Caloric Restriction and Exercise for Protection From Anthracycline Toxic Effects (CREATE)

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) tumor size at end of treatment in neoadjuvant patients (interventions will reduce tumor 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.