This is a study protocol for a two-armed prospective randomized controlled trial that
will explore the cardioprotective effect of a structured exercise program, compared
to standard care, in adult women undergoing anthracycline-containing chemotherapy
(AC-CT) for early BC. The study design and protocol adhere to the Standard Protocol Items: Recommendations
for Interventional Trials (SPIRIT) guidelines (Additional file 1). The study design is outlined in Figure 1.
This study will be conducted in compliance with the Declaration of Helsinki Ethical
Principles (1975) and it received approval by the Ethics Committee of the Centro Hospitalar de Vila Nova de Gaia/Espinho (CHVNG/E; Vila Nova de Gaia, Portugal)
(reference number: 145/2018-1). The study is registered in the International Standard
Randomised Controlled Trial Number (ISRCTN32617901). Any protocol amendments will be submitted to the CHVNG/E for ethical approval and
updated on the ISRCTN.
We intend to recruit 90 adult women with early invasive BC, scheduled to receive AC-CT
and followed-up in the Medical Oncology Department of the CHVNG/E. Participants will
be recruited considering the eligibility criteria presented in Table 1. Recruitment
will take place in two distinct phases. In a first instance, potential participants
will be identified in the multidisciplinary consultation involving medical oncologists,
surgeons and radioncologists. After this preliminary phase, the eligibility of each patient will be confirmed by the oncologist during a medical consultation.
The oncologist will present the study to the patients considered eligible, explaining,
offering the inclusion and providing written informed consent. Written informed consent
will be obtained from all patients and they will be informed that they are under no
obligation to participate and they may withdraw their consent at any time. The withdrawal
from the study or non-participation, will have no consequences for medical follow-up
and care. Where possible, the reasons for withdrawal from the study will be recorded.
All the participants will be followed from the acceptance period (t0) and after 3
months of the end of the AC-CT (t3). If recruitment is not achieving the target sample
size, we will extend the recruitment for additional hospitals.
After confirmation of eligibility and baseline assessments (t0), patients will be
randomized through an Internet software (www.sealedenvelope.com), with a 1:1 ratio between a supervised exercise group (intervention group) and a
usual care group (control group), using a permutated block design with random block
sizes (4, 6, 8) with stratification by two dichotomous variables, known as risk factors
Age (Under/50 years or older).
Receive anti-HER2 therapy (Yes/No).
This process will be performed by an external individual who is blinded to the study
and who will place the sequence in a numbered, opaque, sealed envelope. The allocation
of participants will then be reported to an oncologist (AJ) who will subsequently
inform the patients about the assignment group.
Patients allocated to the intervention group will perform a supervised exercise program
specifically developed for BC patients, based in the guidelines of the American College
of Sports Medicine (27) and in a close cooperation between physical sports researchers
(PA, DE, AA) and medical staff (oncologists, surgeons, radiologists, physiatrist,
and physiotherapist) of the CHVNG/E. The exercise program comprises 3 weekly sessions guided in small groups (<5 patients)
in an appropriately equipped room of the CHVNG/E, supervised by the main author (PA)
and a physiotherapist. Each session will involve an initial warm-up (5 min), followed
by resistance and aerobic training (60 min), and ending with a cooldown phase (5 min).
The program will be started after 1-2 days of the first AC-CT session and will be
conducted over the respective treatment of each patient. It should be noted that the
proposed exercise intervention will never be intended to replace or interfere with
the current standard BC care.
Aerobic training: It will include the combination of treadmill, stationary bike, and stepping. This
phase will be monitored through HR (each participant will wear a heart rate monitor
during exercise training sessions) and RPE measure by a 0-10 point modified Borg Scale
(minimal effort = 0; maximum effort = 10) (29). During the first two weeks, the participants
will perform 20 minutes (divided equally among the three exercise modes) of aerobic
training in a light intensity [<50% of measured HR reserve (based on maximum HR reached
in the cardiorespiratory test), reporting 2-4 (‘easy’ to ‘somewhat easy’) on modified
Borg scale]. After this period, 3 minutes will be added every two weeks until a volume
of 30 minutes of aerobic training is reached. At this stage, participants will be encouraged to perform moderate-to-high intensity
training [65%-80% of measured HR reserve, reporting 5-8 (‘somewhat hard’ to ‘hard’) on modified Borg scale] until the end of the intervention.
Participants will be reminded weekly (through email and phone) of their exercise training
schedule and the importance of adherence to achieve the established objectives.
Resistance training: It will include upper body (shoulder press, chest press, lat pulldown, biceps curls,
and triceps extension) and lower body (squat, calf raise, leg press, leg extension,
and leg curl) weight-training exercises. All the exercises will be performed at the
maximum possible joint range of motion, using resistance machines and free weights.
