Exercise in Older Women With Breast Cancer During Systemic Therapy - a Randomized Controlled Trial (Breast Cancer Exercise Study)
Phase: NA
Conditions: Breast Cancer
Sponsor: Herlev and Gentofte Hospital

 
 
1 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
 
 
 
 
 
 
Clinical Study Protocol 
Exercise in older women with breast cancer during systemic therapy – a 
randomized controlled trial 
 
The study is one of five studies included in the TOLCA project “Translational and clinical research 
focused on OLder patients with CAncer aiming to improve patient survival and quality of life”. 
 
 
 
 
 
 
 
 

 
 
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Indholdsfortegnelse 
 
Synopsis ........................................................................................................................ 4 
Generel information .................................................................................................... 8 
List of abbreviations .................................................................................................... 9 
1. Introduction ........................................................................................................... 10 
1.1 The aging process......................................................................................................................... 10 
1.2 Cancer and aging .......................................................................................................................... 11 
1.3 Sarcopenia and cancer cachexia ................................................................................................... 11 
1.4 Exercise training .......................................................................................................................... 13 
1.5 Breast cancer ................................................................................................................................ 13 
1.5.1 Exercise training in patients with breast cancer ................................................................ 16 
2. Study rationale and aim ........................................................................................ 17 
3. Research questions and hypotheses ..................................................................... 17 
3.1 Research questions ....................................................................................................................... 17 
3.2 Study hypotheses.......................................................................................................................... 18 
4. Design and methods ............................................................................................... 18 
4.1 Design .......................................................................................................................................... 18 
4.2 Recruitment of patients ................................................................................................................ 18 
4.3 Inclusion criteria .......................................................................................................................... 19 
4.4 Exclusion criteria ......................................................................................................................... 19 
4.5 Stratification at randomization ..................................................................................................... 20 
4.6 Intervention .................................................................................................................................. 20 
4.7 Study assessments and data collection ......................................................................................... 23 
4.8 Inflammatory biomarkers (data collection and assessment) ........................................................ 27 
4.9 Time of data collection and tests .................................................................................................. 29 
4.10Analyses and statistics ................................................................................................................ 29 
4.10.1 Sample size ...................................................................................................................... 29 
4.10.2Analysis plan .................................................................................................................... 30 
5 Ethical considerations ............................................................................................ 30 

 
 
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6 Potential risks and disadvantages ......................................................................... 31 
6.1 Radiation exposure ....................................................................................................................... 31 
7 Publication of study results ................................................................................... 31 
8 Economy .................................................................................................................. 32 
9 Scientific statement ................................................................................................. 32 
10 Clinical perspectives and implementation ......................................................... 33 
11 References ............................................................................................................. 34 
Appendix 1: Performance status .............................................................................. 34 
Appendix 2: Patient questionnaire (Danish) ........................................................... 35 
Appendix 3: M.D. Anderson Symptom Inventory (Danish version) .................... 38 
Appendix 4: EORTC Quality of Life Questionnaire (Danish version) ................ 41 
DANISH............................................................................................................................................. 44 
Appendix 5: The Hospital Anxiety and Depression Scale (Danish Version) ....... 45 
References .................................................................................................................. 47 
 
 
 
 

 
 
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Synopsis 
 
Title  
Exercise in older women with breast cancer during systemic therapy – a 
randomized controlled trial. 
Introduction 
Although cancer is predominantly a disease of the elderly, older cancer 
patients are underrepresented in clinical trials. Aging itself is associated 
with limitations in physical function, reduced reserve capacity, a poorer 
resilience to physiological stressors, and an increased burden of 
comorbidities. A diagnosis of cancer and its accompanying treatments can 
lead to numerous symptoms and side effects, physical disability, 
psychological distress and increased health care needs. The interplay 
between age-related and cancer-related declines in health increases 
vulnerability and the risk of development of short and long-term disability. 
Research has shown that exercise training has several beneficial effects in 
cancer patients and survivors both during and after anti-cancer treatment. 
However, older patients have often been underrepresented in these studies, 
and only few exercise-based intervention studies have specifically focused 
on older cancer patients. Breast cancer is a malignancy associated with 
aging. Research projects that investigate the effect of interventions that 
may reduce symptoms, maintain physical function, and optimize QOL are 
wanted.  
 
The TOLCA Breast Cancer Exercise study will be conducted similar to the 
ongoing PACE-MOBIL-PBL study regarding physical therapy. 
Design 
TOLCA Breast Cancer Exercise study is a two-armed 1:1 randomized 
controlled study in older patients with breast cancer treated with adjuvant 
or first-line palliative systemic therapy.  
Target population 
Older patients with breast cancer who are treated with adjuvant or first-line 
palliative systemic therapy.  
Number of Centers 
and setting 
Single center. Department of Oncology and Department of Occupational 
Therapy and Physiotherapy, Herlev and Gentofte Hospital.  
Objectives 
To investigate the effect of an exercise-based intervention on physical 
function and capacity, cancer-related symptoms and side-effects, 
depression and anxiety, quality of life, body composition, treatment 
tolerance and toxicity, inflammation, hospital admissions, and survival.  
Selection Criteria 
Inclusion criteria: 
• Be operated for primary breast cancer within 12 weeks or 
• Be diagnosed with locally advanced or metastatic breast cancer. Be 
treated with adjuvant or first-line palliative therapy defined as 
chemotherapy ± HER2 directed treatment, ± antihormonal treatment, 
antihormonal treatment ± HER 2, directed treatment ± CDK 4/6 
inhibitor.    
• Be ≥ 70 years of age at the time of signing the informed consent 
form 
• Have an Eastern Cooperative Oncology Group (ECOG) performance 
status score ≤ 2 
• Be able to speak and read Danish, and to provide a signed informed 
consent form 
 

 
 
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Exclusion criteria; patients with: 
• Any physical condition that hinder the execution of physical exercise 
training 
• Other types of cancer 
• Documented and uncontrolled brain metastases that hinder 
participation in an exercise-based trial, based on the referring 
oncologist’s assessment 
• Dementia, psychotic disorders, or other cognitive diseases or 
conditions that hinder written consent  
• Unstable medical disease or history of serious or concurrent illness; 
any medical condition that might be aggravated by exercise training 
or that cannot be controlled, including, but not restricted congestive 
heart failure (NYHA class III-IV), unstable angina pectoris, 
implantable cardioverter defibrillator (ICD), or myocardial infarction 
within 6 months, based on the referring oncologist’s assessment 
 
In patients with documented bone metastases:   
• A bone metastatic burden or location that poses a risk of injury in the 
performance of exercise training, as assessed by the referring 
oncologist 
Study arms 
Included patients will be randomized 1:1 to an intervention group and a 
control group.  
 
Patients in the intervention group will receive standard care and a 12-week 
exercise-based intervention comprised of: 
1. Supervised and group-based exercise training at the hospital setting 
two times a week. Each session will last approximately 60 minutes 
2. Home-based walking with activity tracker assessment. Evaluation and 
goal-setting in relation to activity (step counts) will be conducted once 
weekly 
3. Serving of a protein supplement (protein drink or bar) after each 
supervised training session 
 
Patient in the control group will receive standard care.  
Baseline data and 
endpoints 
Baseline data 
• Demographic and patient-reported data: data on civil status, working 
status, education, smoking, alcohol consumption, weight loss before 
and after cancer diagnosis, and physical activity 
• Clinical and medical data: diagnosis, treatment, performance status 
(ECOG), comorbidity, including Charlson comorbidity score. 
 
End-points 
• Physical function and capacity: 30-second chair stand test (30s-CST) 
(primary outcome), 6-minute-walk-test (6MWT), hand grip strength 
(HST), 6- and 10-meter gait speed, measured at normal and maximal 
gait speed (6MGS & 10MGS) and stair climb test (SCT).  
• Feasibility measures: recruitment rate, attrition, retention, and 
adherence 
• Patient reported outcomes: patient reported performance status 
(ECOG), EORTC Quality of Life Questionnaire (EORTC-QLQ-C30 

 
 
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& BR23), the Hospital Anxiety and Depression Scale (HADS), and 
M.D. Anderson Symptom Inventory (MDASI) 
• Physical activity: step counts, distance, and energy consumption 
measured with an activity tracker 
• Treatment tolerance and toxicity: completion of scheduled therapy, 
dose-reductions, discontinuations, toxicity (according to the National 
Cancer Institute Common Toxicity Criteria for Adverse Events v4) 
• Body measures and composition: weight, height, body mass index 
(BMI), and body composition measured by bioimpedance assessment 
and DXA scans 
• Inflammatory biomarkers: C-Reactive Protein (CRP), Interleukin 6 
(IL-6), YKL-40, GDF11 and GDF15. 
• Hospital admissions: numbers, causes, length of hospitalizations and 
contact to the Emergency Room (ER) with falls. 
• Mortality/survival 
Number of patients / 
sample size 
 
No prior studies have reported the minimal clinically important difference 
in the 30s-CST in older patients, or in cancer patients. However, based on 
results from a prior study focusing on patients with osteoarthritis, a 
clinically important change in the 30s-CST was set at 2.6 repetitions. Based 
on results from other studies focusing on patients with advanced cancer, a 
standard deviation (SD) of around 3 in 30s-CST was reported. To be able 
to detect a change of 2.6 repetitions in the between group difference at the 
12-week assessment, and to obtain a type I error rate of 5% and a power of 
90%, a sample size of 29 patients per study arm will be needed. To account 
for an expected dropout rate of approximately 40%, we decided to increase 
this number to a group size of 50. Hence, a total of 100 patients will be 
included in the study.  
Statistical Analysis 
 
Feasibility measures will be reported as numbers and percentages. Reasons 
for declining participation will be analyzed descriptively with numbers and 
percentages of patients declining for various reasons. Baseline 
characteristics will be calculated for all patients included (total), and 
separately for the intervention group and the control group. For all 
quantitative variables, the median number and interquartile range (IQR) 
will be calculated, and for nominal variables the number and percentage 
distribution will be calculated. Results from physical tests, blood test, body 
measures, and questionnaires will be reported as means and standard 
deviations (SD) or as median and IQR, as appropriate. Change over time 
in ordinal categorical values will be evaluated by a trend test using logistic 
regression. In-group and between- group differences in continuous-level 
data, will be performed using a repeated measurement analysis. Survival 
analyses will be conducted with Kaplan-Meier method, competing risk 
analyses and Cox regression analyses. The significance level of all tests is 
set a p < 0.05, and analyses will be carried out in SAS or R by Zoltan 
Szallasi (DTU) in collaboration with the study group. 
Publication of results 
Positive, negative, or inconclusive results from the TOLCA-Breast Cancer 
Exercise study will be published in relevant international peer-reviewed 
journals. Co-authorship for the upcoming publications will be offered to 
members of the project group or other collaborators based on contributions 
to the current work, and in accordance with the Vancouver 
recommendations. 

 
 
7 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
Potential risks 
and 
disadvantages 
There are a few potential risks and disadvantages for patients in the 
intervention groups, including exercise injuries and discomfort in 
performing the exercise program. However, risks and disadvantages are 
limited. If a patient reports any discomfort or incidence of injury during the 
intervention, the safety and further program-continuation for the patient 
will be discussed in the research group, and in consultation with the patient 
and the responsible physician. Data on adverse events will be collected 
systematically throughout the intervention period.   
Body composition will be assessed for all included patients at baseline and 
after 12 weeks using DXA technology. At each of the two DXA scans 
patients will be exposed to a small radiation dose of approximately 3 μGY 
(= 0.003 mSv).  
Scientific statement 
The TOLCA - Breast Cancer Exercise study is expected to involve low risk 
of adverse events and discomfort for patients involved. It is the project 
group’s assessment that it is necessary to carry out the current research 
project to gain important knowledge about the effect and feasibility of 
exercise-based intervention as a rehabilitative approach to older patients 
with breast cancer. The project group estimates that the TOLCA-Breast 
Cancer Exercise intervention will maintain or increase physical function 
levels, reduce symptoms and side effect, increase tolerance to oncological 
treatment, and improve psychological well-being and QOL in older 
patients with breast cancer and that the expected benefits of the 
intervention exceeds the estimated limited risks for patients involved.  
 
