Abstract
BackgroundAnthracycline chemotherapy agents are commonly used to treat breast cancer, but also result in cardiac injury, and potentially detrimental effects to vascular and skeletal muscle. Preclinical evidence demonstrates that exercise and caloric restriction can independently reduce anthracycline-related injury to the heart as well as cancer progression, and may be promising short-term strategies prior to treatment administration. For women with breast cancer, a short-term strategy may be more feasible and appealing, as maintaining regular exercise training or a diet throughout chemotherapy can be challenging due to treatment symptoms and psychosocial distress.MethodsThe Caloric Restriction and Exercise protection from Anthracycline Toxic Effects (CREATE) study will determine whether acute application of these interventions shortly prior to receipt of each treatment can reduce anthracycline-related toxicity to the heart, aorta, and skeletal muscle. Fifty-six women with early stage breast cancer scheduled to receive anthracycline treatment will be randomly assigned to one of three groups who will: 1) perform a single, 30-min, vigorous-intensity, aerobic exercise session 24 h prior to each anthracycline treatment; 2) consume a prepared diet reduced to 50% of caloric needs for 48 h prior to each anthracycline treatment; or 3) receive usual cancer care. The primary outcome is magnetic resonance imaging (MRI) derived left ventricular ejection fraction reserve (peak exercise LVEF – resting LVEF) at the end of anthracycline treatment. Secondary outcomes include MRI-derived measures of cardiac, aortic and skeletal muscle structure and function, circulating NT-proBNP, cardiorespiratory fitness and treatment symptoms. Exploratory outcomes include quality of life, fatigue, tumor size (only in neoadjuvant patients), oxidative stress and antioxidants, as well as clinical cardiac or cancer outcomes. MRI, exercise tests, and questionnaires will be administered before, 2–3 weeks after the last anthracycline treatment, and one-year follow-up.DiscussionThe proposed lifestyle interventions are accessible, low cost, drug-free potential methods for mitigating anthracycline-related toxicity. Reduced toxic effects on the heart, aorta and muscle are very likely to translate to short and long-term cardiovascular health benefits, including enhanced resilience to the effects of subsequent cancer treatment (e.g., radiation, trastuzumab) aging, and infection.Trial registrationClinicalTrials.gov NCT03131024; 4/21/18.
Highlights
Anthracycline chemotherapy agents are commonly used to treat breast cancer, and result in cardiac injury, and potentially detrimental effects to vascular and skeletal muscle
Based on preclinical evidence [23, 24], we previously investigated the effect of 30 min of vigorous-intensity treadmill walking performed 24 h prior to every anthracycline treatment on markers of cardiotoxicity and treatment symptoms in women with breast cancer [25, 26]
Design and ethics The CREATE study is a three-arm, parallel group phase II randomized controlled trial that will compare the effects of a single aerobic exercise session performed 24 h prior to each anthracycline treatment, to 50% caloric restriction for 48 h prior to each anthracycline treatment, to usual care on cardiac, vascular, and skeletal muscle changes in women with breast cancer
Summary
Design and ethics The CREATE study is a three-arm, parallel group phase II randomized controlled trial that will compare the effects of a single aerobic exercise session performed 24 h prior to each anthracycline treatment, to 50% caloric restriction for 48 h prior to each anthracycline treatment, to usual care on cardiac, vascular, and skeletal muscle changes in women with breast cancer. An external party to the study will generate the randomization sequence using a spreadsheet random function This same individual will put the group assignment into sequentially numbered, sealed, opaque envelopes. The primary outcome measure is cardiac function reserve capacity (LVEF reserve), which is calculated as peak exercise LVEF – resting LVEF, at the end of anthracycline treatment relative to the control group.
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