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(Neo-)adjuvant chemotherapy for breast cancer is effective but has deleterious side effects on muscle tissue, resulting in reduced skeletal muscle mass, muscle function, and cardiorespiratory fitness. Various exercise regimens during cancer treatment have been shown to counteract some of these side effects. However, no study has compared the effect of high-intensity training versus low-to-moderate intensity training on muscle tissue cellular outcomes and physical function in patients with breast cancer during chemotherapy.
The aim of this substudy within the Physical Training in Cancer (Phys-Can) consortium is to evaluate and compare the effects of high and low-to-moderate intensity exercise on muscle cellular outcomes, muscle function, and cardiorespiratory fitness in women with breast cancer undergoing (neo-)adjuvant chemotherapy. We further aim to investigate if the effects of chemotherapy including taxanes on muscles will be different from those of taxane-free chemotherapy.
Eighty women recently diagnosed with breast cancer scheduled to start (neo-)adjuvant chemotherapy will be randomized to a combination of strength and endurance training, either at high intensity or at low-to-moderate intensity. Testing of muscle function and cardiorespiratory fitness and collection of muscle biopsies from the vastus lateralis muscle will be performed before the first cycle of chemotherapy (or after 1 week, when not possible) (T0), halfway through chemotherapy (T1), and after completion of chemotherapy (T2). It is estimated that approximately 50% of the participants will be willing to undergo muscle biopsies. To separate the effect of the treatment itself, a usual care group with no supervised training will also be included, and in this group, testing and collection of muscle biopsies will be performed at T0 and T2 only.
This study is funded by Active Against Cancer (Aktiv mot kreft) (May 2013) and the Norwegian Cancer Society (December 2018). Inclusion started in December 2016 and the last participant is expected to be recruited in December 2022. As of June 2022, we enrolled 38 (19 with biopsies) participants to the high-intensity training group, 36 (19 with biopsies) participants to the low-to-moderate intensity training group, and 17 (16 with biopsies) participants to the usual care group. Data analyses will start in fall 2022. The first results are expected to be published in spring 2024.
This study will generate new knowledge about the effects of different training intensities for women with breast cancer during chemotherapy treatment. It will give further insight into how chemotherapy affects the muscle tissue and how physical training at different intensities may counteract the treatment side effects in muscles. The results of this study will inform the development and refinement of exercise programs that are effective and compatible with the multidisciplinary management of breast cancer.
ClinicalTrials.gov NCT05218876; https://tinyurl.com/ysaj9dhm
DERR1-10.2196/40811
Breast cancer is the most common type of cancer in women in Europe [
Our clinical experience suggests that muscle function is more affected during taxane treatment than during anthracycline treatment. One frequent comment from patients during taxane treatment is the feeling of acidification during light and moderate physical activity. Taxanes have been reported to induce peripheral neuropathies [
Strength training improves muscular strength and muscle size [
Endurance training has been reported to reduce the cardiotoxic effects of anthracyclines in rodents [
To date, most studies have compared a single exercise intervention to usual care or interventions with no physical activity. High-intensity training is shown to induce larger improvements in VO2max and muscle strength in both healthy individuals and in various patient populations [
Data from the main study under the Physical Training in Cancer (Phys-Can) consortium showed that combined strength and endurance training with both low-to-moderate intensity and high intensity was feasible in patients with different types of cancer. Furthermore, high-intensity training led to better effects on muscle strength and VO2max compared to low-to-moderate intensity training [
In summary, the direct effects of chemotherapy on muscle tissue in women treated for breast cancer are mostly unknown and previous studies that have investigated the direct effects of (neo-)adjuvant chemotherapy on muscle tissue and how these effects may interfere with the adaptations to strength and endurance training in women diagnosed with breast cancer have had small sample sizes. Furthermore, no previous study has compared the effects of different training intensities on muscle cells in women with breast cancer during (neo-)adjuvant chemotherapy and it is still uncertain whether high-intensity exercise is feasible in all phases of the treatment. Thus, the aim of this study is to evaluate and compare the effects of high and low-to-moderate intensity exercise on muscle cellular outcomes, muscle function, and cardiorespiratory fitness in women with breast cancer undergoing (neo-)adjuvant chemotherapy. We further aim to investigate if the effects of chemotherapy including taxanes on muscle cells are different from those of taxane-free chemotherapy.