 
 

 
 
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Generel information 
 
Primary investigator 
 
Ida Lundager, PhD student 
Department of Occupational Therapy and Physiotherapy, Herlev and Gentofte 
Hospital Herlev Ringvej 75, 2730 Herlev, Denmark 
Telephone: +45 38689570  
Email: ida.katrine.lundager@regionh.dk 
   
Medical 
responsibility 
Dorte Nielsen, Professor, MD, PhD, DMsc. Department of Oncology, Herlev and 
Gentofte Hospital 
   
 
Project group 
• Anders Vinther, MSc in Physiotherapy, PhD. Department of Occupational Therapy and 
Physiotherapy, Herlev and Gentofte Hospital 
• Carsten B. Juhl, MSc in Physiotherapy, PhD. Department of Occupational Therapy and 
Physiotherapy, Herlev and Gentofte Hospital 
• Hanne F. Skall. Department of Occupational Therapy and Physiotherapy, Herlev and 
Gentofte Hospital 
• Marta Kramer Mikkelsen, RN, MHSc, PhD-student. Department of Oncology, Herlev 
and Gentofte Hospital 
• Cecilia Lund, MD, PhD. Departments of Medicine and Oncology, Herlev and Gentofte 
Hospital 
• Julia S. Johansen, Professor, MD, DMSc. Departments of Oncology and Medicine, 
Herlev and Gentofte Hospital 
• Dorte Nielsen, Professor, MD, PhD, DMSc. Department of Oncology, Herlev and 
Gentofte Hospital 
• Anne Polk, MD, PhD-student. Department of Oncology, Herlev and Gentofte Hospital 
• Stig E. Bojesen, Professor, MD, PhD, DMSc. Department of Clinical Biochemistry, 
Herlev and Gentofte Hospital 
 
Statistician 
• Zoltan Szallasi, Professor, PhD. Biological Sequence Analysis, Department of 
Systems Biology, Technical University of Denmark (DTU) 
 
Collaborators 
• 
Charlotte Suetta, Clinical associate professor, MD, PhD, Department of Clinical 
Medicine, Rigshospitalet 
 
Funding 
The TOLCA-Breast Cancer Exercise study is financially supported by a grant from the 
VELUX Foundation. The VELUX Foundation will be mentioned in all written and oral 
presentations and publications. The VELUX Foundation will not have any role in the 
conduction of the study design or protocol, data collection, interpretation of data, or in 
the drafting or approval of coming publications.  
 
Time schedule 
Project preparation: April 2018 – May 2018 
Recruitment and intervention: August 2018 – December 2020 

 
 
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List of abbreviations 
ACSM 
American College of Sports Medicine 
ADL 
Activities of daily living 
BC 
Breast cancer 
BMI 
Body mass index 
BI 
Bioelectrical impedance 
CCI 
Charlson comorbidity index 
CG 
Control group 
CRAG 
Cancer & Aging Research Group 
CRP 
C-reactive protein 
DXA 
Dual-energy X-ray absorptiometry scan.  
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC QLQ-C30 evt. 
suppleret med BR23 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire- C30 
ECOG 
Eastern Cooperative Oncology Group 
ER 
Estrogen receptor 
ESPEN 
European Society for Clinical Nutrition and Metabolism 
EWGSOP  
European Working Group on Sarcopenia in Older People  
5-FU 
5-fluorouracil  
GFR 
Glomerular filtration rate 
HADS 
Hospital Anxiety and Depression Scale 
HCP 
Health care professional 
HR+ 
Hormone receptor positive 
HST 
Handgrip strength test 
HER2 
Human epidermal growth factor receptor 2 
ICF 
Informed consent form 
IG 
Intervention group 
IL-6 
Interleukin 6 
IQR 
Interquartile range  
MDASI 
M.D. Anderson Symptom Inventory 
M:I ratio 
Mortality to incidence ratio [1-(mortality/incidence)] 
PA 
Physical activity 
PRPS 
Patient reported performance status 
PROM 
Patient-reported outcome measure 
PRT 
Progressive resistance training  
PS 
Performance status 
RM 
Repetition maximum 
SCT 
Stair Climb Test 
SD 
Standard Deviation 
SMART 
Specific, measurable, achievable, realistic/relevant and time-based.  
TP  
Thymidine phosphylase  
QOL 
Quality of life 
30s-CST 
30-second chair stand test 
6MGS 
6-meter gait speed 
10MGS 
10-meter gait speed 
6MWT 
Six-minute-walk-test 

 
 
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1. Introduction 
Although the risk of cancer increases with age, and the number of older cancer patients is expected to 
rise in the coming years (1-4), research on older cancer patients and survivors has been limited (3, 5). In 
Denmark, approximately 65% of all cancers are diagnosed among patients ≥ 65 years of age, and the 
number of incident cancers is expected to increase with 30% towards 2030 solely because of the 
increasing elderly population (6). Before discussing the impact of cancer disease in older individuals, it 
is necessary to describe the normal aging process and psychosocial factors related to aging.  
1.1 The aging process 
The age at which a person is considered being ‘elderly’ or ‘older’ varies in the literature and currently 
no definitive consensus exists. Age above 65 years has traditionally been chosen as the ‘cut-off’ as it 
represents the age of retirement in many Western countries. Aging involves a continuum of changes in 
function, biological, psychological and social structures that vary depending on individual differences 
in genetic factors. It must be empathized that older people represent a widely heterogeneous group and 
that chronological age does not accurately describe the capacity, resources and functioning of an older 
person. In a biological view, aging involves physiological changes in the organisms that lead to a decline 
of biological functions and the ability to adapt to metabolic stress. The biological changes involve a 
decrease in cardiac function and capacity due to reduced muscle strength, vascular stiffness, increased 
ventricular wall thickness, atherosclerosis, and loss of elasticity of the vessel walls (7). The respiratory 
tract undergoes structural and functional changes which are often associated with a decrease in lung 
function, limited regeneration and an enhanced susceptibility to infections and pulmonary diseases (8). 
Despite large variation among individuals, aging is also associated with a decline in kidney function, 
including a decreased renal blood flow and glomerular filtration rate (GFR), which makes drug excretion 
more problematic (9). In the gastrointestinal tract, age-related physiological changes (e.g. decrease in 
gastric acid and functional absorption, alterations in gastric motility and gastrointestinal hormones) may 
significantly alter the absorption and metabolisms of nutrients and medications, and thereby places older 
persons at a major disadvantage when they are exposed to weakness or disease (10). The aging process 
typically involves changes in the body composition with an increase in fat mass and a decrease in muscle 
mass. Evidence suggests that age-related loss of muscle mass starts in the fifth decade with an annual 
rate of up to 1-2%, and mainly influences the lower body skeletal muscle mass (11, 12).Loss of muscle 
mass is accompanied by an even faster deterioration of muscle strength (13).With age, the bones 
deteriorate in composition, structure and function. Increased bone resorption and reduction in bone 
formation leads to a fall in bone mineral density, and increased risk of osteoporosis and bone fractures 
(14). Aging also has an effect on immunity, with evidence indicating that the cell-mediated immunity 
consistently displays age-related declines in function (15). The reduction of reserve capacity in bone 

 
 
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marrow that occurs with aging deduces the ability to respond to stressors such as infections or blood loss 
(15, 16). Comorbidity, defined as the occurrence of two or more medically diagnosed diseases, increases 
with age and heightens the risk of disability and mortality (17, 18). Furthermore, the use of multiple 
drugs for multiple diseases, also known as polypharmacy, leads to an increased risk of drug interactions, 
adverse drug reactions, and poor adherence (19). The aging process also entails cognitive and 
psychosocial changes. Despite significant heterogeneity among older individuals, cognitive changes are 
recognized as a normal part of the aging process, and some cognitive abilities such as memory, 
processing speed, and conceptual reasoning decline over time(20). Social structures and roles also 
change with aging because of multiple factors and events such as retirement, limited social network, loss 
of family members or close friends, decreased functional ability, and increased dependency(21).     
1.2 Cancer and aging 
Aging itself is associated with limitations in physical function, reduced reserve capacity, a poorer 
resilience to physiological stressors, and an increased burden of comorbidities (17, 22). A diagnosis of 
cancer and its accompanying treatments can lead to numerous symptoms and side effects, physical 
disability, psychological distress and increased health care needs (23). The interplay between age-related 
and cancer-related declines in health increases vulnerability and the risk of development of short and 
long-term disability (24, 25). Compared to older individuals without a history of cancer, older cancer 
patients and survivors suffer from a greater incidence of limitations in activities of daily living (ADL), 
reduced quality of life (QOL), lower self-rated health, and higher prevalence of geriatric syndromes such 
as depression, falls and osteoporosis (26, 27). Research suggests that older cancer patients derive benefits 
to chemotherapy similar to the benefits derived by younger patients (28-30). However, older cancer 
patients are at increased risk of chemotherapy toxicity due to age-related physiologic changes, e.g. 
decreased stem-cell reserves, reduced ability to repair cell damage, and progressive loss of body protein 
(31). Furthermore, comorbidities and their associated treatments increase risk of chemotherapy toxicity 
even further (31). Recommendations from an expert group meeting in 2016 concluded that rehabilitation 
services should be offered early to older cancer patients to optimize tolerance to cancer treatment, 
minimize toxicity, and improve outcomes (32).  
1.3 Sarcopenia and cancer cachexia 
Loss of muscle mass and strength is a part of the normal aging process, and is often referred to as 
‘sarcopenia’. In accordance with an European consensus report, sarcopenia is a syndrome characterized 
by progressive and generalized loss of skeletal muscle mass and muscle strength (33). Sarcopenia has 
multiple contributing factors including aging process itself, insufficient nutrition, sedentary lifestyle or 
bedrest, and chronic diseases and certain medical drugs. Sarcopenia that occurs solely due to aging is 

 
 
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typically referred to as ‘primary sarcopenia’, while the term ‘secondary sarcopenia’ is used to describe 
sarcopenia that is caused by other factors such as cancer or other chronical diseases (33). Sarcopenia 
may be responsible for functional impairment, increased risk of falls, and loss of independence in the 
elderly population (34). The clinical diagnosis of sarcopenia is made from the presence of low muscle 
mass in combination with low muscle function (either low muscle strength or performance), and can be 
diagnosed with different validated measurement techniques (33). Besides sarcopenia, ‘cachexia’ is 
another depleting syndrome that causes weight loss and muscle wasting due to an underlying disease. 
Cachexia is an important complication among cancer patients, particularly in advanced-stage cancer. 
Cancer cachexia is “a multi-factorial syndrome defined by an ongoing loss of skeletal muscle mass (with 
or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads 
to progressive functional impairment” (35). The pathophysiology of cancer cachexia is complex and 
includes a combination of reduced energy intake, hormonal alterations, and abnormal metabolism and 
inflammation. Cancer cachexia is clinically defined as loss of more than 5% of stable body weight over 
the past 6 months, or loss of more than 2% of body weight in patients who are already showing depletion 
according to Body Mass Index (BMI) (BMI <20kg/m2) or according to skeletal muscle mass 
(sarcopenia) (35). Differentiation between cachexia and sarcopenia can be difficult as loss of muscle 
mass is an important feature of cachexia, and therefore most cachectic subjects will also be sarcopenic, 
whereas most sarcopenic subjects are not considered cachectic (36). Prior studies have identified 
cachexia and sarcopenia as contributors to impaired physical functioning (37), reduced tolerance to anti-
cancer treatment (38-40), higher symptom burden (41), reduced QOL (41, 42), and increased mortality 
(39, 43-46) among patients with cancer. Therefore, it is of upmost importance to focus on prevention, 
identification and treatment of cancer cachexia and sarcopenia in clinical practice. However, research 
has shown that cancer cachexia and sarcopenia are rarely recognized or managed actively by physicians 
(41, 47). Furthermore, older cancer patients may be at particular risk of cachexia and sarcopenia due to 
age-related declines in physical reserves, sedentary life-style, insufficient nutrition and 
comorbidities(48). Evidence suggests that regular exercise training, increased activity level, and 
sufficient energy and protein intake are effective strategies in the prevention and treatment of sarcopenia, 
which also have been shown as promising interventions in the prevention and treatment of cancer 
cachexia (49-51). According to recently published guidelines for nutritional care in cancer patients from 
the European Society for Clinical Nutrition and Metabolism (ESPEN), body resources and physiological 
decline in cancer patients are endangered by a complex pattern of physical and functional derangement 
(52). Therefore, strategies to prevent and treat malnutrition, sarcopenia and cachexia among cancer 
patients should optimally comprise a comprehensive approach, including nutritional advice/therapy, 

 
 
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counseling and guidance to optimize symptom management, and physical rehabilitation/exercise 
training (52).  
1.4 Exercise training 
Exercise training is a strengthening multi-effect strategy that has the capacity to work across multiple 
organ systems. Research has shown that exercise training (e.g. aerobic training, resistance training, and 
balance and flexibility exercises) is safe and beneficial to perform for older people. The beneficial effects 
include increased muscle mass and strength, aerobic capacity, functional mobility and ADL function, 
balance and reduction of falls, improved QOL, and reduction of depressive symptoms (53-56). Also, 
evidence suggests that exercise training alone or in combination with nutritional interventions have some 
effect on the prevention and treatment of age-related sarcopenia (57, 58). The effects of exercise 
interventions have also been widely investigated among cancer patients. Research has shown that 
exercise training is effective in the prevention or reduction of symptoms and side effects from cancer 
disease and treatment (59). Several intervention studies have investigated effects of exercise training in 
cancer patients both during and after oncological treatment, and a myriad of beneficial effects have been 
documented, including reduced levels of fatigue, and improved aerobic capacity, muscular strength, 
physical functioning and QOL (60-62). However, older patients have often been underrepresented in 
these studies, and only few exercise-based intervention studies have specifically focused on older cancer 
patients (63). Among the few studies that investigated the effects of exercise interventions in older cancer 
patients, most focused on older patients with early-stage breast, prostate and colorectal cancer in the 
post-operative treatment period, and excluded patients in active oncological treatment. Especially, 
research investigating the effect of exercise training in older cancer patients with advanced-stage disease 
is lacking (63).  
1.5 Breast cancer 
Breast cancer is the most frequent cancer among women and is a major cause of cancer-related deaths 
worldwide. It is estimated that more than 1.67 million new cases of breast cancer occurred worldwide 
in women in 2012 (65). Breast cancer accounts for approximately 522,000 deaths in the world each year, 
which makes it the 5th most common cause of cancer-related death today in women and men combined 
(64). In 2030 breast cancer is expected to be the 5th leading cause of cancer-related death (65). Every 
year approximately 5000 women are diagnosed with breast cancer in Denmark (68; NORDCAN 2011-
2015; Cancerregisteret Årsrapport 2016).  
At diagnosis, more than 90% of patients present with early breast cancer defined as local disease 
amenable for curative surgery. Depending on patient age, menopausal status and tumor characteristics 
such as size, grade of malignancy, lymph node status, estrogen receptor (ER) and human epidermal 

