An Online Home-based Combined Exercise Intervention With Self-selected Intensity for Women With Breast Cancer: The Home-Combo Randomized Controlled Trial.
Phase: NA
Conditions: Breast Cancer, Chemotherapy Effect
Sponsor: Grupo Lusófona

 
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Title: An online home-based combined exercise intervention with 
self-selected intensity for women with breast cancer: Design and 
rationale of the Home-Combo randomized controlled trial. 
Pedro G.F. Ramos, Eliana V. Carraça, Nuno Dias, Gabriela Valadas, Pedro B. Júdice 
 
Trial registration: submitted to clinicaltrials.gov, 16/04/2024 
Version 1: April 29th, 2024 
 
Funding 
There are no foreseen funding sources. However, some partnerships might be 
made to acquire some expenses that might exist (e.g., participants’ insurance) and 
resources (i.e., equipment or human resources) needed to conduct the study.  
 
Roles and responsibilities 
 
Pedro G.F. Ramos, Centro de Investigação em Desporto, Educação Física, 
Exercício e Saúde (CIDEFES), Universidade Lusófona Centro de Lisboa, project 
conceptualization, manuscript writing, trial implementation, participants’ recruitment and 
assessment, data analysis. 
 
Eliana V. Carraça, Centro de Investigação em Desporto, Educação Física, 
Exercício e Saúde (CIDEFES), Universidade Lusófona Centro de Lisboa, project 
conceptualization, manuscript editing, process supervision. 
 
Nuno Dias, Centro de Investigação em Desporto, Educação Física, Exercício e 
Saúde (CIDEFES), Universidade Lusófona Centro de Lisboa, manuscript review and 
editing. 
 
Gabriela Valadas, Centro Hospitalar Universitário do Algarve, project 
conceptualization, process supervision, participants’ recruitment. 
 
Pedro B. Júdice, Centro de Investigação em Desporto, Educação Física, 
Exercício e Saúde (CIDEFES), Universidade Lusófona Centro de Lisboa, project 
conceptualization, manuscript editing, process supervision. 
 
 

 
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ABSTRACT 
 
Background. Chemotherapy drugs carry many side effects that may hinder the 
functional performance of women with breast cancer (BC). Chemoresistance can lead to 
treatment failure. A relative dose intensity of chemotherapy <85% is associated with a 
worse diagnosis and lower treatment efficacy. Exercise may modulate treatment 
response through its effects on the tumor microenvironment and treatment tolerability. 
The need for a pleasant and sustainable exercise practice is important, considering the 
psychological and physiological stress that accompanies women with a BC diagnosis 
during treatment. Studies investigating the effects of exercise interventions on 
chemotherapy completion rates are needed.  
Purpose. This study aims to investigate the effects of a self-selected intensity 
structured supervised home-based combined exercise intervention on the chemotherapy 
completion rates of women with BC. Secondly, we intend to analyze the impact of this 
intervention on functional performance, quality of life, body composition, and physical 
activity levels. A 3-month follow-up will investigate if physically active behavior is 
sustained post-intervention. 
Methods. A 2-arm randomized controlled trial will be implemented in a real-world 
exercise setting to compare an online structured and supervised group aerobic and 
strength exercise intervention with an active control group during chemotherapy 
treatments. The study recruitment goal is 122 women with a BC diagnosis stage I-III who 
are scheduled to have neoadjuvant or adjuvant chemotherapy. Outcome measures will 
be obtained at baseline, mid-treatment (≈3 months), post-intervention (≈6 months), and 
3-month follow-up. A mediation analysis will also be conducted. 
 
Key-words: Breast cancer; Home-based exercise; Chemotherapy; Functional 
performance; Body composition; Physical activity; Quality of life 
 
 
 
 
 
 
 
 
 

