Exercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study

Abstract

Background: Breast cancer (BC) survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 early-stage BC patients scheduled for AC to determine if 12-months of exercise training (ExT) could attenuate functional disability (primary endpoint), improve cardiorespiratory fitness (VO 2 peak) and prevent cardiac dysfunction. Methods: Women aged 40-75 years with stage I-III BC scheduled for AC were randomized to 3-4 days/wk of aerobic and resistance ExT for 12-months (n = 52) or usual care ([ UC ], n = 52). Functional measures were performed at baseline, 4-weeks following AC (4-months) and at 12-months comprising: 1) cardiopulmonary exercise testing to quantify VO 2 peak and functional disability (VO 2 peak ≤18.0mL/kg/min), 2) cardiac reserve (response from rest to peak exercise) quantified using exercise cardiac magnetic resonance measures to determine changes in left- and right-ventricular ejection fraction [ LVEF, RVEF ], cardiac output [ CO ], and stroke volume [ SV ]), 3) standard-of-care echocardiography-derived resting LVEF and global longitudinal strain [ GLS ], and 4) biochemistry (troponin and B-type natriuretic peptide [ BNP ]). Results: Among 104 participants randomized, greater study attrition was observed among UC participants (P=0.031) with 93 women assessed at 4-months (ExT: n=49, UC: n=44) and 87 at 12-months (ExT: n=49, UC: n=38). ExT attenuated functional disability at 4-months (OR: 0.32 [95% CI 0.11, 0.94], P=0.03), but not at 12-months (OR: 0.27, [95% CI 0.06, 1.12], P=0.07). In a per-protocol analysis, functional disability was entirely prevented at 12-months among participants adherent to ExT (ExT: 0% vs. UC: 20%, P=0.005). As compared with UC at 12-months, ExT was associated with a net +3.5 mL/kg/min improvement in VO 2 peak that coincided with greater CO, SV, LVEF and RVEF reserve (P<0.001 for all). There was no effect of ExT on resting measures of LV function. Post-chemotherapy troponin increased less in ExT than UC (8-fold vs. 16-fold increase, P=0.002). There were no changes in BNP in either group. Conclusions: In women with early-stage BC undergoing AC, 12-months of ExT did not attenuate functional disability but provided large and clinically meaningful benefits on VO2peak and cardiac reserve. Clinical Trial Registration: URL: https://www.anzctr.org.au/ Unique Identifier: ACTRN12617001408370

Reduced cardiovascular reserve capacity in long-term allogeneic stem cell transplant survivors

“…Further, dietary modification (in accordance with established cardiovascular disease prevention nutrition guidelines [53][54][55] ) is an effective strategy for improving traditional cardiovascular risk and body composition profile, and when combined with exercise, may enhance its beneficial effects on cardiac function and VO 2peak . Notably, exercise training and nutritional counselling constitute core components of cardiovascular rehabilitation for individuals with established CVD 46,47,[55][56][57][58][59] , and our group recently demonstrated the utility of combined aerobic and resistance exercise in improving VO 2peak and cardiac reserve (via increased SV reserve) among anthracycline-treated breast cancer patients 60 . Taken together, there is strong theoretical rationale for further investigation into the therapeutic utility of exercise training, nutritional counselling and/or cardioprotective pharmacotherapy to improve VO 2peak , cardiac reserve and body composition profile among allo-SCT survivors.…”

Supervised exercise training in patients with cancer during anthracycline-based chemotherapy to mitigate cardiotoxicity - a randomized controlled trial.

“…While absolute changes of the two studies that assessed GLS at baseline and AC-end are similar to our measurements, 35,37 no information was given on overall PA of the included patients. Although Peck et al analysed the relationship between MVPA and GLS and reported a significant association, 20 the authors relied on self-reported measures which are likely to overestimate time spend at moderate to vigorous intensities.…”

“…A recent study by Foulkes et al in 104 breast cancer patients (mean age 51 years) undergoing AC compared cardiac markers of systolic function and biomarkers of myocardial injury between an exercise and usual care group. 35 ET consisted of 3 weekly 30-60 min aerobic exercise sessions at moderate to high intensity, combined with resistance training over 12 weeks. In their study, GLS deteriorated by 1.3% in the exercise group compared to 1.0% in the usual care group with no differences between the groups.…”

“…First evidence suggesting that protective effects may be lasting comes from the study by Foulkes and colleagues. 35 In addition to resting cardiac parameters, this study compared measures of peak exercise cardiac function and reserve (cardiac output, stroke volume and LVEF) between the exercise and usual care group at the end of AC and after 12 months. They observed a better myocardial function and greater cardiac reserve in the exercise group compared to the usual care group at AC-end and these differences persisted at the follow-up assessment (in adherent patients).…”

Does Physical Activity During Cancer Treatment Preserve Exercise Capacity?

“…4 This issue of Circulation features 2 studies that examine the potential benefit of performing physical activity during receipt of anthracycline-based chemotherapy for breast cancer. In one randomized clinical trial, Foul-kes et al 5 examined the usefulness of a 12-month exercise intervention in preserving exercise capacity among women with breast cancer receiving anthracycline-based chemotherapy. A total of 104 participants were randomized to either usual care, which consisted of encouragement and referral to written recommendations for physical activity, or an individualized multicomponent exercise program consisting of endurance, tempo, and both high-intensity interval and resistance training.…”