 
 
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growth factor receptor 2 (HER2) expressions, approximately 90% of patients with early breast cancer 
are offered systemic adjuvant treatment. This includes some or all of the following; anti-estrogen, anti-
HER2 treatment and chemotherapy (69). The hormone receptor-positive (HR+), human epidermal 
growth factor receptor 2-negative (HER2-) breast cancer subtype is the most prevalent of breast cancer 
subtypes and accounts for approximately 70% of all breast cancers (70).  
Overall, adjuvant chemotherapy decreases risk of recurrence and improves survival, but the absolute 
benefits in patients with a low risk of recurrence may be small. Therefore, the decision to offer 
chemotherapy must consider risk factors of the disease as well as patient age and comorbidities. 
Adjuvant chemotherapy is standard for patients with triple-negative breast cancer and HER2-positive 
breast cancer. Chemotherapy treatment decision-making for women with ER-positive, HER2-negative 
breast cancers is more complicated, owing to the variation in prognosis among women with ER-positive, 
HER2-negative tumors, the effectiveness of adjuvant endocrine therapy at reducing recurrence, and the 
variable sensitivity of ER-positive tumors to chemotherapy treatments. For such patients, the decision 
to administer chemotherapy is based on an assessment of the composite risk of recurrence and likely 
benefit of treatment based upon patient age, tumor lymph node status, size, grade, lymphovascular 
invasion, and the results of a gene expression profile such as PAM50. In Denmark, standard adjuvant 
chemotherapy consists of three series of epirubicin + cyclophosphamide (every 3 weeks) and 3 series of 
paclitaxel (every week) (66). Patients with HER2-positive disease receive trastuzumab 600 mg s.c every 
three weeks in combination with paclitaxel and continuing for 12 months. Risks of chemotherapy include 
acute 
toxicities 
including 
fatique, 
nausea, 
vomiting, 
hair 
loss 
and 
myelosuppression. 
Immunosuppression associated with chemotherapy may also lead to severe infections in some. Taxanes 
are associated with neuropathy, which generally resolves weeks to months after treatment, but may be 
incomplete in severe cases. Longer-term toxicities also include the risks of cardiotoxicity associated with 
anthracyclines and the rare risk of chemotherapy-related leukemia (67). Risk of trastuzumab include flue 
like symptoms immediately after injections and cardiotoxicity. 
About 3-10% of the patients will have distant metastases at the time of diagnosis and the risk of loco-
regional or metastatic relapse after treatment for early breast cancer is approximately 20% (71-73). 
Despite new treatments arising during the past decades metastatic breast cancer remains a largely 
incurable disease. After documentation of distant metastases, the median survival is approximately 2 
years with a 5-year mortality of approximately 80% (73-75). Increased survival and quality of life are 
therefore the primary goal of treatment for these patients. The goals of treatment of metastatic breast 
cancer are to prolong survival and improve quality of life by reducing cancer-related symptoms. In order 
to achieve these goals, an individualized approach is needed since no one strategy can be applied for all 
women. In Denmark, the following strategies are applied: 1) Patients with hormone receptor-negative 

 
 
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HER2- negative breast cancer is offered chemotherapy. In general, sequential use of single-agent 
chemotherapy is used as sequential single-agent treatment is often less toxic and results in similar overall 
survival compared with combination chemotherapy (76); 2) Patients with symptomatic hormone 
receptor-positive breast cancer, in whom endocrine therapy is unlikely to result in a prompt clinical 
response. These include patients with rapid disease progression following more than one endocrine 
therapy (i.e., endocrine-resistant disease) and patients with a large tumor burden involving visceral 
organs and threatening organ function; and 3) Patients with HER2-positive disease will receive 
chemotherapy in combination with HER2-directed treatment (73).  
The majority of patients with breast cancer have ER-positive disease, and in the case of recurrence, they 
will primarily develop metastases to the bones and lymph nodes. In addition, there is often a long 
disease-free interval. Postmenopausal patients with metastatic breast cancer, who have ER-positive and 
HER2-negative tumors, are primarily offered endocrine treatment with an aromatase inhibitor or 
fulvestrant, possibly in combination with a CDK4/6 inhibitor. Patients who are premenopausal are 
offered ovariel suppression in combination with an aromatase inhibitor or fulvestrant in combination 
with CDK4/6 inhibitors. 
CDK4/6 inhibitors are recommended in addition to endocrine treatment in first-line treatment in patients 
with PS 0-1 (68).  
The choice of first line chemotherapy takes into account several factors in an effort to individualize 
therapy as much as possible as there is no ideal sequence of treatments that can be applied to all patients. 
It is likely that patients with metastatic breast cancer will receive many (if not all) available treatments 
throughout the course of their disease.  
For HER-2 negative patient who has been previously exposed to adjuvant chemotherapy the preferred 
regimen will most often be capecitabine. The drug is an orally fluoropyrimidine carbamate that is 
enzymatically-activated to 5-fluorouracil (5-FU) preferentially by thymidine phosphylase (TP) in the 
liver and tumor tissue (77). Capecitabine for metastatic breast cancer has been shown to be well tolerated 
and efficient as both first- and second-line therapy (77, 78). Capecitabine is approved for metastatic 
breast cancer in combination with docetaxel after failure of prior anthracycline treatment, or as 
monotherapy in patients’ resistant to both taxanes and anthracyclines (79). Side effect its primary 
toxicities are hand-foot syndrome and diarrhea, and it can be used in settings of mild hepatic dysfunction. 
It causes very little alopecia or neuropathy. 
For HER-2 negative patient who had not received adjuvant chemotherapy the preferred regimen will 
depend on performance status, tumor burden and patient’s preferences. The most used regimens are 
doxetaxel or capecitabine (see above) (54). Taxanes are among the most active agents for metastatic 
breast cancer. Docetaxel is associated with a significant risk of fluid retention, which is reduced by 

 
 
16 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
premedication. Side effects include alopecia, neuropathy and myalgia, myelosuppression, febrile 
neutropenia, edema, and gastrointestinal toxicities. Therapies that target HER2 have become important 
agents in the treatment of metastatic breast cancer and have altered the natural course of HER2-positive 
breast cancer. Because the use of HER2-directed therapy improves survival for patients with HER2-
positive metastatic breast cancer, such patients receive HER2-directed therapy as first- and later-line 
treatment (69). In HER-2 positive patients the preferred treatment regimen is vinorelbine in combination 
with trastuzumab and pertuzumab (66). The treatment regimen is reasonably well tolerated with 
toxicities consistent with the known safety profiles of the individual agents. Common side effects for 
vinorelbine include: nausea, vomiting, fatigue, and constipation whereas pertuzumab may be associated 
with heart problems, diarrhea, and rash or itching. 
 
1.5.1 Exercise training in patients with breast cancer 
Exercise training for older patients with breast cancer is a relatively unexplored research field. It is 
indicated that physical activity after breast cancer diagnosis is associated with better survival (70, 71).  
Physical activity is safe and effective in improving health-related QOL as well as physiological, 
behavioral and physical outcomes among breast cancer survivors (71). Only a small number of minor 
adverse events have been reported and no evidence of harmful or negative effects of physical activity 
interventions among women diagnosed with breast cancer have been found (71).  
Several exercise interventions among patients with breast cancer receiving adjuvant therapy consist of 
resistance training or a combination of resistance- and aerobic training (72-81). These exercise 
interventions reduce fatigue (74, 77) and symptoms of depression (74) and improve QOL (73, 76, 77) 
for patients with breast cancer receiving adjuvant therapy. Furthermore, exercise interventions have a 
positive effect on minimizing decline in cardiorespiratory fitness and improve muscle strength (75, 76, 
79), physical function, bone mineral density, sleep (82), and shoulder range of motion (75, 82). 
Resistance training in patients with breast cancer during adjuvant chemotherapy significantly reverses 
sarcopenia and dynapenia (72).  
Slimmer, fitter and younger (premenopausal) breast cancer patients receiving chemotherapy are more 
likely to benefit from a higher dose of exercise intervention than their counterparts. This indicates that 
age, menopausal status, obesity, past exercise experience and fitness level should be taking into account 
when exercise is prescribed to cancer patients (76).  
The exercise interventions mentioned above all include patients with breast cancer with a mean age of 
approximately 55 years. Very few trials have examined the effect of exercise among older breast cancer 
patients undergoing treatment (83, 84). One trial has examined the effect of yoga training compared to 

 
 
17 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
routine physical therapy (n = 20) (83). Both types of exercise seemed to have a positive effect on QOL 
(83). Therefore, research exploring exercise training in combination with oncological treatments for 
older breast cancer patients is needed.   
2. Study rationale and aim 
Older cancer patients are underrepresented in clinical trials, including trials within exercise training in 
combination with oncological treatments. Nevertheless, the older cancer population is the largest group 
of cancer patients, and their number is rapidly growing. With a mean age around 65 years at diagnosis, 
breast cancer is associated with aging. Interventions that reduce symptoms, maintain physical function 
and optimize QOL are essential. Since few previous studies have investigated the effect of an exercise-
based intervention specifically focused on older patients with primary or advanced-stage breast cancer 
during chemotherapy, the primary focus of the current study is to investigate the effect and feasibility of 
such an intervention. Hence, the aim of the present “TOLCA - Breast Cancer Exercise” study is to 
investigate the effect of a 12-week exercise-based intervention, comprised of a supervised and group-
based resistance training program, an individualized and home-based walking program in older patients 
(≥ 70 years) newly diagnosed with primary, locally advanced or metastatic breast cancer who are 
undergoing treatment with adjuvant or first-line palliative systemic therapy.  
3. Research questions and hypotheses 
3.1 Research questions 
1. Can the exercise-based intervention increase or maintain physical function levels in older 
patients with breast cancer during treatment with adjuvant or first-line palliative systemic 
therapy?  
2. Is it feasible and safe to recruit and engage older patients diagnosed with breast cancer in the 
exercise-based intervention during treatment with adjuvant or first-line systemic therapy? 
3. Can the exercise-based intervention reduce symptoms and side-effects in older patients with 
breast cancer during treatment with adjuvant or first-line systemic therapy?  
4. Can the exercise-based intervention improve QOL and psychological wellbeing among older 
patients with breast cancer during treatment with adjuvant or first-line palliative systemic 
therapy?  
5. Can the exercise-based intervention affect circulating biomarkers of inflammation in older 
patients with breast cancer during treatment with adjuvant or first-line palliative systemic 
therapy? 

 
 
18 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
6. Are circulating levels and changes in inflammatory biomarkers associated with the development 
of cancer cachexia, sarcopenia, and other changes in body composition in older patients with 
breast cancer during treatment with adjuvant or first-line palliative systemic therapy? 
 
3.2 Study hypotheses 
We hypothesize that the exercise-based intervention will maintain or increase physical function levels, 
reduce symptoms and side effects, improve QOL and psychological wellbeing, and prevent weight loss 
and muscle wasting in patients with breast cancer during treatment with adjuvant or first-line palliative 
systemic therapy. We predict that recruitment of older patients with breast cancer might be challenging 
because of treatment-related side-effects, symptom burden, and age-related factors that affect these 
patients. Also, as prior exercise-based intervention studies targeted patients with advanced stage cancer 
during systemic therapy treatment have experienced considerable attrition rates, we expect that a certain 
percentage of drop-outs during the intervention period will be inevitable. However, we believe that an 
intervention specifically targeted the special needs of older patients with breast cancer treated with 
adjuvant or first-line palliative therapy can be integrated in both the hospital and home setting, will make 
the intervention feasible and effective.  
4. Design and methods 
4.1 Design 
TOLCA – Breast Cancer Exercise is a prospective two-armed randomized controlled trial of a 12-week 
exercise intervention in older patients (≥70 years) with breast cancer who are treated with adjuvant or 
first-line palliative systemic therapy.  
4.2 Recruitment of patients 
Patient will be recruited from the Department of Oncology, Herlev and Gentofte Hospital. Potentially 
suitable patients will be identified and screened by oncologists to find eligible participants. The 
screening procedure aims at confirming that inclusion criteria are met (4.3), and that none of the 
exclusion criteria are present (4.4). The oncologist will inform eligible patients about the possibility to 
participate in the TOLCA – Breast Cancer Exercise study. Patients who are interested in participation 
will hereafter be informed, and potentially recruited and randomized by the primary investigator Ida 
Lundager. Before the information, by the primary investigator, is given to the patient, patients are 
informed about the possible to have an assessor. Patients will be informed both verbally and in writing 
about the TOLCA – Breast Cancer Exercise program, perceived benefits, risks, and safety precautions, 
and about their personal rights in entering the trial. The information will be given to the patients in 

 
 