 
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Introduction 
Background and rationale 
Breast cancer (BC) is the most diagnosed cancer type, with high levels of 
incidence, prevalence, and cancer-related deaths among women worldwide 1,2. 
Chemotherapy is commonly used as an anticancer therapy, consisting of the 
intravenous administration of a combination of cytotoxic drugs to delay cancer growth or, 
in some cases, eradicate the tumor and prevent cancer cell multiplication, invasion, and 
metastasizing 3,4. However, since chemotherapy drugs are not selective to tumor cells or 
normal cells, many side effects hinder functional performance (i.e., a person’s ability to 
perform daily activities involving physical effort with vigor and without excessive fatigue) 
of women with BC 5,3,6. Another problem that may arise during treatment is the 
development of tumor cells’ resistance to chemotherapy, ultimately leading to treatment 
failure 7,8. A relative dose intensity (RDI) (i.e., the dose of drugs delivered to a person 
with cancer each week of treatment)  <85% is associated with a worse disease prognosis 
and lower treatment efficacy 9–12.  
Exercise appears to be a safe and effective cancer co-therapy that improves 
functional performance in women with BC during treatments and may potentially 
enhance treatment efficacy 12–15. Despite the very well-known benefits of exercise for 
women with BC, this population often fails to adhere to a more active lifestyle and comply 
with the recommended physical activity (PA) guidelines due to fatigue, conflicting 
scheduled commitments, sickness, forgetting appointments, pain, procrastination, and 
lack of self-discipline, enjoyment or interest  16–18. 
Some evidence has shown that exercise may modulate treatment response 
through its effects on the tumor and may also improve the tolerability of chemotherapy, 
making it a potential tool to enhance chemotherapy completion rate (i.e., reception of the 
planned treatment doses) 12. So far, evidence shows that exercise does not disrupt 
chemotherapy delivery, but failed to demonstrate that exercise may increase 
chemotherapy completion rates 12,19. For instance, Mijwel et al. (2020) randomized 240 
women to either a resistance and high-interval training group, aerobic and high-interval 
training group, or usual care groups and found no effects of exercise on chemotherapy 
completion rate. Sanft et al. (2023) conducted a home-based exercise and nutrition 
counseling intervention on 173 women with BC undergoing chemotherapy, reporting no 
intervention effects in RDI compared to the usual care group. 
Home-based exercise interventions (i.e., programs performed inside or in the 
immediate surroundings of one’s home 21)  are a convenient and flexible strategy with 
high adherence and proven to be effective and beneficial to improve functional 

 
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performance, raising activity levels, reducing symptoms, and improving overall quality of 
life in women with a BC diagnosis 22–24. 
The need for a pleasant and sustainable exercise practice may be a relevant topic 
when considering the psychological and physiological burden and stress that often 
accompanies women after a BC diagnosis and during the treatment phase when dealing 
with therapy side effects 25,26. Even though some evidence suggests that allowing self-
selection of exercise intensity may not be optimal to maximize health or fitness, 
increasing enjoyment and adherence to exercise practice and creating sustained lifestyle 
changes can be more beneficial 27. Although some exercise methods might be highly 
efficient in potentiating physiological outcomes in women with BC (e.g., high-intensity 
interval training), they may fail to meet this population’s preferences and hinder the 
sustainability of active lifestyle behaviors after the studies’ interventions 28–30. 
Bolam et al. (2019) performed a 2-year follow-up on 206 women with a BC 
diagnosis who participated in either a concurrent high-intensity interval and progressive 
resistance training or a concurrent high-intensity interval training and continuous 
moderate-intensity aerobic exercise to analyze the PA levels of the participants post-
intervention. Results showed that none of the participants in the intervention significantly 
changed their PA levels compared to the usual care group. Ramírez-Parada et al. (2019) 
conducted a questionnaire-based study on a sample of 112 women with BC to 
investigate the exercise preferences among this population, reporting that most 
participants preferred to perform the exercise in a group with other BC survivors at 
moderate intensity in a supervised setting. Studies have shown that participants can 
achieve adequate intensity and improve functional performance with exercise 
interventions where they self-select their training intensity in the general population 33,34. 
Evidence suggests that self-selected intensities seem higher when the participants are 
supervised by a qualified professional 34,35. Ratamess et al. (2008) investigated women’s 
responses and the resistance training intensity selected, with and without professional 
supervision, in a healthy population. Findings in this study showed that women selected 
higher intensities, loads, and ratings of perceived exertion when supervised compared 
to unsupervised settings. 
Also, evidence has shown that developing a program that is tailored and sensitive 
to the participants' needs and consider their preferences is essential to promoting 
continued engagement and long-term behavior changes 36. Gildea et al. 37 Schleicher et 
al.28 stated that to maximize adherence to an exercise program and lifelong active 
lifestyles, the participants' preferences, facilitators, and perceived barriers must be 
considered. 

 
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Studies investigating the effects of exercise interventions on chemotherapy 
completion rates as a primary outcome are still needed to substantiate further findings 
12. Also, to the authors’ knowledge, no study has conducted and analyzed the effects of 
a structured and supervised home-based 21 self-selected intensity exercise program in 
women with a BC diagnosis. 
 
