TY - JOUR
AU - Habibian, Mohsen
AB - The benefits of aerobic exercise have been recognised for many years in cardiovascular, respiratory and neurological health and wellbeing.1 In recent years the benefits of exercise training in cancer patients have also emerged, with improvements in exercise tolerance, quality of life and, possibly, survival.2 The mechanisms of improved benefits are complex and multifactorial, including improved skeletal and cardiac muscle physiology, reduced inflammation and oxidative stress, improvements in pulmonary physiology and ventilatory efficiency, and improved autonomic function with increased vagal tone and reduced sympathetic tone.3 In recent years it has become apparent that the cardiovascular complications of cancer treatment are having a growing impact on morbidity and mortality for cancer patients during and following specific cancer therapies, and particularly for cancer patients in curative treatment pathways.4 Specifically, this relates to acute complications interfering with optimal cancer care with interruptions of chemotherapy and novel targeted molecular therapies, and at long-term follow-up with improved survival following cancer with modern treatments, there is a growing burden of cardiovascular disease leading to premature mortality. This has led to the new subspecialty of cardio-oncology within modern medicine and the emergence of specialist cardio-oncology services.5,6 The role of aerobic exercise in improving cardiovascular health in cancer patients during chemotherapy, with the potential to reduce cardiovascular toxicity from specific oncology treatments such as anthracycline chemotherapy (AC) protocols, has emerged as a new topic for research. The mechanisms underlying AC-induced cardiotoxicity are complex, but involve oxidative stress, mitochondrial dysfunction and apoptosis in both cardiac and skeletal muscle. Aerobic exercise is a promising strategy to prevent and/or treat AC-induced cardiotoxicity with different potential cardioprotective mechanisms, including enhancement of myocardial antioxidant expression, mitigating AC-induced reactive oxygen species release, improved mitochondrial function and energetic metabolism, reduced proapoptotic signalling, and limiting maladaptive changes in myocardial calcium handling (see Figure 1). Figure 1. Open in new tabDownload slide Benefits of exercise training for cancer patients. Previous studies have confirmed a significant reduction in cardiopulmonary exercise performance at completion of a course of AC in breast cancer patients compared with baseline, equivalent to an aging effect of approximately 10 years.7 The mechanisms underlying this appear complex and multifactorial, including direct cardiotoxicity, aging of skeletal muscle and potential disturbance of autonomic physiology. 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 In this issue of European Journal of Preventive Cardiology, Howden and colleagues from Melbourne, Australia report on their study of 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 min aerobic and 30 min resistance training, plus a third unsupervised aerobic exercise session. An important feature of the training schedule was that it coordinated with the individual’s chemotherapy programme, with a lower intensity exercise programme in the week following a dose of chemotherapy when fatigue and immunosuppression are more common, compared with the second and third weeks when patients have generally recovered in the three-week chemotherapy protocol. The overall intensity of the training schedule increased over the total chemotherapy course and was also personalised to the intensity of the chemotherapy protocol (dose-dense vs standard AC). The control arm continued standard medical care without the exercise intervention. The study participants underwent a detailed cardiovascular assessment at baseline and follow-up, including cardiopulmonary exercise testing, advanced cardiac imaging with echocardiography with speckle tracking and cardiac magnetic resonance (CMR) imaging with an exercise CMR protocol to assess left ventricular contractile reserve, and measurement of cardiac troponin and brain natriuretic peptide (BNP). Patients who chose the usual-care arm were older, less active at baseline, had a higher baseline body weight, and lower baseline peak MVO2, consistent with selection of a less athletically fit population. Observations in the standard-care cohort receiving AC are helpful to place in context the effect of exercise training. In the usual-care arm AC was associated with a significant 15% reduction in peak MVO2 at follow-up compared with baseline, with 50% of this usual care cohort achieving a peak MVO2 falling below a threshold considered prognostically relevant (18 ml/kg/min). Reinforcing previous observations, cardiac troponin is the most useful cardiotoxicity serum biomarker in patients during AC, with a significant rise in the mean troponin from normal (2.6±1.0 ng/l) to elevated (35.6 ± 27.2 ng/l) at follow-up, although the number of patients with a rise above the upper limit of normal for their specific assay was not reported. By contrast BNP did not rise in this group. The cardiac imaging assessment showed that a 10% or more reduction of resting left ventricular ejection volume (LVEF) is relatively common (5/14 (17%)) in this patient cohort, although none reduced below 50% and none were associated with a reduction in global longitudinal strain (GLS). Therefore whether these findings reflect subclinical cardiotoxicity or regression to the mean in LVEF measurement is not clear, and correlation with other markers (troponin, ΔpeakMVO2) may be informative. Perhaps surprisingly, and the authors acknowledge against the pre-specified hypothesis, there was not a significant reduction in contractile reserve measured using the CMR exercise protocol in the control arm, although a new abnormality was a steeper rise in heart rate acceleration during the exercise protocol. However the peak achieved LV contractile level was unchanged at follow-up in the control arm with standard care during AC. The authors report that the