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      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

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          Abstract

          Background

          Anthracycline 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.

          Methods

          The 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.

          Discussion

          The 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 registration

          ClinicalTrials.gov NCT03131024; 4/21/18.

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          Most cited references37

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          The Godin-Shephard Leisure-Time Physical Activity Questionnaire

          The aim of this paper is to overview the development process of the Godin and Shephard leisuretime physical activity questionnaire, to present the questionnaire and how to compute an overall score as well as a score related to health benefits. The Health & Fitness Journal of Canada, Vol 4 No 1 (2011): Dr. Roy Shephard: A Tribute to the Dean of Exercise and Physical Activity Science.
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            Protective effects of carvedilol against anthracycline-induced cardiomyopathy.

            The aim of this study was to determine the protective effect of carvedilol in anthracycline (ANT)-induced cardiomyopathy (CMP). Despite its broad effectiveness, ANT therapy is associated with ANT-induced CMP. Recent animal studies and experimental observations showed that carvedilol prevented development of CMP due to chemotherapeutics. However, there is no placebo-controlled clinical trial concerning prophylactic carvedilol use in preventing ANT-induced CMP. Patients in whom ANT therapy was planned were randomized to administration of carvedilol or placebo. We enrolled 25 patients in carvedilol and control groups. In the carvedilol group, 12.5 mg once-daily oral carvedilol was given during 6 months. The patients were evaluated with echocardiography before and after chemotherapy. Left ventricular ejection fraction (EF) and systolic and diastolic diameters were calculated. At the end of 6 months of follow-up, 1 patient in the carvedilol group and 4 in the control group had died. Control EF was below 50% in 1 patient in the carvedilol group and in 5 in the control group. The mean EF of the carvedilol group was similar at baseline and control echocardiography (70.5 vs. 69.7, respectively; p = 0.3), but in the control group the mean EF at control echocardiography was significantly lower (68.9 vs. 52.3; p < 0.001). Both systolic and diastolic diameters were significantly increased compared with basal measures in the control group. In Doppler study, whereas E velocities in the carvedilol group decreased, E velocities and E/A ratios were significantly reduced in the control group. Prophylactic use of carvedilol in patients receiving ANT may protect both systolic and diastolic functions of the left ventricle.
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              Endothelial dysfunction, arterial stiffness, and heart failure.

              Outcomes for heart failure (HF) patients remain suboptimal. No known therapy improves mortality in acute HF and HF with preserved ejection fraction; the most recent HF trial results have been negative or neutral. Improvement in surrogate markers has not necessarily translated into better outcomes. To translate breakthroughs with potential therapies into clinical benefit, a better understanding of the pathophysiology establishing the foundation of benefit is necessary. Vascular function plays a central role in the development and progression of HF. Endothelial function and nitric oxide availability affect myocardial function, systemic and pulmonary hemodynamics, and coronary and renal circulation. Arterial stiffness modulates ventricular loading conditions and diastolic function, key components of HF with preserved ejection. Endothelial function and arterial stiffness may therefore serve as important physiological targets for new HF therapies and facilitate patient selection for improved application of existing agents. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                (780) 492-6874 , amy.kirkham@ualberta.ca
                ip3@ualberta.ca
                Carla.prado@ualberta.ca
                john.mackey@trioncology.org
                kerry.courneya@ualberta.ca
                pituskin@ualberta.ca
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                3 September 2018
                3 September 2018
                2018
                : 18
                : 864
                Affiliations
                [1 ]GRID grid.17089.37, Department of Biomedical Engineering, , University of Alberta, ; 1098 Research Transition Facility, 8308-114 Street, Edmonton, AB T6G 2V2 Canada
                [2 ]GRID grid.17089.37, Department of Medicine, Division of Cardiology, , University of Alberta, ; Edmonton, Canada
                [3 ]GRID grid.17089.37, Department of Agricultural, Food & Nutrition Science, , University of Alberta, ; Edmonton, Canada
                [4 ]GRID grid.17089.37, Department of Oncology, , University of Alberta, ; Edmonton, Canada
                [5 ]GRID grid.17089.37, Faculty of Kinesiology, Sport, and Recreation, , University of Alberta, ; Edmonton, Canada
                [6 ]GRID grid.17089.37, Faculty of Nursing, , University of Alberta, ; Edmonton, Canada
                Author information
                http://orcid.org/0000-0002-3847-1225
                Article
                4778
                10.1186/s12885-018-4778-7
                6122558
                30176834
                5e5ee01f-d3f4-4eee-90f8-f79f1931efca
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 19 August 2018
                : 23 August 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100009634, Susan G. Komen;
                Award ID: PDF17483149
                Award Recipient :
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                anthracyclines,cardiotoxicity,breast cancer,exercise,caloric restriction,magnetic resonance imaging

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