Objectives 
This study will investigate the effects of a structured, supervised, home-based 
combined exercise intervention with self-selected intensity on the chemotherapy 
completion rates of women with BC. We also intend to analyze the impact of this 
intervention on functional performance, body composition, PA levels, and quality of life. 
A 3-month follow-up will be performed to investigate short-term outcomes and active 
lifestyle sustainability post-intervention. 
 
Hypothesis 1: Women in the intervention will have a better completion rate than 
those in the control group.  
Hypothesis 2: Women in the intervention will present better functional 
performance, body composition, PA levels, and quality of life than the control group. 
Hypothesis 3: In the post-intervention period, women in the intervention group will 
maintain a more physically active lifestyle than women in the control group. 
 
Trial design 
This study will be a 2-arm pragmatic and superiority randomized controlled trial 
with an intervention and an active control group, with a 1:1 allocation ratio. It will comprise 
a structured, supervised, home-based combined exercise intervention that will start 1-2 
weeks after chemotherapy treatments begin and continue until  3-4 weeks post-
treatment. Additionally, a 3-month follow-up will be performed. This protocol followed the 
Spirit guidelines 38. 
 
Methods 
 
Study setting 
The Home-Combo study will take place in the Algarve, and the sample will be 
recruited by medical referral from various public and private hospitals, and oncologic 
organizations across the region. 

 
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The intervention design will consider the PA/exercise preferences, perceived 
barriers, and facilitators of women with BC. This information will be collected before the 
intervention through a mixed-methods qualitative study that will include a survey and 
focus groups. The intervention will be conducted online to ensure the participants’ safety 
during the chemotherapy treatment phase, as they may have compromised immunity. 
Also, this option was made to attenuate participants’ burden caused by commuting 
requirements 17,39,40. Due to the specific timings between the first contact and study 
enrolment, participants will be enrolled continuously for one year. Recruitment will 
continue for each cohort until the number of participants per group is achieved. A scheme 
of the study timeline is presented in Table 1.  
 
Eligibility criteria 
Women aged ≥18 years with a BC stage I-III diagnosis, scheduled to receive 
neoadjuvant or adjuvant chemotherapy, and who have access to a computer will be 
considered eligible to participate in the study. Women already at the mid-stage of the 
chemotherapy treatments, with medical counterindication to perform the exercise 
intervention or physical assessments due to concomitant comorbidity, non-controlled 
health conditions or diseases, or psychological illness, currently enrolled in a structured 
exercise program, or women unable to complete the entire program (e.g., due to 
scheduled surgery or personal commitments) will be considered ineligible. Participants 
who get pregnant or have a worsening in their clinical condition during the intervention 
will be discounted from the program. 
The exercise professionals who will perform the interventions and assessments 
must have an academic degree in Exercise Sciences and a specialization in exercise 
with cancer populations or receive education sessions with an exercise professional 
specialized in exercise for BC populations to acquire knowledge and skills to conduct 
exercise sessions online. Also, professionals who conduct the interventions will have to 
perform at least three simulated sessions among each other, supervised by a qualified 
peer, to guarantee consistency in the intervention application.  
 
Interventions 
Combined home-based exercise group. Participants in this group will exercise 
throughout their chemotherapy treatments, starting within 1-2 weeks of its start and 
ending within 3-4 weeks post-treatment completion 41.  
The exercise intervention will be led by qualified exercise professionals, 
comprising two weekly 60-minute online exercise group sessions with a 5-minute warm-

 
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up, a 30-minute resistance training, and a 20-minute aerobic exercise component, 
finishing with a 5-minute cooldown 42. The warm-up will be composed of mobility and 
activation movements, such as cat-camels, butterfly chest stretch, overhead reach, floor 
angels, spine twist in sitting and alternated all fours position, doorway chest stretch, wall 
slides, scissors, pointer, and single leg stances. The resistance training component will 
consist of 9 different exercises, performed either with body weight or free weights, 
completing 2-3 sets of 10-15 repetitions, and will involve movements such as chair sit-
to-stand, multi-directional lunges, calf, and toe raises, double-arm and one-arm rows, 
push-ups, glute bridges, clams, chest press, multi-directional shoulder raises, leg curls, 
and abdominal exercises (i.e., crunches, leg raises, crisscross) 41,42. The aerobic 
component will consist of low-impact dance exercises, moving large muscle groups to 
increase heart rate, involving marching, side steps, knee raises, leg curls, multi-
directional arm movements, and dance movements 42. The cooldown will consist of 
breathing exercises and light stretches. Every exercise professional will follow a written 
protocol to ensure consistency in the intervention program’s application 42.  
Before the beginning of the exercise program, participants will receive an 
education session on how to use Borg’s Perceived Rate of Exertion Scale (RPE) to 
monitor their effort during aerobic and resistance training and tips on when they may 
increase the exercise intensity 43,44. During the training sessions, participants in the 
intervention group will be asked to choose their preferred load to execute each exercise 
in the resistance component, told to perform the aerobic exercises at their preferred 
speed, and informed that they can stop exercising whenever they need to rest. The 
exercise professional may suggest increasing loads in specific exercises, but these 
increases will not be imposed on the participants. Attendance to the sessions in the 
intervention and control groups will be registered. Additionally, women in this group will be 
encouraged to perform brisk walking at their preferred intensity and receive a pedometer 
to increase walking motivation 45–47,42.  
Control group. Women randomized to the control group will receive weekly 30-
minute supervised sessions with breathing, stretching, relaxation exercises, and 
meditation during the intervention period 42. Women in this group will not be forbidden to 
perform PA but will not receive any incentives or advice from the supervising exercise 
professional.  
 
