and endurance training over

the first 12 weeks with the largest chemotherapy induced
immunosuppression. Following studies should include an
increased sample size for a subgroup analysis of chemother-
apy-groups and should analyse the impact over the whole
time of chemotherapy.

Conclusion
CD16/56

0.43
Table 3  (continued)

In conclusion, the results of the present study, support the

current literature and show the possibility of a resistance
T2 Δ between
the groups

and endurance training during chemotherapy without an

p-value

immunosuppression. Scientific and more specific state-

ments about the effect of targeted sports intervention after

13
Journal of Cancer Research and Clinical Oncology
a breast cancer diagnosis such as the dose/effect relation-
ship are possible only after further prospective, standardized
and controlled clinical studies confirming the assumption of
an immunomodulating effect of physical activity. Further
studies should be the focus of these points to enable more
precise statements on the intensity, duration and extent of
sport activities.
Acknowledgements  With kind support of the Cancer Society
Schleswig–Holstein, the Krumme Foundation and of the Foundation
Living with Cancer (Stiftung Leben mit Krebs), O. Stremme, MD, our
medical technicians S. Haman and F. Rösel, our study nurse B. Schütt
and K.Yoo-Ott as well as S. Ussat for technical assistance.
Compliance with ethical standards  tion and treatment-related side effects following breast cancer.
Conflict of interest  There are no conflicts of interest.
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