Our hypotheses are as follows.
Both high-intensity and low-to-moderate intensity strength and endurance training during (neo-)adjuvant chemotherapy will reduce the negative treatment effects on muscle fiber CSA, mitochondrial function, cellular stress, and thus reduce the negative effects on cardiorespiratory fitness and muscle function compared to usual care. High-intensity training will be superior to low-to-moderate-intensity training in counteracting the negative treatments effects.
Both high-intensity and low-to-moderate intensity strength and endurance training during (neo-)adjuvant chemotherapy will increase the muscle and blood levels of potential antitumor myokines compared to usual care.
Treatment including taxane administration will have larger negative effects on muscle fiber CSA, mitochondrial function, cellular stress, and thus cardiorespiratory fitness and muscle function compared to taxane-free treatment, regardless of the training intensity.
This study has been approved by the Regional Committee for Medical and Health Research Ethics South-East, Norway (2015/2360).
This study is a 2-group randomized controlled trial (
Study flowchart. HUH: Haukeland University Hospital; UUH: Uppsala University Hospital.
The primary outcome for this study is muscle fiber CSA, whereas secondary outcomes include muscle function, cardiorespiratory fitness, regulators of muscle fiber size and function (including mitochondrial enzymes, heat shock proteins, protein control systems, and DNA damage), and myokines with putative antitumor effects. All outcomes are listed in
Outcomes and assessments.
Outcomes and specific variables |
Assessment | ||
Muscle fiber size (muscle fiber cross-sectional area) | Cross-sections of muscle biopsies | ||
Number of myonuclei per muscle fiber (myonuclei/fiber) | Cross-sections of muscle biopsies | ||
Number of satellite cells per muscle fiber (satellite cell/fiber) | Cross-sections of muscle biopsies | ||
Proteins involved in muscle hypertrophy (PI3Ka/Aktb/mTORc-pathway, including but not limited to mTORc, P70s6kd, 4EBP1e, eIF4Af) | Western blot | ||
Proteins involved in muscle protein degradation (including but not limited to FOXOg, ubiquitin ligase E2, LC3h (I and II), p62i, myostatin, as well as ubiquitinated proteins) | Western blot | ||
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CSj, COX4k, HADHl | Western blot | |
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Mitochondrial structure | Cross-sections and whole fiber preparations of muscle biopsies | |
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Heat shock protein (Hsp)27, Hsp60, Hsp70 | Cross-sections of muscle biopsies, western blot | |
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DNA damage | Comet assay | |
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Muscle strength | 1 repetition maximum in chest press and knee extension. | |
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Muscular endurance | Repetitions until failure at 30% of 1 repetition maximum | |
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Cardiorespiratory fitness | Maximal oxygen uptake | |
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Lactate threshold | Blood lactate profile | |
Potential antitumor myokines (including, but not limited to interleukin (IL)-6, IL-15, SPARCm, TWEAKn, IL-8, IL-10, IL-1β, IFN-γo, TNF-αp, TNFR1q) | mRNA levels by real-time polymerase chain reaction analyses and protein levels by western blot and enzyme-linked immunosorbent assay | ||
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Lean body mass, total fat mass | Dual |
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BMI | Weight and height | |
Physical activity (level) | SenseWear Armband | ||
Serological outcomes (hemoglobin, creatine, cortisol, high-sensitivity C-reactive protein, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, HbA1c) | Standard clinical measures | ||
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Fatigue | Multidimensional fatigue inventory | |
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Pain | Brief pain inventory | |
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Health-related quality of life | European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30, The European Organization for the Research and Treatment of Cancer Quality of Life for breast cancer | |
Sociodemographic data (age, partnership, number and age of children living at home, education, income, work and sick leave) | Study-specific questionnaire | ||
Lifestyle data (dietary habits, alcohol consumption, physical activity level, weight, and tobacco use) | Study-specific questionnaire | ||
Behavioral data (motivation, self-efficacy, and barriers to training) | Study-specific questionnaire | ||
Disease-specific information (diagnosis, type, and dose of oncological treatment, adherence to oncological treatment) | Medical records | ||
Adverse events (adverse events occurring during exercise training sessions and during muscle biopsy sampling) | Reported by coaches/technicians |
aPI3K: phosphoinositol-3-kinase.
bAkt: protein kinase B.
cmTOR: mechanistic target of rapamycin.