Criteria for discontinuing or modifying allocated interventions  
Participants will be informed in the pre-study initial meeting that they may leave 
the study anytime. Participants will be asked to refrain from continuing the intervention if 
a worsening clinical condition prevents them from exercising and performing the 

 
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assessments safely. The exercise program might be reviewed and tailored to the 
participants’ condition across the intervention. 
 
Strategies to improve adherence  
Before implementing this study, a survey and focus-group-based study will be 
performed to adjust the exercise program to the preferences, perceived barriers, and 
facilitators of women with a breast cancer diagnosis, considering the environmental and 
cultural context from where the intervention will be conducted. The supervising 
professional will monitor adherence to the supervised sessions through presence 
registration. This study will also consider the participants’ adherence to the control group. 
To attempt dropout minimization, we will have an active control group. 
 
Concomitant care  
Physiotherapy treatments prescribed by the participant’s primary physician and 
any exercises prescribed to be performed at home prescribed by the physiotherapist will 
be allowed during the intervention. Participants in the study will be asked not to engage 
in other exercise and PA programs or activities outside the program. Participants in the 
control group will not be prohibited from performing physical activities like brisk walking.  
 
Outcomes 
Assessments will be performed at four-time points: baseline (T0, 1-2 weeks post-
chemotherapy start), mid-treatment (T1, planned mid-cycle), post-intervention (T2, 3-4 
weeks post-chemotherapy finishing), and 3 months post-intervention finishing (T3, follow-
up). The primary outcome of this study will be the chemotherapy completion rates. 
Secondary outcomes will include functional performance, body composition, PA levels, 
sedentary behavior (SB) (i.e., behaviors with energy expenditure ≤1.5 METs while sitting, 
or lying 48), and quality of life. Demographical information (age, education level, marital 
status, socioeconomic status), PA history, and clinical history data (disease and 
treatment history, concomitant comorbidities, and other existing health problems besides 
BC) will also be collected as covariates in the data analysis.  
 
Participant timeline 
 
*** Table 1*** 
 
 
 

 
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Sample size 
Considering this study design, sample size calculations were made for the 
primary outcome with a factorial variance analysis with repeated measures as reference 
statistical analysis, giving an initial estimation of 82 participants. Based on previous 
findings and considering a 20% dropout, the sample size was estimated at 98 
participants with a moderate effect size (a=0.05; statistical power=0.80) according to 
Cohen’s D calculations, using G* Power 3.1 49,50. 
 
 
Recruitment 
Recruitment will occur through medical referrals from primary physicians of 
several public and private hospitals in the Algarve region. Additionally, the project will be 
presented at breast cancer-themed congresses and events, and digital flyers with 
information about the study will be made to assist in disseminating the project and the 
recruitment process. A research team member will then contact patients referred by the 
doctors to receive detailed information about the study. Optionally, patients can call the 
research team directly or contact them through email if they prefer. After confirming 
eligibility criteria and interest in participating in the study, patients will be asked to attend 
an initial session where more information will be given, and the informed consent will be 
signed. During that session, participants will be told they are not obliged to participate in 
the study and may decide to leave the project. Consent for data collection or sharing will 
also be obtained.  
 
Assignment of interventions 
 
Allocation 
Sequence generation  
After signing the informed consent form, participants will be given a number, 
randomly generated through Excel and emailed by a non-interventionist team member, 
which will be their participant number throughout the study. Participants will be instructed 
not to reveal their number to the research team or the other participants and to keep it 
with them until the end of the study. After all baseline assessments, participants will be 
randomly assigned to either the intervention or control arm through an online program 
(https://www.graphpad.com/quickcalcs/randomize1/). If recruitment takes longer than 
expected, adjustments in allocation may be made.  
 