Rating perceived exertion (RPE) will be measured using a 0-10-point OMNI-Resistance
Exercise Scale (OMNI-RES, minimal effort = 0; maximum effort = 10) (28). During the
first week, participants will perform 2 sets and 10 repetitions of each exercise without
additional resistance or with the lowest available [reporting 2-4 (‘easy’ to ‘somewhat
easy’) on the OMNI-RES]. After this phase, if no adverse events or symptoms were reported
for a specific exercise, resistance will be added so that each participant could be
able to perform 3 sets with 12 maximal repetitions (12-RM) of each exercise. When
the participants can complete 3 sets and more than 12-RM at the set weight in 3 consecutive
sessions, then the resistance will be increased between 5%-10%.
Usual care group
Patients allocated to the usual care group will receive the standard BC care. The
CG will not receive any specific advice regarding physical activity and will not be
asked to be inactive. In compensation for the participation in this study, it will
be offered the possibility of performing the same exercise program after the final
assessments are completed.
The schedule of the study outcome assessments is outlined in Figure 2. Study assessments
will be scheduled upfront and participants will be regularly reminded (through email
and phone) to ensure a complete follow-up. Primary, secondary and exploratory outcomes
will be measured in all participants at three different moments:
t0 (baseline assessments): Between 0-14 days prior to the first chemotherapy session.
t2 (post-treatment assessments): Between 1-5 days after the end of AC-CT.
t3 (follow-up assessments): After 3 months of t2.
In addition, for analysis of circulating NT-proBNP, blood samples will be collected between 1-24 hours before each AC-CT cycle (t1: during-treatment assessments). Patients will be instructed and remembered to avoid drinking alcoholic and caffeine-containing
beverages, to abstain from smoking for 12 hours prior and to avoid vigorous physical
activities 24 hours prior to all examinations.
Circulating NT-proBNP levels
Resting LV global longitudinal strain
Resting LV ejection fraction
Self-reported physical activity level
Health-related quality of life
Assessment of the primary outcomes
Resting LV ejection fraction and resting LV longitudinal strain
Resting LV ejection fraction will be calculated using the biplane method of disks
(modified Simpson’s rule) from the apical four- and two-chamber view (30). For resting
LV global longitudinal strain assessment, two-dimensional grey-scale images will be
acquired in the apical four-, two- and three-chamber views, with a frame rate of 60
to 100 fps. Three cardiac cycles will be digitally stored and Velocity Vector Imaging
(VVI) software (Siemens Medical Solutions United States of America Inc) will be used in the analysis.
Echocardiographic acquisitions will be performed by a single experienced cardiologist
blinded to the patient assignment group.
Circulating NT-proBNP levels
Nonfasting venous blood samples will be drawn by a nurse oncologist. The assessment
of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels will be conducted in
the local clinical analysis laboratories of the CHVNG/E, which are certified by the
United Kingdom National External Quality Assessment Service. This professional staff
will be blinded to the patient assignment group.
Assessment of the secondary outcomes
Resting blood pressure and resting HR
Resting blood pressure (systolic and diastolic blood pressure) and resting HR will
be measured using a standard automated device Philips SureSignsVM6 (Philips Medical
System, Andover, United States of America). Two measurements will be carried out.
The first measurement will be preceded by 5 minutes resting period and a second reading
will be taken after 3 minutes. If necessary, additional records shall be obtained
until two consecutive stable measurements (differences <5 mmHg for blood pressure
and <7 bpm for HR) are obtained. The average of the two stable measurements will be
considered for the analysis. This procedure will be carried out by a study investigator
(ALA) not blinded to the patient assignment group.
HRV is a non-invasive method to analyse cardiac autonomic function through the measurement
of successive heart beats variations (RR). Resting HRV will be analysed using a HR
monitor Polar V800 (Polar Electro Oy, Kempele, Finland) with a Polar H7 chest strap.
During the RR recording, patients will be seated in a comfortable position. They shall
be required to breathe spontaneously, to avoid any movements and to maintain neutral
thoughts during the time of data acquisition. The first 5 minutes will be excluded
(stabilization period) and the remaining 5 minutes will be used to calculate the time-domain
(standard deviation of successive normal RR [SDNN], and root mean square of successive normal RR [RMSSD]) and frequency-domain indices (low-frequency spectral component [LF], and high-frequency spectral component [HF]). In all the cases, the RR recordings will be exported to the Kubios v2 HRV software
(Biosignal Analysis and Medical Imaging Group at the Department of Applied Physics,
University of Kuopio, Kuopio, Finland). Occasional, artefact noise shall be automatically
replaced with the interpolated adjacent RR interval values (filter power <low). This
procedure will be carry out by the first author (PA) not blinded to the patient assignment
Recovery HR will be determined as the absolute difference between the HR at peak effort
during the cardiorespiratory exercise test (CRET) and the HR at 60-seconds, and 120-seconds
post-exercise. HR values will be derived from a continuous record obtained via CRET
(Mortara X-Scribe, Mortara,
United States of America). This procedure will be carried out by study investigators (EV, MT), blinded to
the patient assignment group.
