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. 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 will be a 2-arm pragmatic randomized controlled trial, Home-Combo, which will target Portuguese women with a breast cancer diagnosis undergoing either neo-adjuvant or adjuvant chemotherapy. The Home-Combo study primarily aims to investigate the effects of a structured, supervised, home-based combined exercise intervention with self-selected intensity, conducted across the chemotherapy treatment period, on the chemotherapy completion rates of women with BC. Secondly, this study intends 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. 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 98 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. 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.
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 across the region. 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. Participants will be enrolled in two cohorts. 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 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, the investigators 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. 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. 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. 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 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) 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 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 enhances 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. 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. A Fisher's exact test will compare the proportion of participants who needed chemotherapy adjustments from those who did not. 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 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). 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. Indirect effects testing will be performed using Preacher and Hayes' procedures. 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. Research ethics approval 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. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
TRIPLE
Enrollment
98
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. 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.
Universidade Lusófona, Centro de Lisboa
Lisbon, Portugal
Chemotherapy completion rates
The 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. 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. Successful chemotherapy completion rate will be considered if the RDI is ≥85% of the planned treatment. 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. The RDI results from the actual dose intensity received are divided by the planned dose intensity.
Time frame: Assessments will be performed at three time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months).
Functional performance
The 6-minute walk test will assess aerobic endurance, a standardized field test performed indoors in a 30-meter corridor with two turning points. Participants will be asked to walk the maximum distance possible.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Functional performance
Arm curls will assess upperbody strength. Participants will be instructed to perform as many repetitions as possible for 30 seconds with a 5-pound dumbbell.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Functional performance
Sit-to-stand tests assess lower body strength. Participants will be instructed to stand upright and sit entirely back on a chair as many times as possible within 30 seconds, maintaining their feet steady on the ground and the arms crossed with hands on the shoulders
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Functional performance
Handgrip strength will be measured using a dynamometer and considered to the nearest 0.1kg. 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.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Functional performance
Timed up-and-go tests 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.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Functional performance
A goniometer will perform shoulder flexion and abduction angular measures on both sides.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Functional performance
Upper limb flexibility will be assessed using the back scratch test. Participants will be instructed to pass one hand over the shoulder and the other from the bottom of the back, trying to reach both hands as close as possible.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Body composition
Body composition will be measured through bioelectrical impedance (Impedimed Australia). Data regarding weight, fat mass, lean mass, water percentage, bone mass, visceral fat, and phase angle will be collected from the scale. Participants will be asked to maintain their dietary patterns before the test and refrain from intense exercise the day before. The measurement will be performed under standardized conditions. 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. Body weight will be measured to the nearest 0.1kg with a digital scale. 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.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Body composition
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 barefoot.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Body composition
Body weight will be measured with a digital scale to the nearest 0.1kg.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Body composition
BMI (kg/m2) will be calculated from weight (kg) and height (m).
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Physical Activity and Sedentary Behavior
PA levels and SB will be assessed using accelerometry (GT9 link, Actigraph). Participants will be instructed to wear the device on an elastic belt on the non-dominant hip for seven days during all waking hours, removing only to sleep. 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. According to specific established thresholds, the accelerometer counts will be categorized into sedentary, light, moderate, and vigorous activity levels. Any interval of 60 or more minutes with continuous zero counts will be considered non-wear time.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
Physical Activity and Sedentary Behavior
The International Physical Activity Questionnaire Short-Form (IPAQ-SF) comprises nine 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.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
General quality of life and breast-cancer specitfic quality of life
Quality of life will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).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).
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
General quality of life and breast-cancer specitfic quality of life
The specific module EORTC QLQ-BR45 will measure breast cancer-related quality of life. The breast cancer module QLQ-BR45 comprises five functional subscales (body image, future perspective, sexual functioning, sexual enjoyment, and breast satisfaction) and seven symptoms subscales (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.
Time frame: Assessments will be performed at four time points: baseline (throughout recruitment period completion, 1 year ), mid-treatment (3-6 months), post-intervention (6-12 months), 3 month follow-up (throughout the study completion up to 2 years)
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