 

 
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Allocation concealment mechanism  
Participants and research team members will be unaware of group allocation 
during recruitment and baseline assessments. A non-interventionist research team 
member will fill in the measurements’ results during the field tests. This team member 
will be the only person, besides the participant, who will know the participant’s number. 
The participants will identify the questionnaires with their numbers. 
Implementation  
After all questionnaires have been received, the random allocation will be 
performed. The non-interventionist team member will email all participants the numbers 
allocated in each group (intervention or control).  
 
Blinding (masking)  
Participants will be told they are part of an exercise intervention without any mention 
of a control group. The healthcare professionals responsible for the chemotherapy 
prescription and administration and registering all clinical information will be blinded to 
the participants’ groups. None of the research team members will know the number of 
participants, so data analysis will be performed in a blinded setting. The exercise 
professional conducting the assessments will be blinded to the participant’s number but 
not to which group the participant belongs. If, at any given moment, a participant reveals 
her number to a research team member, all posterior data from that participant will be 
disregarded. If a participant decides to leave the study or must abandon it due to health 
complications, the team member with the number information will be informed, and all 
further data will be disregarded from the analysis. 
 
Data collection, management, and analysis 
 
Data collection methods  
Assessments will be conducted in standardized conditions, in a clinical setting, in 
a calm and comfortable environment, in small groups, and performed by a qualified 
exercise professional. The assessments will be conducted in the morning, starting with 
the body composition measurements, followed by a 15-minute pause so participants can 
eat (since they will be weighted while fasting), preceded by a 10-minute warm-up with 
general movements to mobilize big muscle groups and the physical tests, that will be 
performed in the following order: shoulder angular measurements, strength, mobility, and 
aerobic endurance. Participants will be divided into small groups to facilitate instruction 
and conduction of the tests. Participants will receive the accelerometers one week before 

 
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the field tests and return them on the physical assessment day. After the field 
measurements, all questionnaires will be delivered and answered through email (Google 
Forms). Summarized information regarding assessment time points and tools can be 
found in Table 1. 
 
Primary outcome  
Chemotherapy completion rates. Chemotherapy completion rates will be 
assessed at T0, T1, and T2. This outcome will be reported as the mean RDI (mg.m-2/wk-
1), which corresponds to a fraction of the planned chemotherapy dose intensity, by 
dividing the dose of chemotherapy per square meter (of surface area where the drug is 
related) in each cycle by the number of weeks in a cycle 52,9,19. Information regarding the 
planned chemotherapy treatment and the effectively received treatment (i.e., dose, type, 
and duration) will be acquired from medical records after signing the informed consent 
53,19. A successful chemotherapy completion rate will be considered if the RDI is ≥85% of 
the planned treatment, as an RDI below this cut-off is associated with a worse disease 
prognosis and lower treatment efficacy 12. Calculations to compare the actual 
chemotherapy dose intensity received and the initially planned dose intensity will be 
calculated as total milligrams of chemotherapy divided by the product of the body surface 
(in square meters) and total weeks of treatment 19. The RDI results from the actual dose 
intensity received are divided by the planned dose intensity 9,19. 
 
Secondary outcomes  
Functional performance. Functional performance will be assessed at T0, T1, T2, 
and T3. The test battery will consider aerobic capacity, upper and lower body strength, 
grip strength, shoulder mobility, and overall mobility. Aerobic endurance will be assessed 
using the 6-minute walk test, a standardized field test performed indoors in a 30-meter 
corridor with two turning points marked every 3 meters along the course, that has been 
considered valid and reliable for evaluating aerobic capacity in cancer patients 54–56. In 
this test, participants will be asked to walk the maximum distance possible in 6 minutes 
on a flat and hard surface, whereas the distance walked is the outcome 54–56. The arm 
curl and sit-to-stand tests will be used to test the lower and upper body strength, 
respectively, since they are valid and reliable in these populations 57,58. Handgrip strength 
will be measured using the JAMAR dynamometer since it has shown reasonable validity 
and reliability in measuring this variable among adults ≥50 years old and used in 
oncologic samples 59–61. While performing the handgrip test for each hand, participants 
will be instructed to stand upright with feet at hip width and elbows completely stretched 
while applying the maximum grip continuously for more than 3 seconds, and 30 seconds 

 
12 
of rest will be given between measurements 62–64. Handgrip strength will be considered 
to the nearest 0.1 kilograms, with each participant performing 2 attempts in each hand, 
and a best value will be considered 64. The timed up-and-go test will assess participants’ 
overall mobility. Participants will be instructed to rise from a chair, walk 2.44 meters, turn 
around, walk back to the chair, and sit down 65,57. Shoulder flexion and abduction angular 
measures will be performed on both sides using a validated and reliable goniometer to 
measure this variable 66,51. Upper limb flexibility will be assessed using the back scratch 
test 65,57. 
 
