Acute Exercise Cardioprotection From Doxorubicin

The Effects of Exercise Before Doxorubicin Chemotherapy on Cardiac Function

In rodents, a single bout of exercise prior to injection of a chemotherapy agent used to treat breast cancer prevents or attenuates a number of markers of cardiac injury. This study will investigate whether this finding translates to human breast cancer patients. Participants scheduled to receive chemotherapy for breast cancer will be randomized to exercise or no exercise 24 hours prior to every chemotherapy treatment. The effect on cardiac function will be compared between groups noninvasively by echocardiography and electrocardiography and a venous blood draw at baseline before chemotherapy, after the first treatment and at the end of chemotherapy.

1. Purpose The purpose of this study is to investigate whether performing a single bout of exercise 24 hours prior to receiving infusions of the anthracycline chemotherapy agent doxorubicin for breast cancer can prevent some of the damaging cardiac effects. Currently, doxorubicin is the most effective chemotherapy agent for breast cancer but is also the most damaging. As such, increased risk of cardiovascular disease is a growing concern in doxorubicin-treated patients. Current strategies for minimizing cardiac injury are dose reduction and discontinuation of therapy, which compromise the effectiveness of the treatment. Interventions that can minimize the cardiac injury associated with doxorubicin could reduce cancer-related and cardiovascular disease-related mortality in women diagnosed with breast cancer.
2. Hypotheses 1. Performing an acute bout of exercise within 24 hours before anthracycline infusion will decrease the acute negative change in subclinical markers of cardiotoxicity after the first anthracycline infusion seen in those who do not exercise for 72 hours prior.

2. Performing exercise within 24 hours before every infusion of anthracycline will decrease the negative change in markers of cardiac dysfunction seen at the end of chemotherapy in those who do not exercise for 72 hours prior to each infusion.

3) Justification An acute exercise bout prior to induction of a myocardial infarction in animals provides cardioprotective benefit by reducing the size of the infarct relative to control animals. Recently, acute exercise performed 24 hours before anthracycline injection in rodents has also provided a cardioprotective benefit. Oxidative stress and apoptosis of cardiomyocyte mitochondria are primary mechanisms of anthracycline-induced cardiotoxicity. The single acute bout of exercise prevented or attenuated some of the anthracycline-induced negative effects on cardiomyocytes including oxidative stress, apoptosis, mitochondrial dysfunction, as well as systolic dysfunction. There are no studies to date that have investigated the cardiac effects of an acute bout of exercise in close proximity to anthracycline infusion in humans. Aerobic exercise training is recommended throughout chemotherapy treatment, but there are no guidelines in place in terms of the timing of exercise in relation to receipt of chemotherapy infusions.

4) Objectives

1. To compare the acute effect of performing exercise (within 24 hours before the first infusion) compared to no exercise (no exercise for 72 hours prior to the first infusion) on markers of subclinical cardiotoxicity 24-48 hours after the first anthracycline infusion.
2. To compare the chronic effect of performing exercise (within 24 hours before every infusion) compared to no exercise (no exercise for 72 hours prior to every infusion) on markers of cardiotoxicity 7 to 14 days after the final anthracycline infusion 5) Research Method This study will be a two-arm randomized control trial. Twenty-four women aged 18 or older newly diagnosed with stage I-IIIA breast cancer, and scheduled to receive neoadjuvant or adjuvant doxorubicin chemotherapy in cycles of 2-3 weeks will be recruited by oncologist referral and posters. Participants will be randomized to one of two conditions: i) an acute bout of exercise performed ≤24 hours prior to each cycle of anthracyclines and no exercise for 48 hours post; or ii) no exercise for 72 hours prior or 48 hours post each cycle of anthracyclines.

6) Statistical Analysis The primary outcome will be global longitudinal strain measured by echocardiography. The secondary outcomes will be the NT-proBNP and cardiac troponin T cardiac biomarkers measured with an assay of blood taken via venous blood draw, echocardiography-derived left ventricular twist. The exploratory outcome measure will be treatment symptoms as reported by the Rotterdam Symptom Checklist. Cardiac outcome measures will be performed at the following time points: 1) Post diagnosis and prior to the first cycle of anthracyclines; 2) 24-48 hours after the first cycle; 3) at least one week after the last cycle of anthracyclines, but before subsequent chemotherapy treatments. The Rotterdam will be performed at baseline and within the last few days of each treatment cycle.

Baseline characteristics of the two groups will be compared with independent t-tests. Descriptive statistics and frequencies will be calculated for all continuous and categorical variables. The acute effect will be determined by the difference between time points 1) and 2). The chronic effect will be determined by the difference between time points 1) and 3). For each analysis, a linear mixed model with time as a fixed and repeated effect, group as a fixed effect, and a time by condition (2 x 2) interaction will be used. If the interaction effect is not statistically significant, the main effects of time and condition will be explored. An alpha of 0.05 will be used for all analyses.

Inclusion Criteria:

• newly diagnosed with stage I-IIIA breast cancer
• scheduled to receive neoadjuvant or adjuvant doxorubicin chemotherapy in cycles of 2-3 weeks long
• receive their oncologist's approval to exercise
• be able to complete first time point of data collection prior to first chemotherapy cycle
• be able to understand and provide written informed consent in English

Exclusion Criteria:

• concurrent participation in a structured exercise program or study
• have orthopedic limitations to exercise
• pre-existing cardiovascular disease
• uncontrolled hypertension (blood pressure ≥ 140/90 mmHg)
• uncontrolled diabetes
• respiratory disease
• current smoking status