Cardiorespiratory fitness will be evaluated by means of a symptom-limited CRET on
a treadmill (Mortara X-Scribe, Mortara, United States of America), using a modified
version of the Bruce protocol (31). Expired gases will be continuously collected throughout
exercise and analysed for ventilatory volume (VE) and for oxygen (O2) and carbon dioxide (CO2) content, using dedicated analysers. Standard spirometry [forced expiratory volume
in 1 second (FEV1)] and forced vital capacity (FVC) will also be undertaken before the test. Equipment calibration and measurements will
be done in accordance to the recommendations of the American Thoracic Society and
American College of Chest Physicians (32). The following parameters will be calculated
and considered for analysis: peak oxygen consumption (peak V̇o2, measured in millilitre per kilogram per minute), peak respiratory exchange ratio (RER), defined by the ratio of CO2 production to O2 consumption at peak effort, oxygen
consumption at the anaerobic threshold (AT), defined as the point at which CO2 production increases disproportionately in relation
to O2 consumption, obtained from a graph plotting O2 consumption against CO2 production,
and total exercise duration (measured in seconds). The maximum HR achieved will also
be recorded. The CRET will be conducted on an independent day to the remaining outcomes
assessments out by study investigators (EV, MT) blinded to the patient assignment
group. Patients will be in a fasted state and will not be asked to discontinue current
medication before the test.
Upper limb strength
Upper limb strength will be evaluated by the maximal voluntary grip strength (measured
in kilograms), using a digital handgrip dynamometer (Saehan Corporation, Masan, South
Korea – model SH5003). Each subject will perform six trials, three in each arm, with
an alternating bilateral sequence. The results will be given by the average of the
three trials, respectively for operated and non-operated limb. This procedure will
be carried out by the first author (PA), not blinded to the patient assignment group.
Lower limb functionality
Lower limb functionality will be evaluated by the sit-to-stand test using a straight-backed
chair (40-centimetre high). It will be required that each subject, keeping plantar
support flat on the floor and arms crossed at the chest, sit and stand as many times
as possible for 30 seconds. The score of the test will be determined by the number
of repetitions done respecting the above procedure. This procedure will be carried
out by the first author (PA), not blinded to the patient assignment group.
Self-reported physical activity level
International Physical Activity Questionnaire-Short (IPAQ-SF) will be used to calculate the metabolic equivalent (MET) minutes per week spent in
walking, moderate and vigorous activities. Sedentary behaviour will be determined
based on time spent sitting per day (minutes). Considering the obtained scoring, participants
will be categorised as a low, moderate, or high physical activity level. In this study
will be used the Portuguese language of the IPAQ-SF (33). Scoring will be analysed by the first author (PA), not blinded to the patient assignment
Health-related to quality of life and fatigue
The European Organization for Research and Treatment in Cancer (EORTC) Quality of Life
C-30 (QOL-C30) is a self-administered, validated questionnaire to assess HR-QOL in cancer patients
(34). It is composed of nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue,
pain, and nausea and vomiting), and a global health and quality-of-life scale. Additionally, there are five single items of commonly reported symptoms by cancer patients (dyspnea, sleep disturbance, appetite loss, constipation and diarrhea), and an item
that evaluates the perceived financial impact of the disease. In this study, the third version of this questionnaire will be used, in the Portuguese
language (35). Analyses will include the five functional scales, fatigue scale and the global health and quality-of-life scale. The scoring of the several scales will be carried out by the first author (PA), not blinded to the patient assignment
Demographic, anthropometric and clinical data
Demographic, anthropometric and clinical data will be recorded during the enrolment
process (−t0). Demographic data includes age, sex, and education. Anthropometric data includes
weight, height, and body mass index. Clinical data includes disease, treatment information,
past medical history and current medication. These data will be extracted from the
patients’ electronic medical files by two study coordinators (ALA, AJ) not blinded
to the patient assignment group.