dP70s6k: ribosomal protein S6 kinase.
e4EBP1: eukaryotic translation initiation factor 4E-binding protein 1.
feIF4A: eukaryotic initiation factor-4A.
gFOXO: forkhead box O.
hLC3: microtubule-associated protein 1 light chain 3.
ip62: ubiquitin-binding protein p62.
jCS: citrate synthase.
kCOX4: cytochrome c oxidase subunit 4.
lHADH: 3-hydroxyacyl-CoA-dehydrogenase.
mSPARC: secreted protein acidic and rich in cysteine.
nTWEAK: TNF-related weak inducer of apoptosis.
oIFN-γ: interferon γ.
pTNF-α: tumor necrosis factor-α.
qTNFR1: tumor necrosis factor receptor 1.
Women recently diagnosed with breast cancer starting (neo-)adjuvant chemotherapy (a combination of taxanes and anthracyclines or only one of the treatments or in combination with radiation therapy or endocrine therapy) are recruited from Haukeland University Hospital. Patients in the usual care group (see above) will also be recruited from Uppsala University Hospital. All potential participants must fulfill the following eligibility criteria: (1) diagnosed with stage I-III breast cancer, (2) >18 years old, (3) can understand and communicate in the Norwegian or Swedish language, and (4) scheduled to undergo (neo-)adjuvant chemotherapy with a combination of taxanes and anthracyclines or only one of the treatments or in combination with radiation therapy or endocrines. Women who are (1) not able to perform basic activities of daily living, (2) show cognitive disorders or severe emotional instability, and (3) experiencing other disabling comorbidities that might hamper physical training (eg, heart failure, chronic obstructive pulmonary disease, orthopedic conditions, neurological disorders) will be excluded. All eligible women will receive written information. Women who meet the inclusion criteria will be offered further information and invited to query any question about the study before being invited to participate.
Power calculations are based on findings in the Physical Exercise and Prostate Cancer trial [
Participants from Haukeland University Hospital will be randomized in a 1:1 ratio into the 2 training groups stratified by treatment (neoadjuvant or adjuvant treatment). The investigator performing the analyses on muscle biopsies will be blinded for this randomization. As described, participation in the usual care group will be from patients living too far away from the study site at Haukeland University Hospital or from Uppsala University Hospital and will not be randomized.
All participants in the training groups will perform both strength and endurance training throughout the course of treatment with chemotherapy, which is approximately 6 months. Trained coaches will guide both strength and endurance training.
The first 2-4 weeks after inclusion will be a familiarization period where the participants become familiar with the exercises and tests as well as how to use the Omni scale for self-reported perceived exertion [
During the 2-4 weeks familiarization period, participants will familiarize themselves with the use of the heart rate monitor and perceived exertion by using the Borg scale [
Muscle biopsies are obtained from the midsection of the vastus lateralis muscle under local anesthesia (xylocaine adrenaline, 10 mg·ml-1 + 5 μg·ml-1, AstraZeneca). Briefly, a 1-2-cm incision will be made in the skin and the fascia of the vastus lateralis muscle. Biopsies are collected using a 6-mm Pelomi needle (Bergström technique) with manual suction to obtain muscle samples (~200 mg). Biopsies will be rinsed in ice cold saline (0.9% NaCl) and carefully dissected free of visual fat, connective tissue, and blood. All pieces but 2 will be frozen in isopentane, precooled on dry ice, and stored at –80 °C for later analysis. The last 2 pieces (~10 mg) will be transferred to 500 μL of RNAlater stabilization solution (Invitrogen) and stored at 4 °C for at least 24 hours before 1 piece is transferred to –20 °C for long-time storage while the RNAlater solution is removed from the last piece before long-term storage at –80 °C.
Muscle fiber CSA represents the primary muscle cellular outcome. Muscle fiber CSA will be measured by immunohistochemical analysis of the cross-sections of the muscle biopsies. Briefly, transverse serial sections of the muscle biopsy (8-μm thick) will be cut using a cryostat microtome at –22 °C and mounted on glass slides. Serial cross-sections will be immunohistochemically stained for fiber types (type I, type IIa, and IIx) for CSA measurements. Muscle fiber CSA will be measured for the different fiber types separately.
