Rationale and design of the Caloric Restriction and Exercise protection from Anthracycline Toxic Effects (CREATE) study: a 3-arm parallel group phase II randomized controlled trial in early breast cancer

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.

A randomized trial to evaluate the impact of exercise-based cardiac rehabilitation for the prevention of chemotherapy-induced cardiotoxicity in patients with breast cancer: ONCORE study protocol

“…); and (iv) evaluation methods (echocardiography, cardiopulmonary exercise testing, indirect estimation of VO2, blood tests, etc.). In addition, some studies [ 45 , 50 , 51 ] and protocols [ 52 – 54 ] have taken into account a broad spectrum of measurements for cardiac function assessment. Kirkham et al [ 50 ] analysed the efficacy of a single aerobic bout performed 24 h prior to each anthracycline treatment in the prevention of breast cancer cardiotoxicity.…”

Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity

“…Since both ischemic heart disease and anthracycline-mediated cardiotoxicity share common pathological pathways, therapies for one disease could also be beneficial for the other. Trials with more original approaches, such as remote ischemic conditioning or physical exercise and caloric restriction, strategies that were beneficial in the setting of ischemic heart disease, have been started with the purpose to reduce cardiotoxicity caused by chemotherapy (78,79). Results of these trials are not yet available.…”

Break a sweat to reduce cardiotoxicity – the benefits of exercise training during anthracycline chemotherapy

“…Investigators have therefore started to assess the impact of exercise training before and during AC on cardiac function, overall cardiopulmonary exercise performance, and the impact to mitigate cardiotoxicity and deterioration in cardiopulmonary exercise performance triggered by AC. (8)(9)(10)(11)(12) In this issue of European Journal of Preventive Cardiology Howden and colleagues from Melbourne, Australia studied the effect of an exercise training protocol in a cohort of 30 women with early invasive, and hence potentially curable, breast cancer receiving AC (either doxorubicin+cyclophosphamide or 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC-D)) as part of an adjuvant chemotherapy protocol. (13) Eligible women were offered the voluntary exercise intervention protocol which involved a cyclical weekly exercise intervention programme with two supervised training sessions, each comprising 30 minutes aerobic and 30 minutes resistance training, plus a third unsupervised aerobic exercise session.…”

“…Investigators have therefore started to assess the impact of exercise training before and during AC on cardiac function, overall cardiopulmonary exercise performance, and the impact to mitigate cardiotoxicity and deterioration in cardiopulmonary exercise performance triggered by AC. 8–12…”