Titre officiel
The Effects of Short-term Exercise or Caloric Restriction on Anthracycline Chemotherapy-related Treatment Toxicity
Sommaire:
La doxorubicine et l’épirubicine font partie de la classe
des anthracyclines, des agents chimiothérapeutiques fréquemment utilisés pour
le traitement du cancer du sein. Même si ces traitements fonctionnent bien
contre la tumeur, on sait qu’ils causent des lésions au muscle cardiaque, ce
qui entraîne un fonctionnement cardiaque réduit pouvant être permanent, et ils
peuvent aussi endommager les vaisseaux sanguins et les muscles squelettiques.
Cette étude vise à déterminer si l’application à court terme de ces
interventions, en respectant un calendrier précis pour l’administration de
chaque traitement, peut prévenir les effets négatifs d’un traitement par les
anthracyclines sur le cœur, l’aorte (la plus grosse artère qui part du cœur) et
les muscles squelettiques, améliorer la qualité de vie et réduire la taille des
tumeurs. Cinquante-six patients atteints d’un cancer du sein au stade précoce
recevront un traitement par une anthracycline et seront répartis aléatoirement
dans trois groupes de traitement qui devront faire ce qui suit : 1) les
patients devront effectuer une séance d’exercice aérobique de 30 minutes, 24
heures avant chaque traitement; 2) les patients mangeront 35 % de calories de
moins que dans leur régime alimentaire habituel, au cours des 48 heures
précédant chaque traitement; 3) les patients recevront les soins liés au cancer
habituels. L’imagerie par résonance magnétique (IRM) servira à mesurer avec précision
le fonctionnement du cœur, de l’aorte et des muscles squelettiques de la jambe
au repos, puis pendant l’effort, afin de déceler les signes subtils de lésions.
Nous mesurerons également la capacité à l’effort (c.-à-d. la capacité
aérobique), les lésions microscopiques aux cellules du muscle cardiaque, un
marqueur sécrété dans le sang en réponse aux lésions cardiaques associées aux
anthracyclines, la taille des tumeurs chez les patients recevant une
chimiothérapie avant une intervention chirurgicale, la qualité de vie et la
fatigue. Ces mesures seront effectuées avant le traitement, au terme de ce
dernier, puis 1 an plus tard.
Description de l'essai
Primary Outcome:
- Change in left ventricular ejection fraction reserve (peak exercise - rest)
Secondary Outcome:
- Change in NT-proBNP
- Change in aortic distensibility
- Change in skeletal muscle oxygen extraction reserve (peak exercise - rest)
- Change in skeletal muscle oxygen consumption reserve (peak exercise - rest)
- Change in resting LV strain
- Change in peak exercise LV strain
- Change in cardiac T1
- Change in peak LVEF
- Patient-reported treatment symptoms
- Change in cardiac output
- Change in LV volumes
- Change in resting LVEF
- Change in LV mass
- Change in thigh skeletal muscle mass and quality
- Change in peak oxygen consumption
Research Question: Is there a practical, widely available, non-pharmacological intervention
that can be used to reduce the detrimental effects of anthracycline treatment to improve
breast cancer patient cardiovascular health, well-being?
Primary Hypothesis: short-term application of aerobic exercise or caloric restriction prior
to anthracycline chemotherapy treatments for breast cancer will reduce the detrimental
effects of anthracyclines on heart, vessels and skeletal muscle.
Exploratory Hypothesis: these interventions will enhance the anticancer effects of
anthracyclines and/or reduce the detrimental effects of anthracyclines on health-related
quality of life.
Primary Study Aims: to investigate the effect of a single aerobic exercise session performed
24 hours prior to anthracycline treatment and the effect of 50% caloric restriction for 48
hours prior to anthracycline treatment relative to usual care control. Specifically, we will
measure the intervention effects on:
I) Cardiac structure and function: 1) circulating NT-proBNP (interventions will mitigate
unwanted increase in this prognostic marker of development of later cardiotoxicity); 2) left
ventricular ejection fraction reserve (interventions will mitigate unwanted reduction in
ability to augment heart function with exercise challenge) and 3) cardiac T1 mapping
(interventions will mitigate unwanted increase in this marker of formation of myocardial
fibrosis)
II) Vascular Function: 1) Aortic distensibility (rest) (interventions will mitigate unwanted
increase in vascular stiffness)
III) Skeletal Muscle Structure and Function: 1) skeletal muscle oxygen consumption 2)
skeletal muscle oxygen extraction (interventions will mitigate unwanted loss of oxygen
consumption, extraction at peak exercise and in recovery) and 3) skeletal muscle mass and
quality (interventions will mitigrate unwanted loss of skeletal muscle mass and quality).
Exploratory Study Aims: to investigate the effects of these interventions relative to the
control group on: 1) tumour size at end of treatment in neoadjuvant patients (interventions
will reduce tumour size) and 2) quality of life and fatigue at end of treatment and one year
after treatment (interventions will improve quality of life and fatigue) and 3) long-term
clinical cardiac and cancer outcomes.
Design and Recruitment:
This study will be a three-arm randomized control trial of fifty-six early stage breast
cancer patients receiving adjuvant or neoadjuvant anthracycline-containing chemotherapy
treatment. Following completion of the baseline assessment, participants will randomized to
one of three groups who will: 1) complete a supervised vigorous intensity aerobic exercise
session 24 hours prior to each anthracycline treatment; 2) restrict their caloric intake by
50% for 48 hours prior to each treatment; or 3) control condition receiving oncological usual
care only. Participants will be recruited via oncologist referral from the Cross Cancer
Institute.
Sample Size Determination:
Cardiac MRI is extremely reproducible and thus sensitive to detecting change in ejection
fraction. It has been previously demonstrated that n=15 patients are required to detect a 3
percentage point change of resting ejection fraction with cardiac MRI, an 85% reduction in
sample size required to detect the same change using echocardiography. Using a n=15 sample
size per group for a three-arm, three-repeated measures design, there is >90% power to detect
a medium effect size at p=0.05 (G*Power Version 3.0.10, F-test with repeated measures and a
within-between factor design). The primary outcome in the current study, ejection fraction
reserve (peak ejection fraction minus resting ejection fraction) is expected to be more
sensitive than resting ejection fraction and therefore this sample size is expected to detect
a difference between the intervention groups and the control group. We will enrol n=56 total
(n=18-19 per group) to allow for a 20% rate for dropout, death, and technical difficulties.
Statistical Methods:
Given the longitudinal study design with data collected at 3 time points for each subject, a
linear mixed model analysis that includes both fixed and random effects, with an intention to
treat approach will be used. The repeated measures on a single subject result in correlated
outcome data, and the random effects allow this correlation to be explicitly modeled. An
additional advantage is that it allows for missing data on a subject without deleting all the
data for that subject. The model also allows for covariates to be tested and can include time
varying covariates (e.g. treatments received post anthracyclines). One assumption of mixed
models is that the residuals from the model are normally distributed. Pilot data indicates
that this assumption will hold for this study. If that is not the case, a Generalized Linear
Mixed Model analysis, which can fit other distributions, will be used. All analyses will be
performed using SPSS 24.0.
An interim analysis of resting ejection fraction only (standard parameter used to monitor
cardiotoxicity within oncology practice) will be completed by a paid statistician not
associated with the study. Resting ejection fraction will be compared between groups after
completion of the end of treatment assessment for the first thirty participants. A second
interim analysis will be performed upon suggestion by the statistician.
Voir cet essai sur ClinicalTrials.gov