The secondary muscle cellular outcomes reflecting the regulators of muscle fiber size are (1) number of myonuclei per muscle fiber, (2) number of satellite cells per muscle fiber, (3) proteins involved in muscle protein degradation (muscle breakdown), and (4) regulators of muscle protein synthesis (local growth factors). Muscle fiber myonuclear and satellite cell content per muscle fiber will be measured by immunohistochemical analysis of the cross-sections of muscle biopsies. Myonuclei and satellite cell contents per muscle fiber will be assessed for the different muscle fiber types separately. Regulators of muscle fiber size, that is, proteins involved in muscle protein synthesis and protein degradation will be measured by western blot analysis in the muscle homogenate. See
Proteins involved in protection against cellular stress (heat shock protein [Hsp]27, αB-crystallin, Hsp60, and Hsp70) as well as enzymes involved in mitochondrial function (citrate synthase, cytochrome c oxidase subunit 4, and 3-hydroxyacyl-CoA-dehydrogenase) will be assessed in muscle homogenates by western blot analysis. In addition, mitochondrial structures will be studied in cross-sections and whole fiber preparations of muscle biopsies by immunohistochemistry. DNA damage and repair will be assessed using the comet assay [
Exploratory analyses on the effects of the training on the expression levels of myokines, previously proposed to have an antitumor effect, will be conducted. Relevant targets, including, but not limited to, interleukin (IL)-6, IL-15, secreted protein acidic and rich in cysteine, and TNF-related weak inducer of apoptosis will be evaluated at the mRNA level by real-time polymerase chain reaction analyses (RNA extracted from biopsies) and at the protein level by western blot and enzyme-linked immunosorbent assays (muscle and blood samples). Blood samples will be obtained by venipuncture and participants are asked to avoid smoking and alcohol and not to engage in any strenuous physical activity 24 hours before the blood sample collection. The levels of IL-6, IL-8, IL-10, IL-1β, IFN-γ, tumor necrosis factor (TNF)-α, and TNFR1 will be measured using enzyme-linked immunosorbent assay–based methods. Frozen sera will be saved for further analyses that can be included later.
1RM testing will be performed as described previously [
Muscle endurance will be measured as the number of repetitions the patient is able to perform in a continuous set at 30% of 1RM at the corresponding time point in knee extension.
Cardiorespiratory fitness will be measured as VO2max during maximal walking/running until exhaustion on a treadmill (PPS Med 55, Woodway Inc). The protocols start at 5 km/h with an incline of 5%. The inclination increases with 1% every minute until it reaches 12%, from which the speed increases by 0.5 km/h per minute until exhaustion. Oxygen consumption and minute ventilation will be measured continuously using an oxygen analyzer (Oxycon Pro, Erich Jaeger GmbH; Vyntus CPX, Vyaire Medical GmbH). Heart rate will be measured using a heart rate monitor (T34, Polar Electro KY).
The patients will walk or run in 5 minutes at bouts with increasing submaximal workloads. Heart rate will be monitored continuously, and capillary blood samples will be taken and analyzed for lactate levels (Lactate Scout+, EKF GmbH) after each workload. The test will terminate when the patients show increased lactate concentrations by more than 1.6 mmol/L from the last workload or when the lactate increases above 4 mmol/L.
Total and regional lean body mass and fat mass together with bone mineral density will be measured by dual energy X-ray absorptiometry (iDXA, GE Lunar). Participants will be scanned from head to toe in a supine position, providing values for total and regional lean body mass fat mass, bone mineral content, and bone mineral density.
Participants’ physical activity level will be measured using SenseWear Armband Mini (BodyMedia Inc). All participants will be instructed to wear the SenseWear Armband for 7 consecutive days. Only valid days with at least 80% wearing time will be included in the analyses. The step count cut points corresponding to moderate intensity will be 3 metabolic equivalents of task [
The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [
Participants will provide self-reports about age, partnership, number and age of children living at home, education, income, work, sick leave, dietary habits, alcohol consumption, physical activity level, weight, tobacco use, motivation, self-efficacy, and barriers to training by using a study-specific questionnaire. In addition, past illnesses and other medical problems are recorded. Information about the medical situations such as treatment, stage of disease, and comorbidity as well as chemotherapy treatment compliance and adverse events will be collected at all 3 assessment points (T0, T1, and T2) from medical records.