adherence to the prescribed exercise training programme was relatively disappointing by contemporary exercise trials, with only half of the intervention arm achieving 80% or higher of the 24 prescribed exercise sessions (mean 76%) although there was effective adherence to the home self-reported exercise training (mean 76 min/week). Given that these patients were a motivated cohort who volunteered for the exercise intervention arm, rather than being independently allocated via randomisation, this highlights the challenges specific to cancer patients undergoing AC chemotherapy. It would be interesting to know if compliance reduced over time, perhaps reflecting the cumulative general toxicity of AC, or was present from the early cycles and related to motivation. Also it would be interesting to know if there were any clinical or laboratory parameters (e.g. Hb, WCC, troponin) which correlated with reduced compliance and could serve as new biomarkers to intensify motivational strategies to support improved compliance. The most important results resulting from the intense exercise programme intervention are the reported prevention of AC-induced reduction in functional capacity on CPEX testing, with preservation of peak MVO2 at follow-up in the exercise cohort (4% reduction vs 15% in control), and prevention of the AC-induced rise in troponin (21.4 ng/l vs 35.6 ng/l). The preservation of peak exercise performance in the exercise group was matched by preserved arterio-venous O2 difference suggesting preservation of cardiac output and possibly skeletal muscle O2 extraction efficiency may have been improved. However the amount and duration of exercise, and peak MVO2 in the exercise arm are all higher at baseline, and of course are also potentially performed as part of the training programme, and therefore both the potential for familiarity with the exercise protocol and technical ability to complete the protocol may also influence the results observed. Given the findings in the control arm, it is not surprising that exercise intervention did not have an impact upon the variables which were unchanged in the control arm at completion of AC, including resting LVEF and left ventricular GLS, BNP and imaging-based cardiac reserve during exercise CMR. The authors acknowledge the main limitations that this is a small study without randomisation to the active intervention and therefore a strong bias for the younger more active breast cancer patients to select the exercise programme offered, and this may have influenced the differences observed. This study contributes to the growing body of literature supporting the benefits of aerobic exercise training in oncology patients during and after cardiotoxic cancer treatments in order to improve quality of life, and potentially reduce the cardiovascular complications and associated morbidity and mortality (see Figure 1). The trials published to date have been small phase II trials, and a recent meta-analysis of the pooled data from over 3500 patients in 48 randomised controlled trials of exercise in cancer patients reports a consistent benefit.14 It would now be timely to have a definitive larger appropriately powered phase III randomised control trial to objectively assess the ability for real-world populations to adhere to the prescribed protocols, the impact on both cardiovascular and oncology clinical end-points, and help to persuade funding for specific exercise programmes by healthcare providers. The importance of having adherence in populations not usually accustomed to regular exercise is critical as they reflect the highest risk group, and also the cohort with potentially the most to gain. The use of the new Exercise Prescription in Everyday Practice and Rehabilitative Training (EXPERT) exercise prescription tool from the European Association of Preventive Cardiology is one strategy to improve compliance which may be helpful.15 Given the potential to improve oncology outcomes as well as cardiovascular outcomes, this may serve as a very attractive and persuasive argument for cancer patients to increase their exercise capacity. Unanswered questions include the specific type and duration of exercise, the delta change from baseline level required to achieve a relevant clinical outcome, and whether an absolute level of exercise performance is required to be achieved or a relative change from baseline for an individual which is required to receive the clinical benefit.16 Another area of research is with regard to whether there are particular high-risk subgroups who may benefit, including patients with pre-existing CVD and especially those with heart failure at the time of cancer diagnosis and treatment.17 The mechanisms underlying the benefits are also areas of further research, in order to determine if it is possible to reproduce the benefits with a specific pharmacological or device intervention. Based upon currently available data, including the study of Howden and colleagues, it is incumbent upon cardiologists, oncologists and other healthcare professionals to encourage regular aerobic exercise in patients with cardiovascular disease or cancer, and the growing population with both. Declaration of conflicting interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ARL reports research grants from Servier and Pfizer, and speaker fees, advisory board fees and/or consultancy fees from Servier, Pfizer, Novartis, Roche, Takeda, Boehringer Ingelheim, Amgen, Clinigen Group, Ferring Pharmaceuticals, Bristol Myers Squibb, Eli Lily and Janssens-Cilag Ltd. MH has no COI to declare. Funding The author(s) received no financial support for the research, authorship and/or publication of this article. 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TI - Break a sweat to reduce cardiotoxicity – the benefits of exercise training during anthracycline chemotherapy
JO - European Journal of Preventive Cardiology
DO - 10.1177/2047487318821239
DA - 2019-02-01
UR - https://www.deepdyve.com/lp/oxford-university-press/break-a-sweat-to-reduce-cardiotoxicity-the-benefits-of-exercise-DDKAXDbm0s
SP - 301
EP - 304
VL - 26
IS - 3
DP - DeepDyve
ER -