19 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
undisturbed settings at outpatient department of oncology. After all information have been delivered and 
understood, patients will be informed about their right for time to consider participation in the study (a 
minimum of 24 hours). Hereafter, informed consent forms (ICF) will be signed and collected from 
patients who want to participate in the trial. Included patients will receive a copy of the signed ICF.  
Due to ethical considerations, and challenges with significant information load, patients will first be 
approached and informed about the TOLCA – Breast Cancer Exercise trial after the first treatment dose 
of either adjuvant or first-line palliative systemic therapy. 
4.3 Inclusion criteria 
Patients must: 
• Have undergone surgery for primary breast cancer within 12 weeks or 
• Be diagnosed with locally advanced or metastatic breast cancer  
• Be treated with adjuvant or first-line palliative therapy with chemotherapy ± HER2 directed 
treatment, ± antihormonal treatment, antihormonal treatment ± HER 2, directed treatment ± CDK 
4/6 inhibitor 
• Be ≥ 70 years of age at the time of signing the ICF 
• Have an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2  
• Be able to speak and read Danish, and to provide a signed ICF 
 
4.4 Exclusion criteria 
Patients with: 
• Any physical condition that hinder the execution of physical exercise training 
• Other type of cancer 
• Documented and uncontrolled brain metastases that hinder participation in an exercise-based 
trial, based on the referring oncologist’s assessment 
• Dementia, psychotic disorders, or other cognitive diseases or conditions that hinder formal 
consent 
• Unstable medical disease, condition, or history of serious or concurrent illness; any medical 
condition that might be aggravated by exercise training or that cannot be controlled, including, 
but not restricted to congestive heart failure (NYHA class III-IV), unstable angina pectoris, 
implantable cardioverter defibrillator (ICD), or myocardial infarction within 6 months, based on 
the referring oncologist’s assessment 
In patients with documented bone metastases:   

 
 
20 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
• A bone metastatic burden or location that poses a risk of injury in the performance of exercise 
training, as assessed by the referring oncologist 
 
4.5 Stratification at randomization 
Patients included in the study will be randomized 1:1 to the intervention group and control group. As 
cancer stage and performance status are expected to influence the outcomes of interest, stratification will 
be performed at randomization. Patients will be stratified at randomization based on: 
• Cancer stage and treatment. 
Randomization and stratification will be performed through the randomization module in REDCap. 
 
4.6 Intervention 
4.6.1 Exercise intervention 
Patients in the intervention group will receive usual care and the exercise-based intervention. Based on 
recommendations from the Cancer and Aging group NCU U13 (63), this intervention will be initiated 
early after cancer diagnosis. Focusing on a group of older patients with breast cancer and treated with 
adjuvant or first-line palliative systemic therapy several factors have been considered in targeting the 
intervention, including the debilitating symptoms and side-effects, age-related physical limitations and 
comorbidities, and the rapid physical decline seen among patients with advanced cancer. The overall 
focus of the TOLCA – Breast Cancer Exercise intervention lies on maintaining muscular strength, 
physical function and mobility. In addition to the PRT, an individualized light to moderate intensity 
walking program, based on step counts, will be developed for each patient with the aim of avoiding 
inactivity and to keep patients active on days when they are not engaged in the PRT program. The 
exercise-based intervention is composed in a way that allows individualization based on each patients’ 
physical state, psychosocial state, and motivation throughout the intervention period. Patients included 
in the intervention group will receive a 12-week exercise-based intervention composed of the following 
components:  
 
1. Supervised and group-based exercise program: Patients in the intervention group will participate 
in the supervised exercise program two times a week, and each session will last approximately 60 
minutes. The exercise program consists of warm-up exercises, including exercises for balance and 
flexibility (15 minutes), a program of PRT that comprises seven resistance training exercises 
targeting the large muscle groups (chest press, low row, hamstring curls, knee extension, leg press, 
abdominal crunches, back extensions) (35 minutes), and stretching and relaxation (10 minutes). In 

 
 
21 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
week 1-2, patients will be introduced to the PRT and the program will be initiated with high 
repetition numbers and low load. The intensity is progressed during the intervention period from 
two to three sets with a load corresponding to 15 to 8 repetition maximum (RM) (the load that can 
be lifted to 15 and 8 repetitions, respectively, using proper technique as assessed by the 
physiotherapist). This model of PRT is in accordance with the recommendations from the American 
College of Sports Medicine (ACSM) (85). The progression will be tailored to each individual patient 
regarding potential comorbidities and physical limitations, and will be closely monitored by the 
responsible physiotherapist. In patients with documented bone metastases, a very conservative 
approach to progression will be taken, which involves very small increments in resistance. The 
supervised exercise training will take place at the Department of Occupational Therapy and 
Physiotherapy at Herlev and Gentofte Hospital, and will be led by an experienced physiotherapist. 
When entering the project, all patients will receive a ‘replacement training program’ that includes a 
few effective exercises for the major muscle groups and can be performed at home. If a patient for 
unforeseen reasons cancels a group-based training session during the intervention period, the patient 
will be recommended to perform the exercises in the replacement-program instead. All patients will 
be thoroughly introduced to these replacement exercises when entering the study.  
 
2. Individualized walking program based on step counts (pedometer assessment). After 
randomization, patients in the intervention group will receive an activity tracker and will be asked 
to wear it for three consecutive days. Based on each patient’s starting point (a mean of the three pre-
measured days), preferences and motivation, an individualized walking program will be conducted 
to increase or maintain the level of activity. Goal-setting in relation to step counts will be set once 
weekly in collaboration between each patient and the primary investigator (Ida Lundager). Even 
though the overall aim is to increase activity level/step counts during the intervention, it is also 
possible to maintain or even reduce the step-goals in some weeks if an increase is not realistic due 
to physical or psychosocial reasons, or if patients are already sufficiently active. Each patient will 
receive a booklet at the introduction meeting with information and advice about walking, and goal-
setting and evaluation schemas for the 12-week intervention. Evaluation and goal-setting will be 
conducted once a week before or after the supervised training session, or by telephone (based on 
patients’ preferences). Patients will also be asked about their beliefs and confidence about reaching 
their next goal (self-efficacy rating).  
 

 
 
22 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
3. Nutritional supplement after supervised exercise session: a nutritional supplement (protein bar 
or protein drink) will be given to patients immediately after the supervised exercise training session 
at the hospital setting.  
The TOLCA – Breast Cancer Exercise intervention is illustrated in Table 1.  
Table 1. Components of the multimodal TOLCA – Breast Cancer Exercise intervention 
 
 
Supervised exercise training  
 
Nutritional supplement 
 
Home-based walking 
Content 
• Warm up  
• Exercises for balance 
• Exercises for flexibility 
• Progressive resistance 
training 
• Stretching 
• Relaxation  
Protein drink or protein bar (~ 
200-300 calories, 12-18 grams 
of protein). 
Walking/activity based on step 
counts from the activity tracker. 
Individualized goal-setting and 
evaluation once weekly. 
Frequency 
2 times a week, for 60 minutes 
per session.  
2 times a week after supervised 
training session.  
Continuously over the 12-week 
intervention. Evaluation and 
goal-setting once weekly.  
Setting 
Dept. of Occupational Therapy 
and Physiotherapy, Herlev and 
Gentofte Hospital.  
Dept. of Occupational Therapy 
and Physiotherapy, Herlev and 
Gentofte Hospital. 
Home-setting.  
Evaluation and goal-setting will 
be conducted at the hospital 
setting or by telephone (based 
on patients’ preferences).  
 
4.6.2 Theoretical framework 
The elements of exercise training in the TOLCA – Breast Cancer Exercise study are designed in 
accordance with Danish and international basic principles and recommendations for exercise training in 
healthy individuals, healthy older individuals, cancer patients, and older cancer patients (82, 85, 86). 
Both Danish and international guidelines emphasize the importance of adapting exercise training to both 
cancer site, symptoms and side effects, and with consideration for each individuals’ health status, 
physical limitations, and comorbidities (82, 86). Focusing on older cancer patients, Danish 
recommendations specifically underline that exercise interventions should focus on maintaining 
mobility and physical function (86). With an overall purpose of empowering and activating patients 
involved, goal-setting will be incorporated as an element in the intervention (home-based walking 
program). Goal setting is widely recognized as an effective method to achieve behavioral changes and 
enhance self-efficacy in people (87). In the rehabilitation setting it is generally agreed that goals must 

 
 
23 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
be specific, measurable, achievable, realistic/relevant and timed-based (SMART). Furthermore, goal-
setting should be carried out through a continuous process that involves planning, evaluation and 
reassessment, in collaboration between the patient and HCP (88, 89).  
4.7 Study assessments and data collection 
The following assessments and data collection will be performed: 
1. Clinical data and medical outcomes: data on diagnosis, time of diagnosis, treatment regime, 
performance status (ECOG) (Appendix 1), and comorbidities (assessed by Charlson comorbidity 
index (CCI) (90) will be registered and assessed from medical records. Risk of systemic therapy 
toxicity (toxicity score) will be calculated using the Cancer & Aging Research Group (CARG) 
toxicity score with data from medical records and patient questionnaire (28). 
 
2. Demographic and patient-reported data: data on civil status, working status, education level, 
smoking habits, alcohol consumption, weight loss before and after cancer diagnosis (kg/percent), 
and physical activity level before cancer diagnosis and current will be collected through patient 
questionnaire (Appendix 2). 
 
3. Physical function: To measure physical capacity and lower extremity strength, the 30-second 
Chair Stand Test (30s-CST) will be used (primary outcome). The 30s-CST is a widely used 
physical measure, especially among older people and those with significant weakness, and is 
regarded as a prerequisite for functional independence (91).The 30s-CST has also been used and 
tested in cancer patients (92). Using a chair with a seat of 45 cm above the floor, patients will be 
instructed to sit in the middle of the chair with their back straight, arms crossed over the chest, 
and both feet resting flat of the floor (93). The correct technique will be demonstrated for patients 
before assessment. On the instructor’s signal patients will be asked to stand straight and then 
return to the seated position as many times as possible in 30 seconds. A modified version of the 
30s-CST, where patients are allowed to use armrests, can be used in patients who are not able to 
rise from a chair without using their arms. Use of the modified version will be registered, and 
will be carried out in accordance with the test manual (93). The 30s-CST has proved to be a valid 
and reliable method in measuring lower body strength among healthy community-dwelling older 
adults  (91). Physical performance will also be assessed with a 6-meter gait speed test (6mGS) 
and 10 meter gait speed test (10mGS) at normal and maximal gait speed (94). Gait speed is a 
suitable measure to use in the clinical evaluation and rehabilitation setting when focusing on 
older individuals, as it is easy to administer, and has documented predictive value for health-

 
 
24 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
related outcomes such as functional and cognitive decline, falls, hospitalization, independence, 
and mortality (94, 95).To measure physical capacity and endurance, the six-minute-walk-test 
(6MWT) will be used. The 6MWT measures the distance an individual can walk over a total of 
six minutes on a hard and flat surface. It was originally developed for use in frail older patients, 
but it has been used and validated in a variety of chronic diseases and populations (e.g. cardiac, 
cancer and pulmonary patients) (96, 97). Prior studies have demonstrated that the 6MWT is a 
reliable and valid measure of physical capacity and endurance in older adults and in cancer 
patients, and that the test may have prognostic value among cancer patients (98, 99). To measure 
physical function of the upper-body, the handgrip strength test (HST) will be used. Handgrip 
strength will be measured using a hand-held Jamar dynamometer and with three attempts 
performed for each hand. Measurements of grip strength with the Jamar dynamometer have 
evidence for good reliability and validity (100). Patient will be sitting down during the 
assessment with their elbow flexed at 90⁰. The best measure in the strongest hand will be used 
as test score. Research has shown that handgrip strength may be independently associated with 
functional capacity, QOL and survival in patients with advanced cancer (101). To measure lower 
extremity muscle power a stair climb test (SCT) will be used. The patient will climb a flight of 
stairs (20 steps) as fast as possible. The best of three trials will be used as test score. Leg power 
is an influential factor in the mobility performance of older adults (102). The SCT is a clinically 
relevant measure of lower extremity power among older adults and is associated with more 
complex modes of testing power (103). All physical tests will be conducted by blinded 
physiotherapists.    
 
4. Feasibility measures: feasibility of the intervention will be evaluated as acceptability, attrition 
and adherence. Acceptability will be measured as the number of eligible patients who agree to 
participate in the study. Also, reasons for refusing participation will be registered and evaluated.  
Attrition is the number of patients who do not complete the study (drop-outs). For each 
component of the intervention (supervised exercise, protein supplement after exercise sessions, 
and walking program) adherence to the intervention will be assessed. Safety (adverse event) and 
tolerability will be evaluated at every training session and at the weekly evaluation of the walking 
program. 
 