Data will be analyzed according to the intention-to-treat principle. Analyses will include standard descriptive statistics, 2-sided
This study is funded by Active Against Cancer (Aktiv mot kreft) (May 2013) and the Norwegian Cancer Society (December 2018). It has been registered at ClinicalTrials.gov (identifier NCT05218876). At Haukeland University Hospital, inclusion started in December 2016 and the last participant is expected to be recruited in December 2022. As of June 2022, we enrolled 38 (19 with biopsies) participants to the high-intensity training group, 36 (19 with biopsies) participants to the low-to-moderate intensity training group, and 5 (4 with biopsies) participants to the usual care group. The recruitment to the usual care group from Uppsala University Hospital started in December 2018 and is finished with a total of 12 patients completing all data collection. Data analyses of the patients from Haukeland University Hospital will start in fall 2022. Data analyses of the patients at Uppsala University Hospital started in January 2022 and is ongoing. The first results are expected to be published in spring 2024.
The main aim of this study is to compare the effects of a high-intensity strength and endurance training program with those of a low-to-moderate intensity strength and endurance training program on muscle cellular outcomes, muscle function, and cardiorespiratory fitness in women undergoing breast cancer chemotherapy. These results will also be compared with those of the group treated with usual care to investigate how (neo-)adjuvant treatment with chemotherapy will affect these variables and how high and low-to-moderate intensity trainings can counteract the effects of treatment. We hypothesize that the usual care control group will experience negative treatment effects on muscle fiber CSA and mitochondrial function, leading to reduced muscle function and cardiorespiratory fitness. We further expect that both high-intensity training and low-to-moderate intensity training performed by the training groups will counteract the negative treatment effects and that high-intensity training will be superior to low-to-moderate-intensity training. The results of our study are expected to provide insights on how regular exercise during treatment may counteract the side effects of chemotherapy on physical functioning and muscle tissue and how training intensity impacts these effects. Such knowledge can be used to design effective physical exercise programs, helping an increasing number of individuals with breast cancer during and following chemotherapy and possibly reducing the long-lasting side effects and ultimately improve the quality of life.
Forty women recently diagnosed with breast cancer, with 20 in each group, will give us a larger study population than those in previous studies on muscle cellular outcomes [
Although the primary outcome of this study is muscle fiber CSA, we are also including a wide range of biological measurements, including specific proteins involved in skeletal muscle hypertrophy, protein degradation/protein control, and regulators of muscle fiber function. These analyses will provide further insight into the underlying mechanism through which chemotherapy affects muscle tissue and therefore, muscle function, and how training with different training intensities could be used as a therapeutic measure to counteract the side effects of chemotherapy. We will recruit patients undergoing chemotherapy with anthracyclines, taxanes, or a combination of both. Given a large enough number of patients receiving different treatments, this will give us the opportunity to investigate if different chemotherapy regimens affect the adaptations to training at different intensities. Due to individual treatment protocols, there probably will be differences between participants in the treatment regimen, for example, different type and doses of chemotherapy. This might lead to differences between the 2 training groups and between the training groups and the usual care control group in treatment. The lack of randomization to the usual care control group is also a limitation. This will, together with the fact that most participants in this group are treated at a different site than the training groups, further increase the risk of differences between the training groups and the usual care control group in the treatments and other relevant factors. The results from this study are planned to be published in scientific peer review journals and at scientific congresses.
In summary, previous research underlines the positive potential of regular physical exercise during cancer treatment on outcomes such as physical function, mental health, fatigue, and quality of life in women with breast cancer [
Peer review report by: Norwegian Cancer Society (Oslo, Norway).
cross-sectional area
heat shock protein
interleukin
Physical Training and Cancer
repetition maximum
test period before the first chemotherapy cure
test period halfway into the treatment
test period after completion of treatment
tumor necrosis factor
maximal oxygen uptake
This study is funded by Active Against Cancer (Aktiv mot kreft) (May 2013) and the Norwegian Cancer Society (December 2018).
The data that will be generated from this study is planned to be included in the scientific articles that will be published. Data not included in published articles will be available from the corresponding author on reasonable request.
TR, SB, KN, and ID conceived the original study idea and designed this study. THW, TR, SB, OV, and ES designed the data collection tools and methods. OV, THW, and TR will perform data analyses. THW and IT perform project administration. OV drafted the original manuscript while all authors reviewed and approved the manuscript. TR and IT were responsible for funding acquisition.
None declared.