Body composition. Body composition will be measured through bioelectrical 
impedance (Impedimed Australia) at T0, T1, T2, and T3 at the beginning of each 
assessment 67. Data regarding weight, fat mass, lean mass, water percentage, bone 
mass, visceral fat, and phase angle will be collected from the scale 67. Participants will 
be asked to maintain their dietary patterns before the test and refrain from intense 
exercise the day before 68. The measurement will be performed under standardized 
conditions (i.e., in the morning, 8-hour fasting, bladder voiding before the assessment, 
controlled room temperature, and no exercise before the measurement)  69,70,51. The 
height measurement will be considered to the nearest 0.1 cm of the participants and will 
be performed using a balance-mounted stadiometer (SECA, Germany), with the 
participants standing and bare-footed 71,51. Body weight will be measured to the nearest 
0.1kg with a digital scale (SECA, Germany) 51. BMI (kg/m2) will be calculated from weight 
(kg) and height (m). Participants will be asked to maintain their dietary patterns before 
the test and refrain from intense exercise the day before 68. The measurement will be 
performed under standardized conditions (i.e., in the morning, 8-hour fasting, bladder 
voiding before the assessment, controlled room temperature, and no exercise before the 
measurement)  69,70,51. 
 
Physical Activity and Sedentary Behavior. PA levels and SB will be assessed 
at T0, T1, T2, and T3 using a motion sensor (GT9 link, Actigraph) and the International 
Physical Activity Questionnaire Short-Form (IPAQ-SF) 72,73,51,74. Accelerometers have 
been previously reported as valid and reliable tools to objectively measure PA levels in 
general and clinical populations 75,72,76,74. Participants will be instructed to wear the device 
on an elastic belt on the non-dominant hip for 7 days during all waking hours, removing 
only to sleep 77,51. The sampling units (epochs) will be settled to 1s to ease data analysis 
and ensure the appropriate sensitivity of the device during low-intensity activities. The 
accelerometer counts will be categorized into sedentary, light, moderate, and vigorous 
activity levels according to specific established thresholds 78,79.  Any interval of 60 or 

 
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more minutes with continuous zero counts, will be considered as non-wear time 78. The 
IPAQ-SF comprises 9 items that measure the weekly time spent on all intensities PA (i.e., 
light, moderate, and vigorous) and time spent sitting on week and weekend days. Total 
PA scores are calculated from the collected data and discriminated by intensity 73.  
 
Quality of life. Quality of life will be assessed at T0, T1, T2, and T3, using the 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLQ-C30). The specific module EORTC QLQ-BR45 will 
measure breast cancer-related quality of life. Both tools demonstrated adequate validity 
and reliability, specifically for cancer patients 80,81. The EORT QLQ-C30 questionnaire 
consists of 30 items, grouped into 8 multi-item scales (i.e., functional: physical, role, 
emotional, cognitive, and social; symptom: fatigue, pain, and nausea), one global health 
status and quality of life subscale, and 6 single-item questions (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties) 51,80. The breast cancer 
module QLQ-BR45 comprises 5 functional sub-scales (body image, future perspective, 
sexual functioning, sexual enjoyment, breast satisfaction) and 7 symptoms sub-scales 
(arm symptoms, breast symptoms, endocrine therapy, skin mucositis, endocrine sexual 
symptoms, systemic therapy side effects, and upset hair loss), for a total of 45 items (the 
previous 23 items found in QLQ-BR23 plus 22 new items) 82,81,83. High scores on the 
functional scales determine better functioning, and high scores on the symptoms scale 
and body image mean higher issues 80,84. Because the QLQ-BR45 algorithm has not yet 
been validated, the QLQ-BR23 algorithm will be used to score the questionnaire 85. 
 
Covariates  
Demographics, physical activity and medical history. Participants’ 
demographic information (e.g., age, education, marital status, and economic status) 
and PA history will be collected through a general information questionnaire, and 
clinical history data will be retrieved from their medical records after they sign the 
informed consent form. 
 