5. Patient-Reported Outcomes Measures (PROMs): Patient reported performance status (PRPS) 
will be assessed using ECOG PS (Appendix 1). PS is a known and common-used prognostic tool 
for assessment and decision making in oncology and palliative settings. Evidence suggests that 

 
 
25 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
patients are reliable assessors of their own performance status, and that PRPS is a predictor of 
cancer-related outcomes (104). To measure symptom burden, M.D. Anderson Symptom 
Inventory (MDASI) will be used (Appendix 3). MDASI is a multi-symptom PROM to assess the 
severity of symptoms and the interference with daily living as assessed by cancer patients based 
on the last 24 hours (105). MDASI consists of 13 core symptom items representing symptoms 
that have been found to have the highest frequency and/or severity among cancer patients with 
various cancers and treatment types, and 6 interference items representing commonly 
experienced symptom interference with daily activities (105). To assess QoL the European 
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 
and the breast cancer specific module QLQ-BR23 (EORTC QLQ-C30 & BR23) will be used 
(Appendix 4). EORTC QLQ-C30 comprises 30 items, is designed to be cancer specific, and 
consists of six functional scales (physical, role, cognitive, emotional, social functioning, and 
global QOL) and symptom scales (fatigue, nausea/vomiting, sleep disturbance, constipation, 
diarrhea, appetite loss, dyspnea) (69, 106). EORTC QLQ-C30 is developed in a way that is 
appropriate for self-administration and for use across a range of cultural setting. To assess 
symptoms of depression and anxiety, the Hospital Anxiety and Depression Scale (HADS) will 
be used (Appendix 5). HADS comprises a total of 14 items and is designed to measure general 
anxiety and depression by self-administration (107).  
 
6. Physical activity: Data of steps counts will be assessed daily for patients in the intervention 
group. Data of walked steps, distance and energy consumption for all patients (intervention group 
and control group) will be assessed in a 3-days period both before and after the intervention 
period (at baseline and 12-week post-intervention). Data on physical activity will be measured 
with an activity tracker.   
 
7. Chemotherapy tolerance: data on completion of scheduled chemotherapy, dose-reductions, 
treatment discontinuations, toxicity (according to the National Cancer Institute Common 
Toxicity Criteria for Adverse Events version 4) will be registered from medical records. 
 
8. Body composition: data on weight, height, BMI, and body composition will be registered. 
Weight, height and BMI will be assessed using standard procedures (no shoes, light clothing). 
Body composition will be assessed by whole-body dual-energy x-ray absorptiometry scan 
(DXA) and by bioelectrical impedance (BI) assessment. The DXA technology is a special type 
of X-ray that is based on a three-component model that determines fat-free-mass, body fat, bone 

 
 
26 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
mass, and bone mineral density (111). DXA is acknowledged as a valid method to evaluate body 
composition, and it is frequently used both in research and in the clinical setting (111, 112). 
However, all available single methods for the assessment of body composition have their 
limitations. Focusing on DXA, it has previously been questioned whether the validity is affected 
by patients’ hydration status, and, prior studies have also shown that the validity may be impaired 
in very lean or in very obese persons (112, 113). Therefore, assessment of body composition will 
be supplemented with BI assessment. BI is a portable, easy-to-use, and non-invasive method to 
estimate body composition (114). BI measures the resistance of different body tissues to the flow 
of a low-level electrical signal which is sent through the body. The electrical flows at a different 
rate through the various body tissues, which allows for the analyses of estimated body fat 
percentage, fat mass, fat-free mass, muscle mass, body water, and bone mass (114). The validity 
of BI measures of body composition can be affected by several factors, including body position, 
distribution of body fat, skin temperature, and dietary intake (112, 115). Incidence of cancer 
cachexia will be determined as loss of more than 5% of stable body weight over the last 6 months, 
or loss of more than 2% of body weight in patients with BMI < 20kg/m2 or in patients with 
sarcopenia (35). Incidence of sarcopenia will be determined by the consensus criteria from the 
European Working Group on Sarcopenia in Older People (EWGSOP), and will determined by 
exact cut-off value representing incidence of both low muscle mass and low muscle function 
(performance or strength) (33).   
 
9. Biomarkers: Results from prior studies have shown that inflammation is a critical component of 
cancer development and progression (116, 117). Inflammation has also been linked to important 
clinical outcomes, such as cancer-related fatigue and cancer cachexia (43, 118). Although not 
yet fully elucidated, it also seems that exercise training may have the potential to affect tumor-
specific and anti-cancer treatment outcomes through regulations of inflammatory processes and 
functions (119). Loss of skeletal muscle mass (sarcopenia) is an independent prognostic factor 
predicting poor outcome in a wide range of cancers (108). In recent years, there has been an 
increased focus on the possible importance of growth differentiation factor 11 (GDF-11) and 
growth differentiation factor 15 (GDF-15) for the development of sarcopenia. GDF-11 and GDF-
15 belong to both the TGFβ family shown via the ActRII/ALK4/5 signaling pathway to inhibit 
skeletal muscle growth. High levels of GDF-11 and GDF-15 have been shown to be associated 
with frailty and increased comorbidity in older subjects and, quite recently, also shown to be up-
regulated in cancer and related to the muscle loss seen in conjunction with cancer and cachexia 
(109, 110). Data on biomarkers will be collected and registered as an exploratory translational 

 
 
27 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
part of the study (see detailed description in section 4.8). Included patients must give their 
separate informed consent to participate in the biomarker study. Patients who refuse to participate 
in the biomarker study will still be allowed to participate in the TOLCA – Breast Cancer Exercise 
study. Recruitment to the biomarker study will be performed in accordance with the described 
and approved manner in the biomarker study. Data on the biomarkers serum C-reactive protein 
(CRP), interleukin 6 (IL-6), YKL-40, GDF11 and GDF15 will be used in analyses in the TOLCA 
– Breast Cancer Exercise study to investigate whether the exercise-based intervention affects the 
inflammatory process, and to investigate the association between these biomarkers and clinical 
outcomes. Transmission of the biomarkers data to the TOLCA Breast Cancer Exercise study will 
be done in accordance to the regulations of the Danish Data Protection Agency and all necessary 
approvals will be obtained.   
 
10. Hospital admissions: numbers, causes, and length of hospitalizations during the intervention and 
follow-up period. Contact to the Emergency Room with falls will be noted. 
 
11. Mortality/survival: with a purpose to investigate whether the intervention may affect survival 
time/mortality, incidences of deaths (cancer-related and other cause) will be registered 
throughout the intervention period and during follow-up.   
4.8 Inflammatory biomarkers (data collection and assessment) 
At Herlev and Gentofte Hospital, translational research will be performed for all patients participating 
in the TOLCA – Breast Cancer Exercise study, provided that included patients give their separate 
informed consent to participate in these biomarker studies. Patients who refuse to participate in the 
biomarker studies will still be allowed to participate in the TOLCA – Breast Cancer Exercise study.  
Patients will be informed and asked to participate in the biomarker study ‘Prospektiv indsamling af 
blodprøver hos patienter med cancer mammae – giver biomarkører i blod ny information om diagnose, 
behandlingseffekt, bivirkning og prognose?” (PRIMA-b-protokollen) as described in the approved 
PRIMA-b protocol. Entering the PRIMA-b study, 30 ml blood will be collected at baseline (before the 
other baseline data is collected in TOLCA Breast Cancer Exercise Study), before the second cycle of 
chemotherapy (approximately midway intervention, 6 weeks), and at the time of CT scanning 
(approximately post intervention, 12 weeks) according to the PRIMA-b protocol (VEK ref.: KA-H-3-
2014-120,; and Datatilsynet: HE-2014-083, I-Suite 03140). Blood samples will be stored as serum, 
plasma or buffy-coat for biomarker analyses in the approved PRIMA B biobank at Herlev Hospital until 
2024. Transmission of the biomarkers data to the TOLCA Breast Cancer study, will be done in 

 
 
28 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
accordance to the regulations of the Danish Data Protection Agency and all necessary approvals will be 
obtained.      
Serum high sensitive CRP is measured by routine method at Department of Clinical Biochemistry at 
Herlev and Gentofte Hospital. Serum IL-6 is determined by ELISA (R&D) and YKL-40 is determined 
by ELISA (Quidel) at Department of Medicine, Herlev and Gentofte Hospital. 92 cancer- and-
inflammatory protein profiles will be determined using the Olink array (www.Olink) at BioXpedia, 
Århus. Serum GDF11 and GDF15 are determined by ELISA at Department of Sports Science and 
Clinical Biomechanics, University of Southern Denmark. Data on the inflammatory biomarkers will be 
used in analyses in the present study to investigate whether the exercise-based intervention affects the 
inflammatory process, and to investigate the association between these biomarkers and clinical 
outcomes. 
 
 

 
 
29 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
4.9 Time of data collection and tests 
Data collection and tests will be performed at baseline, midway intervention (6 weeks), post-intervention 
(12 weeks), and follow-up (16 weeks). Schedule for data collection and tests are shown in Table 2. 
Table 2 Data collection and tests. 
 
Inclusion 
(baseline) 
Midway 
(6 weeks) 
 
Post-intervention  
(12 weeks) 
Follow-up 
(16 weeks) 
Informed consent, TOLCA 
X 
 
 
 
Informed consent (PRIMAB) 1 
X 
 
 
 
Clinical and medical data 
X 
X 
X 
X 
Demographics 
X 
 
 
 
Health status (ECOG, CCI, CARG 
toxicity risk score) 
X 
 
 
 
Feasibility measures  
Recruitment rates  
Retention 
Adherence 
Adverse events 
Patients satisfaction  
 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
X 
 
PROMs 
PRPS 
MDASI (measured once weekly) 
EORTC QLQ-C30 & BR23 
HADS 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Physical tests 
30s-CST (primary outcome) 
6MWT 
Gait speed, 6 m and 10m 
Handgrip strength 
Stair climb test 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Physical activity  
X 
 
X 
 
Biomarkers related to inflammation 
X 
X 
X 
 
Oncological treatment/toxicity 
X 
X 
X 
X 
Body measures and composition 
Weight, BMI  
DXA scan 
BI 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
1For patients with breast cancer who accept participation in the PRIMA B trial. 
4.10Analyses and statistics 
4.10.1 Sample size 
No prior studies have investigated the minimal clinically important difference in the 30s-CST focusing 
on cancer patients. However, according to a previous study focusing on patients with osteoarthritis, the 
clinically important change in the 30s-CST was set at 2.6 repetitions (120). Based on results from prior 
studies focusing on patients with advanced cancer, a standard deviation (SD) of around 3 has been 
reported in the 30s-CST(121, 122). To be able to detect a difference of 2.6 repetitions in the between-
group difference in the 30s-CST at the 12-week assessment, and to obtain a type I error rate of 5% and 
a power of 90%, a sample size of 29 patients per study arm will be needed. To account for an expected 

 
 
30 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
dropout rate of ~40%, we decided to increase this number to a group size of 50. Thus, a total of 100 
patients will be included in the study. 
4.10.2Analysis plan 
4.10.2.1 Quantitative data 
Feasibility measures (acceptability, attrition, adherence, and adverse events) will be reported as numbers 
and percentages. Reasons for declining participation will be analyzed descriptively with numbers and 
percentages of patients declining for various reasons. Baseline characteristics will be calculated for all 
patients included (total) and separately for intervention group and control group. For all quantitative 
variables the median number and interquartile range (IQR) will be calculated, and for nominal variables 
the number and percentage distribution will be calculated. Results from physical tests, blood test, body 
measures, and questionnaires will be reported as means and standard deviations (SD) or as median and 
IQR, as appropriate. Change over time in ordinal categorical values will be evaluated by a trend test 
using logistic regression. In-group and between- group differences in continuous-level data, will be 
performed using a repeated measurement analysis. Survival analyses will be conducted with Kaplan-
Meier method, competing risk analyses and Cox regression analyses. Using the Kaplan-Meier method, 
cancer-specific and overall survival time will be assessed for the intervention group and the control 
group, and comparison in survival between groups will be assessed using the log-rank test. To account 
for competing risks (deaths from other causes than cancer), the cumulative incidence of cancer-specific 
death will be assessed using competing risk analyses, and comparison between groups will be conducted 
using Grey’s test. Cox proportional hazards regression will be used to estimate the hazards (risk) of 
death, and cause specific Cox proportional hazards regression will be used to assess the risk of cancer-
related death. The significance level of all tests is set a p < 0.05, and analyses will be carried out in SAS 
or R by statisticians in collaboration with the primary investigator. 
5 Ethical considerations 
Study approval will be obtained by the Scientific Ethics Review Committee of the Capital Region of 
Denmark and the Danish Data Protection Agency. The study will also be registered at ClinicalTrials.gov. 
TOLCA – Breast Cancer Exercise will be carried out in accordance with the protocol, and according the 
Helsinki Declaration. All personal data will be treated with confidentiality and security in accordance 
with the Danish Personal Data Act.  
All potential participants will be provided with full and adequate verbal and written information about 
the project and will have the right to ask questions about the study. Each patient will be informed about 
their personal rights when entering the study. It is emphasized that participation in the study is voluntary, 

 
 