The safety of the intervention will be assessed by weekly tracking and monitoring
the number of adverse events according to the National Cancer Institute Common Terminology
Criteria for Adverse Events version 4.0 (
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm). A meeting between the study investigators will be held every weekly to review and
discuss the reported adverse events. All serious adverse events will be immediately
reported to the CHVNG/E ethics commission, to all study members and will be reported
in the study results. Adverse events will be evaluated by the study investigators
who will make the decision to stop the study early if there is an increased risk of
Study data will be managed by two study investigators (PA, AJ) using a predesigned
criterion to data collection form [Microsoft Office Excel version 2016 (Microsoft
Corporation, Redmond, WA,
United States of America] and
Statistical Package for the Social Sciences files
version 23.0 (IBM Corporation, Armonk, NY, United States of America)] with double-entry. Regularly data checks will be performed to ensure data quality. To ensure patients’ anonymity, they will be identified by codes and only the authors involved in the trial will have access
to the full identification. The total number of patients who meet the study eligibility will be recorded, as will
the number of patients who will agree or not agree to participate in the study, the
number of patients who assigned to each study arm, the number of patients who participated
in all sessions, the attendance of each patient in the intervention sessions, the
number of patients who provided follow-up data, the number of patients included in
the final analysis and the number of withdrawals.
Sample size calculation
Sample size was carried out by a power calculation based on resting LV ejection fraction
outcome, using a non-commercial statistical power analysis program (G*Power Version
188.8.131.52). Based on an effect size of 0.6 in resting LV ejection fraction presented
in a previous study (26), to ensure a statistical power of 80% and a significance
level of 0.05, through a t-test for two independent groups, the recruitment of 72
participants is required. Predicting a 20% dropout rate (19), we estimate that a total
of 90 patients will be needed (n= 45 in each arm). There are no early planned stopping
rules. Adverse events will be evaluated by the study investigators who will make the
decision to stop the study early if there is an increased risk of clinical relevance.
Statistical data analysis will be performed using Statistical Package for the Social Sciences. The statistical
significance will be set at a p< 0.05. An intention-to-treat and per protocol approaches
will be used both for all analyses. Data analysis will start with standard descriptive
methods to describe the data (means and standard deviations will be calculated for
continuous variables and absolute and relative frequencies for categorical variables).
The comparison of the continuous variables between the two study groups will be made
one-way analysis of covariance (ANCOVA),
adjusted for the effect of the baseline values (covariate). A linear two-way mixed
ANCOVA model with repeated measures (t1, t2 and t3) will be performed to test the
difference over time between the two study groups and interaction (Group × Time), on
primary and secondary outcomes, with the same covariate as the one-way ANCOVA.
Bonferroni’s post-hoc procedure will be performed to locate the pairwise differences. Normality
will be verified by the Kolmogorov-Smirnov test and the homogeneity of the variance
will be validated by the Levene's test. Effect size will be calculated to estimate
variance between moments through partial eta-squared. The cut-off values were interpreted
as 0.02 for small effect size, 0.13 for moderate and 0.26 for large (36).
The chi-squared test will be used to check the existence of a relationship between categorical
variables. Effect size will be calculated using Cramer’s V test and their interpretation
will be based on the following cut-off values: 0.10 for a small effect, 0.30 for a
medium effect and 0.50 for a large effect. (36)
No interim analyses will be conducted.</p>
This study will involve the prescription of exercise sessions. To carry out a rigorous
exercise prescription and to ensure an adequate follow-up of each patient, participants,
physical trainer (PA), medical oncologists (AJ) and nurse oncologists (ALA) will not
be blinded to group assignment. Due to the lack of resources, only the evaluators that will make the acquisition of echocardiographic outcomes (resting LV ejection fraction and LV
global longitudinal strain), circulating NT-proBNP levels, cardiorespiratory fitness and recovery HR data, will
be blinded to the group assignment.
There are some limitations to this study, which should be noted. Firstly, we will
only include patients followed from CHVNG/E. Secondly, due to the impossibility of
blinding patients and some of the involved authors about the study group assignment,
the open design of this study may influence the assessments retention rate of participants
who were allocated the control group. Thirdly, we will stratify our sample considering
the age (under/over 50 years old) and use of trastuzumab (yes/no). However, there
are other risk factors associated with ARC, including: total cumulative anthracycline
dose, pre-existing cardiac disease and treatment with mediastinal radiation, that
should also be considered (19). Although these hinderances should be acknowledged,
we believe the findings from the present study will provide important data which will
be of relevance to the contemporary literature in this subject.
Findings of this study will be involved in a doctoral thesis of the main author, will
be submitted to a peer-reviewed journal for publication and presented at relevant
conferences and disseminated to the public by the partnership with CHVNG/E, Universidade
da Beira Interior (Covilhã, Portugal) and community stakeholders.