Plans to promote retention  
The conducting exercise professional will control participants’ adherence to the 
exercise program through a presence registry collected by the research team member 
with access to the list of participants’ numbers. After the session, the non-interventionist 
research team member will pass the presence list to the respective numbers of the 
participants for program adherence analysis. If a participant fails to attend a session, 
contact will be made to ensure the participant’s welfare and motivate them to participate 

 
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in the next session. The data analysis will not consider participants who fail to attend 
50% or more sessions. Positive feedback will be given to the participants during the 
sessions, as positive feedback is proven to enhance feelings of competence, enjoyment, 
and interest in the activity 86.  Additionally, participants will be encouraged to keep an 
activity diary where they may register all activities performed autonomously. Participants 
will be contacted one week before the assessment to confirm their availability and 
presence. Data from participants who fail to perform the assessments during the 
intervention period will be excluded from data analysis. After the intervention, participants 
will be contacted monthly to check their well-being and keep their interest and motivation 
in engaging in the follow-up assessment. 
 
*** Table 2*** 
 
 
Data management  
All the data collected in this study will be kept confidential, computerized, and 
encrypted in a database without any elements that may allow identification of the 
participants. After the participants have expressed interest and written informed consent, 
a number corresponding to the participant ID during the study will be provided. When the 
participant receives her ID number, all data inserted in the databases will not be directly 
linked to the participant’s personal identification. A dataset will be created for each 
assessment time point. All datasets will be maintained by the members responsible for 
the investigation on a secure server of CIDEFES-UL for ten years and will be used 
exclusively for research purposes. Datasets used for specific analyses or to develop sub-
studies will contain only the necessary variables and the demographical indicators 
provided to the research team members upon request to the leading investigator. 
 
Statistical methods 
All data will be analyzed using IBM SPSS (version 29.0). Factorial ANCOVAS 
with repeated measures will be used for the primary and secondary outcomes, adjusted 
for potential covariates (e.g., concomitant treatments, BC diagnosis, neo-adjuvant/ 
adjuvant chemotherapy). Independent sample T-tests will be used to compare results 
between groups at each time point, considering chemotherapy completers versus non-
completers 19. A Fisher’s exact test will compare the proportion of participants who 
needed chemotherapy adjustments from those who did not 19. The intention-to-treat 
analysis will be conducted to ensure that all participants are included in the overall 
assessment, considering their compliance with the study protocol. The Last Observation 

 
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Carried Forward method will be used to input missing data values. A per-protocol analysis 
will also be conducted without participants who failed to complete at least 50% of the training 
sessions. Normality plots and Kolmogorov-Smirnov tests will be performed to test the 
normality of outcome variables. If normality is not satisfied, non-parametric tests will be 
applied (e.g., Krustal-Wallis). Mediators of change (i.e., mechanisms by which RDI) will be 
explored using structural equation modeling (AMOS 18.0) and multiple mediation analysis 
(PROCESS macro for SPSS) 51. Putative candidates will include treatment (e.g., dose 
planned vs. given dose, planned cycles minimum/maximum, treatment interruption ratios, 
response to treatment, percentage of participants who needed dose adjustments, and the 
mean value of dose adjustment), and physiological (e.g., body composition, functional 
performance, handgrip strength, PA levels) variables. Mediation occurs when a causal effect 
of an independent variable occurs on a dependent variable, partly or entirely explained by a 
mediator 87. Indirect effects testing will be performed using Preacher and Hayes’ procedures 
88.  
 
Monitoring 
 
Data monitoring 
A data monitoring committee will not be required for this trial as the interventions pose 
minimal risk, and participants will be protected by personal insurance throughout the study. 
 
 
Harms  
All participants will have their adverse events monitored throughout the study, 
whether directly related to the intervention or not (if applicable). This monitoring will be done 
through self-reporting at the start of each session, registered for analysis and report 
purposes, or by their primary care physicians. Participants will be advised to contact the 
clinical team if they have difficulties. 
 
Auditing 
Two authors will supervise all trial procedures and cross-check the interventionist 
actions and study processes. Additionally, an independent person external to the project will 
review the protocol. 
 
Ethics and dissemination 
 
Research ethics approval  

 
16 
This study has received ethical approval from the collaborating hospital (UAIF 
069/2024). This trial will follow the World Medical Association’s Declaration of Helsinki for 
Human Studies 89.  
 
 
 
Protocol amendments  
Any changes to the protocol will be promptly communicated to all participants 
involved in the study or data manipulation. The lead investigator will inform all cooperating 
institutions, sponsors, or funding agencies. Modifications to the protocol will be submitted for 
approval to all the Ethics committees involved in the project. The published protocol or the 
informed consent form will be amended, and updated, if necessary. 
 