31 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
and that any included patients at any given time can cancel participation in the study. If the oncological 
treatment regime is changed or discontinued for included patients in the study, these patients will still 
be allowed to continue in the TOLCA – Breast Cancer Exercise study. Written informed consent forms 
will be obtained from all patients when entering the study. The primary investigator will also sign each 
informed consent form to confirm that all verbal and written information has been provided.  
6 Potential risks and disadvantages 
There are a few potential risks and disadvantages for patients in the intervention group, including 
exercise injuries and discomfort in performing the exercise program. However, risks and disadvantages 
are considered to be limited. An experienced physiotherapist will supervise all exercise sessions at the 
hospital setting. If a patient shows any signs of being physically unwell during an exercise session, the 
patient’s blood pressure, heart rate, respiratory rate, and temperature will be measured, and appropriate 
actions will be taken. For safety reasons, patients will not be allowed to participate in the training 
sessions if there is fever (≥38.5ºC). If a patient reports any discomfort or incidence of injury during the 
intervention period, the safety and further program continuation for the patient will be discussed in the 
research group, and in consultation with the patient and the responsible physician. The investigators and 
the responsible oncologists have the rights to exclude a patient from the study at any given time, if it is 
considered unsafe for the patient to continue. Data on adverse events will be collected systematically 
every week, and patients will furthermore be informed to contact the primary investigator immediately 
if injuries or other adverse events related to the intervention program should occur.   
6.1 Radiation exposure 
Body composition will be assessed for all patients (intervention group and control group) by DXA scan 
and BI technique at baseline and after 12 weeks. BI causes no radioactive radiation and is a completely 
harmless method for assessment of body composition. DXA scans will be conducted with the Lunar 
iDXA from GE Healthcare (123). Depending on individual body size, patients will be exposed for a 
small radiation dose of approximately 3 μGY (= 0.003 mSv) in each of the two DXA scans (123). This 
dose of radiation is low and corresponds the radiation a person is exposed to by flying at 10 kilometers 
altitude (during the scan time = approximately 6 minutes). All patients will be informed, both verbally 
and in writing, about the DXA scans and about the expected radiation exposure before entering the study.  
7 Publication of study results 
Potentially positive, negative, or inconclusive results from the TOLCA – Breast Cancer Exercise study 
will be published in relevant international peer-reviewed journals. Co-authorship for the upcoming 

 
 
32 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
publications will be offered to members of the project group or other collaborators based on 
contributions to the current work, and in accordance with the Vancouver recommendations.   
8 Economy 
The initiator of the TOLCA – Breast Cancer Exercise study is Dorte Nielsen, Professor, MD, PhD, 
DMSc, at Department of Oncology, Herlev and Gentofte Hospital 
The TOLCA – Breast Cancer Exercise study is financially supported by grants from the VELUX 
Foundation (a total of 1,308.069 DKK). The support from The VELUX Foundation covers the salary for 
PhD student Ida Lundager during the 3-year period. The VELUX Foundation will be mentioned in all 
written and oral presentations, and in future publications. The VELUX Foundation (or other future 
funding organizations) will not have any role in the conduction of the study design or protocol, data 
collection, interpretation of data, or in the drafting or approval of coming publications. There is no 
commercial or politically binding relationship between any members of the TOLCA project group and 
the VELUX Foundation. Financially support from other funding organizations will be applied, to cover 
expenses related to the TOLCA – Breast Cancer Exercise study. The Scientific Ethics Review 
Committee of the Capital Region of Denmark and participants in the study will be informed about any 
further grants.    
Patients included in TOLCA – Breast Cancer Exercise study will not receive any financial fees by 
participating in the trial.  
9 Scientific statement 
The TOLCA – Breast Cancer Exercise study is expected to involve low risk of adverse events and 
discomfort for patients involved. The intervention and all assessments will be led and conducted by 
experienced therapists and other health care practitioners with all relevant safety precautions installed. 
Patients involved in the research program will not experience any delays in their treatment due to 
participation in the program. Included patients can withdraw from the program at any time and without 
any specific reasons. It is the project group’s assessment that it is necessary to carry out the current 
research project to gain important knowledge about the effect and feasibility of a exercise-based 
intervention as a rehabilitative approach to older patients with breast cancer during oncological treatment 
adjuvant or first line palliative systemic therapy. The project group estimates that the TOLCA – Breast 
Cancer Exercise intervention will maintain or increase physical function levels, reduce symptoms and 
side effect, increase tolerance to oncological treatment, and improve psychological well-being and QOL 

 
 
33 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
in older patients with primary advanced breast cancer, and that the expected benefits of the intervention 
exceed the estimated limited risks for patients involved.  
10 Clinical perspectives and implementation 
With the aging population and expected increase of cancer incidence (especially among older people), 
new approaches of early rehabilitation are needed to maintain physical function levels and independence 
in older cancer patients. The TOLCA – Breast Cancer Exercise study has the potential to become a new 
model of early rehabilitation care for older patients with breast cancer. In the long term, it is our goal to 
investigate the program’s effect among older patients with various malignancies in order to map out the 
effects, common features, and the differences across cancers, with an overall focus on the older cancer 
population. The TOLCA – Breast Cancer Exercise study supports the development of future health 
promotion guidelines for older cancer patients during anti-cancer treatment by reducing the complex 
symptom burden, supporting treatment tolerance, maintaining physical function and thereby enabling a 
better quality of life. The interventions pragmatic approach and integration in the hospital and home-
setting will be implementable should the study prove effective and implementation is the goal.   
 
 

 
 
34 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
11 References 
Appendix 1: Performance status 
 
The Eastern Cooperative Oncology Group (ECOG) performance status (also known as the WHO or the 
Zubrod score). The ECOG performance score runs from 0-5, with 0 denoting good health with an 
independent and active lifestyle, and 5 death.  
ECOG performance status* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.  
5 
Dead 
* Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of The Eastern Cooperative Oncology Group. 
Am J ClinOncol 1982; 5: 649-655.  
 
Kræftens Bekæmpelse (Danish version)* 
Kræftens Bekæmpelses version af ‘performance status’ 
Score 
Status 
0 
Fuldt aktiv som før man blev syg. 
1 
Kan ikke udføre tungt fysisk arbejde, men alt andet.  
2 
Oppegående mere end halvdelen af dagen og selvhjulpen, men ude af stand til at 
udføre fysisk arbejde. 
3 
I seng eller siddende i stol mere end halvdelen af dagen, og brug for hjælp til at klare 
sig selv.  
4 
Bundet til seng eller stol og har brug for hjælp til alt.  
* Kræftens Bekæmpelse. Ordbog  -performance status. From: https://www.cancer.dk/hjaelp-viden/fakta-om-
kraeft/ordbog/performance-status/ 

 
 
35 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
Appendix 2: Patient questionnaire (Danish) 
 
Deltageroplysninger  
Kære deltager i TOLCA- Bryst Kræft Trænings studiet.  
Du bedes venligst udfylde nedenstående spørgeskema og returnere det til den projektansvarlige 
fysioterapeut (Ida Lundager). 
 
Fødselsdato (DD.MM.ÅR): ___________________ 
Mand □ 
Kvinde □ 
Hvilket land er du født i? ________________________ 
 
 
Hvad er din civilstatus? 
Gift / samboende □ 
Enlig/enke/enkemand □ 
 
 
Hvad er det højeste uddannelsesniveau du har gennemført? 
Mindre end 9. klasse □ 
9. eller 10. klasse (folkeskole) □ 
Gymnasial uddannelse □ 
Erhvervsuddannelse/faglig uddannelse □ 
Kort videregående uddannelse (under 3 år) □ 
Mellemlang videregående uddannelse (3-4 år)□ 
Lang videregående uddannelse (5 år og derover) □ 
 
 
Hvad er din beskæftigelsessituation? 
Pensionist/efterlønsmodtager □ 
Lønmodtager i arbejde eller selvstændig □ 
Sygedagpenge/revalidering □ 
Arbejdsløs □ 
 
Ryger du? 
Ja, jeg ryger dagligt □   
Ja, men kun til festlige lejligheder □ 
Nej, jeg har aldrig røget □ 
Nej, men jeg har tidligere røget □ 
 
Hvis du er aktiv ryger, svar så venligst på følgende:  
- 
Hvor mange cigaretter ryger du dagligt? _______________  
- 
Hvis du ryger andet end cigaretter, angiv hvilket her: _______________, samt antal gram 
dagligt_________ 
- 
I hvor mange år har du røget? ________________ 
 
 

 
 
36 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
 
Hvor mange genstande drikker du typisk på en uge? _________________ antal genstande. 
 
Hvor ofte får du 6 genstande eller mere ved en enkelt lejlighed? 
Aldrig □ 
Sjældnere end én gang om måneden □ 
Månedligt □ 
Ugentligt □ 
Dagligt eller næsten dagligt □ 
 
 
Hvilket aktivitetsniveau passede bedst på dig cirka 3 måneder inden du fik din 
kræftdiagnose? (sæt kun ét kryds) 
□ Stillesiddende (mest stillesiddende aktiviteter såsom at læse eller se fjernsyn)  
 
□ Lettere fysisk aktiv (spadserer, cykler eller har anden lettere motion i under 3 timer pr. uge) 
 
□ Moderat aktiv (regelmæssig fysisk aktivitet mindst 3 timer om ugen – medregn også lettere 
havearbejde 
    og søndagsture).  
 
□ Aktiv (regelmæssig fysisk aktivitet og motion mindst 3 timer om ugen) 
 
□ Meget fysisk aktiv (hård fysisk træning mere end 4 timer om ugen) 
 
 
Hvilket aktivitetsniveau passer bedst på dig i din aktuelle situation? (sæt kun ét kryds) 
□ Stillesiddende (mest stillesiddende aktiviteter såsom at læse eller se fjernsyn)  
 
□ Lettere fysisk aktiv (spadserer, cykler eller har anden lettere motion under 3 timer pr. uge) 
 
□ Moderat aktiv (regelmæssig fysisk aktivitet mindst 3 timer om ugen – medregn også lettere 
havearbejde 
og søndagsture). 
 
□ Aktiv (regelmæssig fysisk aktivitet og motion mindst 3 timer om ugen) 
 
□ Meget fysisk aktiv (hård fysisk træning mere end 4 timer om ugen) 
 
Bruger du hjælpemidler for at komme omkring når du er derhjemme? 
Nej □ 
Ja, rollator □ 
Ja, stok □ 
Ja, gangbuk □ 
Ja, talerstol □ 
Andet: ____________________ 
 
 
 
 
 

 
 
37 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
Bruger du hjælpemidler for at komme omkring når du er udendørs? 
Nej, jeg kommer omkring uden gangredskaber □ 
Ja, rollator □ 
Ja, stok □ 
Ja, gangbuk □ 
Ja, talerstol □ 
Andet: ____________________ 
 
 
Hvordan kommer du omkring i det offentlige rum? 
Jeg har bil og kan selv køre □ 
Jeg har en pårørende/ven der uden besværlighed kan køre mig □ 
Jeg har en pårørende/ven der kan køre mig – dog ikke uden besvær og/eller planlægning □ 
Jeg er afhængig af offentlig transport (bus, tog, metro) □ 
Jeg har ikke bil eller kørelejlighed og er ikke i stand til at tage offentlig transport □ 
 
 
Hvilket funktionsniveau passer bedst på dig i din nuværende situation (ECOG performance 
status)?:  
 
Fuldt aktiv. I stand til at udføre alle aktiviteter som før sygdommen uden begrænsninger □ 
 
Let nedsat ydeevne; kan ikke udføre tungt fysisk arbejde, men alt andet □ 
 
Oppegående mere end halvdelen af dagen og selvhjulpen, men ude af stand til at udføre fysisk 
arbejde □ 
 
I seng eller siddende i stol mere end halvdelen af dagen og begrænset selvhjulpen □ 
 
Bundet til seng eller stol og har brug for hjælp til alt □ 
 
 
Mange tak for din deltagelse! 
 

 
 
38 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
Appendix 3: M.D. Anderson Symptom Inventory (Danish version) 
 
 

 
 
39 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 

 
 
40 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
 

 
 
41 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
Appendix 4: EORTC Quality of Life Questionnaire (Danish version) 
 

 
 
42 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
 
 
 

 
 
43 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
  
EORTC  QLQ - BR23  DANISH  
Patienter fortæller undertiden, at de har følgende symptomer eller problemer. Anfør venligst, i hvilket 
omfang du har haft disse symptomer eller problemer inden for den forløbne uge.  
 
I den forløbne uge:   
Slet  Lidt  En del  Meget  
  
  
ikke  
31. Var du tør i munden?  
1  
2  
3  
4  
32. Smagte mad og drikke anderledes end normalt?  
1  
2  
3  
4  
33. Havde du ondt i øjnene, var øjnene irriterede eller løb de i vand?  
1  
2  
3  
4  
34. Har du haft hårtab?  
35. Skal kun udfyldes, hvis du har haft hårtab:   
1  
2  
3  
4  
 
Var du ked af hårtabet?  
1  
2  
3  
4  
36. Følte du dig syg eller utilpas?  
1  
2  
3  
4  
37. Havde du hedeture?  
1  
2  
3  
4  
38. Havde du hovedpine?  
39. Har du følt dig mindre fysisk tiltrækkende på   
1  
2  
3  
4  
 grund af din sygdom eller behandling?  
40. Har du følt dig mindre kvindelig på grund af din   
1  
2  
3  
4  
 
sygdom eller behandling?  
1  
2  
3  
4  
41. Havde du svært ved at se på dig selv nøgen?  
1  
2  
3  
4  
42. Har du været utilfreds med din krop?  
1  
2  
3  
4  
43. Var du bekymret for, hvordan dit helbred bliver i fremtiden?  
 
1  
2  
3  
4  
I de sidste fire uger:  
Slet  
 
  
 
ikke  Lidt  En del  Meget  
44. I hvilket omfang var du interesseret i sex?  
45. I hvilket omfang var du seksuelt aktiv?   
1  
2  
3  
4  
 
(med eller uden samleje)   
46. Besvar kun dette spørgsmål, hvis du har været   
1  
2  
3  
4  
 seksuelt aktiv: I hvilket omfang nød du sex?  
1  
2  
3  
4  
 
Vær venlig at fortsætte på næste side 

 
 
44 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
DANISH  
  
I den forløbne uge:  
Slet  
 
  
 
ikke  Lidt  En del  Meget 
47. Havde du smerter i armen eller skulderen?  
1  
2  
3  
4  
48. Var armen eller hånden hævet?  
1  
2  
3  
4  
49. Var det svært at løfte armen eller bevæge den til siden?  
1  
2  
3  
4  
50. Har du haft smerter i ”brystområdet”?  
1  
2  
3  
4  
51. Var ”brystområdet” hævet?  
1  
2  
3  
4  
52. Var ”brystområdet” ømfindtligt?  
53. Har du haft hudproblemer i ”brystområdet”  
1  
2  
3  
4  
(f.eks. kløe, tørhed, afskalning)?  
1  
2  
3  
4  
  
  
  
  
© Copyright 1994, 1995  EORTC Study Group on  Quality of Life,   Alle rettigheder forbeholdes. Version 1.0  
 
 

 
 
45 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
Appendix 5: The Hospital Anxiety and Depression Scale (Danish Version) 
 

 
 
46 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
 
 
 

 
 
47 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
References 
1. 
Parry C, Kent EE, Mariotto AB, Alfano CM, Rowland JH. Cancer survivors: a booming population. 
Cancer Epidemiol Biomarkers Prev. 2011;20(10):1996-2005. 
2. 
DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and 
survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252-71. 
3. 
Bellizzi KM, Mustian KM, Palesh OG, Diefenbach M. Cancer survivorship and aging : moving the 
science forward. Cancer. 2008;113(12 Suppl):3530-9. 
4. 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. 
5. 
Scher KS, Hurria A. Under-representation of older adults in cancer registration trials: known 
problem, little progress. J Clin Oncol. 2012;30(17):2036-8. 
6. 
Engholm G FJ, Christensen N, Johannesen TB, Khan S, Køtlum JE, Milter MC, Olafdóttir E, Pukkala 
E, Storm HH. NORDCAN: Cancer Incidence, Mortality, Prevalence and Survival in the Nordic Countries, Version 
6.1 (25.04.2014) http://www.ancr.nu: Association of the Nordic Cancer Registries. Danish Cancer Society;  [ 
7. 
Strait JB, Lakatta EG. Aging-associated cardiovascular changes and their relationship to heart 
failure. Heart Fail Clin. 2012;8(1):143-64. 
8. 
Sharma G, Goodwin J. Effect of aging on respiratory system physiology and immunology. Clin 
Interv Aging. 2006;1(3):253-60. 
9. 
Weinstein JR, Anderson S. The aging kidney: physiological changes. Adv Chronic Kidney Dis. 
2010;17(4):302-7. 
10. 
Bhutto A, Morley JE. The clinical significance of gastrointestinal changes with aging. Curr Opin 
Clin Nutr Metab Care. 2008;11(5):651-60. 
11. 
Janssen I, Heymsfield SB, Wang ZM, Ross R. Skeletal muscle mass and distribution in 468 men 
and women aged 18-88 yr. J Appl Physiol (1985). 2000;89(1):81-8. 
12. 
Frontera WR, Hughes VA, Fielding RA, Fiatarone MA, Evans WJ, Roubenoff R. Aging of skeletal 
muscle: a 12-yr longitudinal study. J Appl Physiol (1985). 2000;88(4):1321-6. 
13. 
Skelton DA, Greig CA, Davies JM, Young A. Strength, power and related functional ability of 
healthy people aged 65-89 years. Age Ageing. 1994;23(5):371-7. 
14. 
Demontiero O, Vidal C, Duque G. Aging and bone loss: new insights for the clinician. Ther Adv 
Musculoskelet Dis. 2012;4(2):61-76. 
15. 
Hawkley LC, Cacioppo JT. Stress and the aging immune system. Brain Behav Immun. 
2004;18(2):114-9. 
16. 
Pritz T, Weinberger B, Grubeck-Loebenstein B. The aging bone marrow and its impact on 
immune responses in old age. Immunol Lett. 2014;162(1 Pt B):310-5. 
17. 
Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, 
frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 
2004;59(3):255-63. 
18. 
Fried LP, Kronmal RA, Newman AB, Bild DE, Mittelmark MB, Polak JF, et al. Risk factors for 5-
year mortality in older adults: the Cardiovascular Health Study. Jama. 1998;279(8):585-92. 
19. 
Hilmer SN, Gnjidic D. The effects of polypharmacy in older adults. Clin Pharmacol Ther. 
2009;85(1):86-8. 
20. 
Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med. 
2013;29(4):737-52. 
21. 
Charles ST, Carstensen LL. Social and emotional aging. Annu Rev Psychol. 2010;61:383-409. 
22. 
Hawkins S, Wiswell R. Rate and mechanism of maximal oxygen consumption decline with aging: 
implications for exercise training. Sports Med. 2003;33(12):877-88. 
23. 
Cheville AL, Mustian K, Winters-Stone K, Zucker DS, Gamble GL, Alfano CM. Cancer 
Rehabilitation: An Overview of Current Need, Delivery Models, and Levels of Care. Phys Med Rehabil Clin N 
Am. 2017;28(1):1-17. 
24. 
Kenzik KM, Kent EE, Martin MY, Bhatia S, Pisu M. Chronic condition clusters and functional 
impairment in older cancer survivors: a population-based study. J Cancer Surviv. 2016;10(6):1096-103. 

 
 
48 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
25. 
Grov EK, Fossa SD, Dahl AA. Short-term and long-term elderly cancer survivors: a population-
based comparative and controlled study of morbidity, psychosocial situation, and lifestyle. Eur J Oncol Nurs. 
2011;15(3):213-20. 
26. 
Mohile SG, Xian Y, Dale W, Fisher SG, Rodin M, Morrow GR, et al. Association of a cancer 
diagnosis with vulnerability and frailty in older Medicare beneficiaries. J Natl Cancer Inst. 2009;101(17):1206-
15. 
27. 
Baker F, Haffer SC, Denniston M. Health-related quality of life of cancer and noncancer patients 
in Medicare managed care. Cancer. 2003;97(3):674-81. 
28. 
Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy 
toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457-65. 
29. 
Muss HB, Berry DA, Cirrincione C, Budman DR, Henderson IC, Citron ML, et al. Toxicity of older 
and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and 
Leukemia Group B Experience. J Clin Oncol. 2007;25(24):3699-704. 
30. 
Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, et al. Predicting the risk of 
chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients 
(CRASH) score. Cancer. 2012;118(13):3377-86. 
31. 
Repetto L. Greater risks of chemotherapy toxicity in elderly patients with cancer. J Support 
Oncol. 2003;1(4 Suppl 2):18-24. 
32. 
Stout NL, Silver JK, Raj VS, Rowland J, Gerber L, Cheville A, et al. Toward a National Initiative in 
Cancer Rehabilitation: Recommendations From a Subject Matter Expert Group. Arch Phys Med Rehabil. 
2016;97(11):2006-15. 
33. 
Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: 
European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in 
Older People. Age Ageing. 2010;39(4):412-23. 
34. 
Rolland Y, Czerwinski S, Abellan Van Kan G, Morley JE, Cesari M, Onder G, et al. Sarcopenia: its 
assessment, etiology, pathogenesis, consequences and future perspectives. J Nutr Health Aging. 
2008;12(7):433-50. 
35. 
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and 
classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-95. 
36. 
Muscaritoli M, Anker SD, Argiles J, Aversa Z, Bauer JM, Biolo G, et al. Consensus definition of 
sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-
anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clin Nutr. 2010;29(2):154-9. 
37. 
Moses AW, Slater C, Preston T, Barber MD, Fearon KC. Reduced total energy expenditure and 
physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense 
oral supplement enriched with n-3 fatty acids. Br J Cancer. 2004;90(5):996-1002. 
38. 
Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Buchler MW, Friess H, Martignoni ME. 
Cachexia worsens prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg. 
2008;12(7):1193-201. 
39. 
Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of weight 
loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 
1980;69(4):491-7. 
40. 
Mir O, Coriat R, Blanchet B, Durand JP, Boudou-Rouquette P, Michels J, et al. Sarcopenia 
predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular 
carcinoma. PLoS One. 2012;7(5):e37563. 
41. 
Sun L, Quan XQ, Yu S. An Epidemiological Survey of Cachexia in Advanced Cancer Patients and 
Analysis on Its Diagnostic and Treatment Status. Nutr Cancer. 2015;67(7):1056-62. 
42. 
Sanchez-Lara K, Turcott JG, Juarez E, Guevara P, Nunez-Valencia C, Onate-Ocana LF, et al. 
Association of nutrition parameters including bioelectrical impedance and systemic inflammatory response 
with quality of life and prognosis in patients with advanced non-small-cell lung cancer: a prospective study. 
Nutr Cancer. 2012;64(4):526-34. 

 
 
49 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
43. 
Fearon KC, Voss AC, Hustead DS. Definition of cancer cachexia: effect of weight loss, reduced 
food intake, and systemic inflammation on functional status and prognosis. Am J Clin Nutr. 2006;83(6):1345-
50. 
44. 
Stephens NA, Skipworth RJ, Gallagher IJ, Greig CA, Guttridge DC, Ross JA, et al. Evaluating 
potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients. J 
Cachexia Sarcopenia Muscle. 2015;6(1):53-61. 
45. 
Peng P, Hyder O, Firoozmand A, Kneuertz P, Schulick RD, Huang D, et al. Impact of sarcopenia on 
outcomes following resection of pancreatic adenocarcinoma. J Gastrointest Surg. 2012;16(8):1478-86. 
46. 
Kudou K, Saeki H, Nakashima Y, Edahiro K, Korehisa S, Taniguchi D, et al. Prognostic Significance 
of Sarcopenia in Patients with Esophagogastric Junction Cancer or Upper Gastric Cancer. Ann Surg Oncol. 
2017;24(7):1804-10. 
47. 
Churm D, Andrew IM, Holden K, Hildreth AJ, Hawkins C. A questionnaire study of the approach 
to the anorexia-cachexia syndrome in patients with cancer by staff in a district general hospital. Support Care 
Cancer. 2009;17(5):503-7. 
48. 
Ali S, Garcia JM. Sarcopenia, cachexia and aging: diagnosis, mechanisms and therapeutic options 
- a mini-review. Gerontology. 2014;60(4):294-305. 
49. 
Rolland Y, Dupuy C, Abellan van Kan G, Gillette S, Vellas B. Treatment strategies for sarcopenia 
and frailty. Med Clin North Am. 2011;95(3):427-38, ix. 
50. 
Zinna EM, Yarasheski KE. Exercise treatment to counteract protein wasting of chronic diseases. 
Curr Opin Clin Nutr Metab Care. 2003;6(1):87-93. 
51. 
Ardies CM. Exercise, cachexia, and cancer therapy: a molecular rationale. Nutr Cancer. 
2002;42(2):143-57. 
52. 
Arends J BV, Bertz H, Bozetti F, Calder PC, Deutz NEP, Erickson N, Laviano A, Lisanti MP, Lobo 
DN, McMillan DC, Muscaritoli M, Ockenga J, Pirlich M, Strasser F, de van der Schueren M, Van Gossum A, 
vaupel P, Weimann A ESPEN expert group recommendations for action against cancer-related malnutrition. 
Clinical Nutrition 2017. 
53. 
Bouaziz W, Vogel T, Schmitt E, Kaltenbach G, Geny B, Lang PO. Health benefits of aerobic 
training programs in adults aged 70 and over: a systematic review. Arch Gerontol Geriatr. 2017;69:110-27. 
54. 
Cardoso F, Costa A, Senkus E, Aapro M, Andre F, Barrios CH, et al. 3rd ESO-ESMO International 
Consensus Guidelines for Advanced Breast Cancer (ABC 3). Annals of oncology : official journal of the European 
Society for Medical Oncology. 2017;28(12):3111. 
55. 
Stewart VH, Saunders DH, Greig CA. Responsiveness of muscle size and strength to physical 
training in very elderly people: a systematic review. Scand J Med Sci Sports. 2014;24(1):e1-10. 
56. 
Catalan-Matamoros D, Gomez-Conesa A, Stubbs B, Vancampfort D. Exercise improves 
depressive symptoms in older adults: An umbrella review of systematic reviews and meta-analyses. Psychiatry 
Res. 2016;244:202-9. 
57. 
Yoshimura Y, Wakabayashi H, Yamada M, Kim H, Harada A, Arai H. Interventions for Treating 
Sarcopenia: A Systematic Review and Meta-Analysis of Randomized Controlled Studies. J Am Med Dir Assoc. 
2017;18(6):553.e1-.e16. 
58. 
Beaudart C, Dawson A, Shaw SC, Harvey NC, Kanis JA, Binkley N, et al. Nutrition and physical 
activity in the prevention and treatment of sarcopenia: systematic review. Osteoporos Int. 2017;28(6):1817-
33. 
59. 
Jones LW, Eves ND, Haykowsky M, Freedland SJ, Mackey JR. Exercise intolerance in cancer and 
the role of exercise therapy to reverse dysfunction. Lancet Oncol. 2009;10(6):598-605. 
60. 
Buffart LM, Kalter J, Sweegers MG, Courneya KS, Newton RU, Aaronson NK, et al. Effects and 
moderators of exercise on quality of life and physical function in patients with cancer: An individual patient 
data meta-analysis of 34 RCTs. Cancer Treat Rev. 2017;52:91-104. 
61. 
Gerritsen JK, Vincent AJ. Exercise improves quality of life in patients with cancer: a systematic 
review and meta-analysis of randomised controlled trials. Br J Sports Med. 2016;50(13):796-803. 
62. 
Adamsen L, Quist M, Andersen C, Moller T, Herrstedt J, Kronborg D, et al. Effect of a multimodal 
high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. 
BMJ (Clinical research ed). 2009;339:b3410. 