 
Consent or assent  
Healthcare professionals will approach potential participants to determine if they 
are interested in participating. If they express interest, they will be referred to a research 
team member who will contact them. Additionally, interested participants will be allowed 
to share the study information with other women who have been diagnosed with breast 
cancer. If any of these women express interest in participating, they will also be 
considered after obtaining medical clearance.  Once the eligibility criteria for the study 
are confirmed and the women express their interest in participating, they will receive the 
Informed Consent through email. In the informational session, women will be asked to 
digitally fill out and sign the Informed Consent. It will be clear to the participants that they 
can withdraw their consent anytime. After the informational session, a PDF copy of the 
signed Informed Consent will be emailed to each participant. The research team will also 
take additional measures to collect and share the participants’ data.  
 
Confidentiality  
The responsible members of the investigation will maintain all datasets on a 
secure server of CIDEFES-UL for ten years. These datasets will be used solely for 
research purposes. Datasets utilized for specific analyses or sub-studies will only contain 
the necessary variables and the demographic indicators provided to the research team 
members upon request by the leading investigator. 
 
Declaration of interests  
The authors declare no competing interests. 

 
17 
 
Access to data  
The corresponding author will make anonymized trial data available for non-
commercial research purposes upon reasonable request. 
 
Ancillary and post-trial care  
Post-trial care is unnecessary as no harm is expected during the trial. However, 
an insurance policy will cover participants if needed during the study. 
 
Dissemination policy  
This trial’s findings will be disseminated through publication in leading international 
oncology scientific journals and presentations at national  and international conferences. In 
addition. the results and mediation analysis will be produced and published. As this is a 
pragmatic trial with highly applicable outcomes for participants and decision-makers, it 
presents potential for future widespread implementation through relevant stakeholders 90. 
 
Authors’ contributions  
Pedro G.F. Ramos conceived the project and wrote the manuscript. Nuno Dias 
revised and edited the manuscript and will randomly assign participants’ numbers and 
random allocation.  Eliana V. Carraça and Pedro B. Júdice assisted in project refinement 
and revised and edited the manuscript. Also, the former authors will supervise the entire 
trial. 
 
Acknowledgements  
We thank Doctor Gabriela Valadas for facilitating open communication between 
the Hospitals and the research team. Without the action of this medical professional, the 
successful implementation of this study would be compromised. 
 
Declaration of Generative AI and AI-assisted technologies in the writing 
process 
While preparing this work, the authors utilized Grammarly's AI-powered writing 
assistance to enhance the manuscript's language and readability. Subsequently, the 
authors reviewed and edited the resulting content as necessary, taking full responsibility 
for the publication's final version. 
 
Discussion 

 
18 
The Home-Combo study aims to expand the knowledge regarding the effects of 
a supervised home-based combined exercise program for women undergoing neo-
adjuvant and adjuvant chemotherapy for breast cancer. The incidence of breast cancer 
has been increasing steadily over the years, particularly among women. 2,1. In specific 
home-based exercise training programs, exercise training programs have already been 
proven safe for women with BC during the treatment phase 24,91. Studies conducting 
structured and supervised home-based exercise programs in women with BC during the 
treatment phase are still scarce 24. Furthermore, since this study also includes 
participants performing neo-adjuvant chemotherapy, it will be possible to verify the 
effects of the intervention in a prehabilitation (i.e., pre-operative) context 92. Also, 
according to Júdice et al. 12, there is a need for more studies that analyze the effects of 
exercise on chemotherapy completion rates. Lastly, to the authors’ knowledge and 
according to the research, no studies have conducted an exercise intervention where 
the intensity of the performed exercise is self-selected by the participants in  a sample 
with a diagnosis of BC during treatments. Therefore, this study may give a significant 
contribution to robust knowledge regarding home-based exercise programs in women 
with BC diagnosis undergoing chemotherapy treatment. Also, this study is expected to 
have immediate benefits to all women with BC enrolling in this study and a potential 
impact on improving interventions designed to promote higher adherence to the study 
and active lifestyle behaviors. The online alternative and the dissemination of an easy-
access exercise program that can be performed at home might be particularly important 
for the region where the study will be conducted, since public transportation is not very 
effective, and many people live in remote areas with little to no access to a nearby sports 
or exercise facilities. If the hypothesis are confirmed, or if at least results show that 
women with a BC diagnosis can stick to the planned chemotherapy sessions and doses, 
with little to no interruptions and no dose adjustments, the results will potentially 
represent less time to treatment exposure, quicker return to everyday life, fewer side 
effects, and better overall and disease-related quality of life. 
 
 
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