 
 
50 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
63. 
Kilari D, Soto-Perez-de-Celis E, Mohile SG, Alibhai SM, Presley CJ, Wildes TM, et al. Designing 
exercise clinical trials for older adults with cancer: Recommendations from 2015 Cancer and Aging Research 
Group NCI U13 Meeting. Journal of geriatric oncology. 2016;7(4):293-304. 
64. 
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and 
mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 
2015;136(5):E359-86. 
65. 
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer 
incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United 
States. Cancer Res. 2014;74(11):2913-21. 
66. 
Ejlertsen B. Retningslinier: medicinsk behandling: Danish Breast Cancer Cooperative Group; 
2017 [updated 07.04.2017. HER2-rettet behandling til patienter med HER- postitiv operabel brystkræft]. 
Available from: http://www.dbcg.dk/PDF%20Filer/Kap_6_Medicinsk_behandling-07.04.2017.pdf. 
67. 
Azim HA, Jr., de Azambuja E, Colozza M, Bines J, Piccart MJ. Long-term toxic effects of adjuvant 
chemotherapy in breast cancer. Annals of oncology : official journal of the European Society for Medical 
Oncology. 2011;22(9):1939-47. 
68. 
DBCG. Danish Breast Cancer Cooperative Group: Danish Breast Cancer cooperative group; 2018 
[Available from: http://www.dbcg.dk/. 
69. 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76. 
70. 
Bradshaw PT, Ibrahim JG, Khankari N, Cleveland RJ, Abrahamson PE, Stevens J, et al. Post-
diagnosis physical activity and survival after breast cancer diagnosis: the Long Island Breast Cancer Study. 
Breast Cancer Res Treat. 2014;145(3):735-42. 
71. 
Lahart IM, Metsios GS, Nevill AM, Carmichael AR. Physical activity for women with breast cancer 
after adjuvant therapy. Cochrane Database Syst Rev. 2018;1:Cd011292. 
72. 
Adams SC, Segal RJ, McKenzie DC, Vallerand JR, Morielli AR, Mackey JR, et al. Impact of 
resistance and aerobic exercise on sarcopenia and dynapenia in breast cancer patients receiving adjuvant 
chemotherapy: a multicenter randomized controlled trial. Breast cancer research and treatment. 
2016;158(3):497-507. 
73. 
Cadmus LA, Salovey P, Yu H, Chung G, Kasl S, Irwin ML. Exercise and quality of life during and 
after treatment for breast cancer: results of two randomized controlled trials. Psycho-oncology. 
2009;18(4):343-52. 
74. 
Carayol M, Bernard P, Boiche J, Riou F, Mercier B, Cousson-Gelie F, et al. Psychological effect of 
exercise in women with breast cancer receiving adjuvant therapy: what is the optimal dose needed? Annals of 
oncology : official journal of the European Society for Medical Oncology. 2013;24(2):291-300. 
75. 
Casla S, Lopez-Tarruella S, Jerez Y, Marquez-Rodas I, Galvao DA, Newton RU, et al. Supervised 
physical exercise improves VO2max, quality of life, and health in early stage breast cancer patients: a 
randomized controlled trial. Breast cancer research and treatment. 2015;153(2):371-82. 
76. 
Courneya KS, Segal RJ, Mackey JR, Gelmon K, Reid RD, Friedenreich CM, et al. Effects of aerobic 
and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized 
controlled trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2007;25(28):4396-404. 
77. 
Schmidt ME, Wiskemann J, Armbrust P, Schneeweiss A, Ulrich CM, Steindorf K. Effects of 
resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: 
A randomized controlled trial. International journal of cancer. 2015;137(2):471-80. 
78. 
Schmidt T, Weisser B, Durkop J, Jonat W, Van Mackelenbergh M, Rocken C, et al. Comparing 
Endurance and Resistance Training with Standard Care during Chemotherapy for Patients with Primary Breast 
Cancer. Anticancer research. 2015;35(10):5623-9. 
79. 
Travier N, Velthuis MJ, Steins Bisschop CN, van den Buijs B, Monninkhof EM, Backx F, et al. 
Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised 
controlled trial. BMC medicine. 2015;13:121. 

 
 
51 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
80. 
van Vulpen JK, Schmidt ME, Velthuis MJ, Wiskemann J, Schneeweiss A, Vermeulen RCH, et al. 
Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant 
chemotherapy. Breast cancer research and treatment. 2018;168(2):421-31. 
81. 
van Waart H, Stuiver MM, van Harten WH, Geleijn E, Kieffer JM, Buffart LM, et al. Effect of Low-
Intensity Physical Activity and Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on 
Physical Fitness, Fatigue, and Chemotherapy Completion Rates: Results of the PACES Randomized Clinical Trial. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(17):1918-27. 
82. 
Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvao DA, Pinto BM, et al. 
American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine and 
science in sports and exercise. 2010;42(7):1409-26. 
83. 
Yagli NV, Ulger O. The effects of yoga on the quality of life and depression in elderly breast 
cancer patients. Complementary therapies in clinical practice. 2015;21(1):7-10. 
84. 
Payne JK, Held J, Thorpe J, Shaw H. Effect of exercise on biomarkers, fatigue, sleep disturbances, 
and depressive symptoms in older women with breast cancer receiving hormonal therapy. Oncology nursing 
forum. 2008;35(4):635-42. 
85. 
American College of Sports Medicine position stand. Progression models in resistance training 
for healthy adults. Med Sci Sports Exerc. 2009;41(3):687-708. 
86. 
Sundhedsstyrelsen. Fysisk aktivitet - håndbog om forebyggelse og behandling 2011. Version 3.1. 
https://www.sst.dk/da/sundhed-og-livsstil/fysisk-
aktivitet/~/media/6B3A4AE698BC42139572C76C5854BA76.ashx 2011 [ 
87. 
Locke EA, Bryan JF. The effects of goal-setting, rule-learning, and knowledge of score on 
performance. Am J Psychol. 1966;79(3):451-7. 
88. 
Schut HA, Stam HJ. Goals in rehabilitation teamwork. Disabil Rehabil. 1994;16(4):223-6. 
89. 
Bovend'Eerdt TJ, Botell RE, Wade DT. Writing SMART rehabilitation goals and achieving goal 
attainment scaling: a practical guide. Clin Rehabil. 2009;23(4):352-61. 
90. 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83. 
91. 
Jones CJ, Rikli RE, Beam WC. A 30-s chair-stand test as a measure of lower body strength in 
community-residing older adults. Res Q Exerc Sport. 1999;70(2):113-9. 
92. 
Loenbro S DU, Primdahl, Overgaards J, Overgaard K. . Feasibility and efficacy of progressive 
resistance training and dietary supplements in radiotherapy treated head and neck cancer patients -- the 
DAHANCA 25A study. . Acta Oncol 2013;52(2):310-8. 
93. 
Rikli R JJ. Senior Fitness Test Manual-2nd Edition. Human Kinetics. 2001. 
94. 
Guralnik JM, Ferrucci L, Pieper CF, Leveille SG, Markides KS, Ostir GV, et al. Lower extremity 
function and subsequent disability: consistency across studies, predictive models, and value of gait speed 
alone compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci. 2000;55(4):M221-
31. 
95. 
Cesari M, Kritchevsky SB, Penninx BW, Nicklas BJ, Simonsick EM, Newman AB, et al. Prognostic 
value of usual gait speed in well-functioning older people--results from the Health, Aging and Body 
Composition Study. J Am Geriatr Soc. 2005;53(10):1675-80. 
96. 
Schmidt K, Vogt L, Thiel C, Jager E, Banzer W. Validity of the six-minute walk test in cancer 
patients. Int J Sports Med. 2013;34(7):631-6. 
97. 
Rikli RE JC. The Reliability and Validity of a 6-Minute Walk Test as a Measure of Physical 
Endurance in Older Adults. Journal of Aging and Physical Activity 1998;6:363-75. 
98. 
Kasymjanova G, Correa JA, Kreisman H, Dajczman E, Pepe C, Dobson S, et al. Prognostic value of 
the six-minute walk in advanced non-small cell lung cancer. J Thorac Oncol. 2009;4(5):602-7. 
99. 
Hayashi K, Yokoyama Y, Nakajima H, Nagino M, Inoue T, Nagaya M, et al. Preoperative 6-minute 
walk distance accurately predicts postoperative complications after operations for hepato-pancreato-biliary 
cancer. Surgery. 2017;161(2):525-32. 
100. 
Mathiowetz V, Weber K, Volland G, Kashman N. Reliability and validity of grip and pinch 
strength evaluations. J Hand Surg Am. 1984;9(2):222-6. 

 
 
52 Protocol TOLCA - Breast Cancer Exercise v8 18.06.2018 
 
101. 
Kilgour RD, Vigano A, Trutschnigg B, Lucar E, Borod M, Morais JA. Handgrip strength predicts 
survival and is associated with markers of clinical and functional outcomes in advanced cancer patients. 
Support Care Cancer. 2013;21(12):3261-70. 
102. 
Bean JF, Kiely DK, Herman S, Leveille SG, Mizer K, Frontera WR, et al. The relationship between 
leg power and physical performance in mobility-limited older people. Journal of the American Geriatrics 
Society. 2002;50(3):461-7. 
103. 
Bean JF, Kiely DK, LaRose S, Alian J, Frontera WR. Is stair climb power a clinically relevant 
measure of leg power impairments in at-risk older adults? Archives of physical medicine and rehabilitation. 
2007;88(5):604-9. 
104. 
Blagden SP, Charman SC, Sharples LD, Magee LR, Gilligan D. Performance status score: do 
patients and their oncologists agree? Br J Cancer. 2003;89(6):1022-7. 
105. 
Cleeland CS, Mendoza TR, Wang XS, Chou C, Harle MT, Morrissey M, et al. Assessing symptom 
distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer. 2000;89(7):1634-46. 
106. 
Life EQo. QLQ-C30 devolpment  [Available from: http://group.eortc.be/qol/qlq-c30-
development. 
107. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67(6):361-70. 
108. 
Rier HN, Jager A, Sleijfer S, Maier AB, Levin MD. The Prevalence and Prognostic Value of Low 
Muscle Mass in Cancer Patients: A Review of the Literature. The oncologist. 2016. 
109. 
Glass DJ. Elevated GDF11 Is a Risk Factor for Age-Related Frailty and Disease in Humans. Cell 
metabolism. 2016;24(1):7-8. 
110. 
Breit SN, Tsai VW, Brown DA. Targeting Obesity and Cachexia: Identification of the GFRAL 
Receptor-MIC-1/GDF15 Pathway. Trends in molecular medicine. 2017;23(12):1065-7. 
111. 
Lukaski HC. Soft tissue composition and bone mineral status: evaluation by dual-energy X-ray 
absorptiometry. J Nutr. 1993;123(2 Suppl):438-43. 
112. 
Fosbol MO, Zerahn B. Contemporary methods of body composition measurement. Clin Physiol 
Funct Imaging. 2015;35(2):81-97. 
113. 
Pietrobelli A, Wang Z, Formica C, Heymsfield SB. Dual-energy X-ray absorptiometry: fat 
estimation errors due to variation in soft tissue hydration. Am J Physiol. 1998;274(5 Pt 1):E808-16. 
114. 
Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gomez JM, et al. Bioelectrical 
impedance analysis--part I: review of principles and methods. Clin Nutr. 2004;23(5):1226-43. 
115. 
Kushner RF, Gudivaka R, Schoeller DA. Clinical characteristics influencing bioelectrical 
impedance analysis measurements. Am J Clin Nutr. 1996;64(3 Suppl):423s-7s. 
116. 
Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-7. 
117. 
Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk 
between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759-71. 
118. 
Bower JE. Cancer-related fatigue: links with inflammation in cancer patients and survivors. Brain 
Behav Immun. 2007;21(7):863-71. 
119. 
Hojman P. Exercise protects from cancer through regulation of immune function and 
inflammation. Biochem Soc Trans. 2017. 
120. 
Wright AA, Cook CE, Baxter GD, Dockerty JD, Abbott JH. A comparison of 3 methodological 
approaches to defining major clinically important improvement of 4 performance measures in patients with 
hip osteoarthritis. J Orthop Sports Phys Ther. 2011;41(5):319-27. 
121. 
Litterini AJ, Fieler VK, Cavanaugh JT, Lee JQ. Differential effects of cardiovascular and resistance 
exercise on functional mobility in individuals with advanced cancer: a randomized trial. Arch Phys Med Rehabil. 
2013;94(12):2329-35. 
122. 
Oldervoll LM, Loge JH, Lydersen S, Paltiel H, Asp MB, Nygaard UV, et al. Physical exercise for 
cancer patients with advanced disease: a randomized controlled trial. Oncologist. 2011;16(11):1649-57. 
123. 
Healthcare G. Lunar iDXA - intelligent DXA: GE imagination at work;  [cited 2017 9 December]. 
Available from: http://www.activexray.com/pdf/idexa.pdf.