Timing of exercise therapy when initiating adjuvant chemotherapy for breast cancer: a randomized trial.

AIMS: The most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer. METHODS AND RESULTS: Using a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens-concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20-50 min at 55%-100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, -0.88 mL O2·kg-1·min-1; 95% confidence interval (CI): -3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg-1·min-1, P < 0.001). CONCLUSION: There was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

Feasibility, safety, and efficacy of aerobic training in pretreated patients with metastatic breast cancer: A randomized controlled trial.

BACKGROUND: The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer. METHODS: Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had ≥ 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate (<20%) and attendance (≥70%). Secondary endpoints were safety, objective outcomes (VO2peak and functional capacity), and patient-reported outcomes (PROs; quality of life). RESULTS: One of the 33 patients (3%) receiving aerobic training was LTF, whereas the mean attendance rate was 63% ± 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention-to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity ≥ 70%), and this led to improvements in VO2peak and functional capacity (P values < .05). CONCLUSIONS: Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018;124:2552-60. © 2018 American Cancer Society.

Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

PURPOSE: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. METHODS: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. RESULTS: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. CONCLUSIONS: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

Lower-limb resistance training reduces exertional dyspnea and intrinsic neuromuscular fatigability in individuals with chronic obstructive pulmonary disease.

Skeletal muscle atrophy, dysfunction, and fatigue are important complications of chronic obstructive pulmonary disease (COPD). Greater reliance on glycolytic metabolism and increased type III/IV muscle afferent activity increase ventilatory drive, promote ventilatory constraint, amplify exertional dyspnea, and limit exercise tolerance. To investigate whether muscular adaptation with resistance training (RT) could improve exertional dyspnea, exercise tolerance, and intrinsic neuromuscular fatigability in individuals with COPD (n = 14, FEV1 = 62 ± 21% predicted), we performed a proof-of-concept single-arm efficacy study utilizing 4 wk of individualized lower-limb RT (3 times/wk). At baseline, dyspnea (Borg scale), ventilatory parameters, lung volumes (inspiratory capacity maneuvers), and exercise time were measured during a constant-load test (CLT) at 75% maximal workload to symptom limitation. On a separate day, fatigability was assessed using 3 min of intermittent stimulation of the quadriceps (initial output of ∼25% maximal voluntary force). Following RT, the CLT and fatigue protocols were repeated. Compared with baseline, isotime dyspnea was reduced (5.9 ± 2.4 vs. 4.5 ± 2.4 Borg units, P = 0.02) and exercise time increased (437 ± 405 s vs. 606 ± 447 s, P < 0.01) following RT. Isotime tidal volume increased (P = 0.01), whereas end-expiratory lung volumes (P = 0.02) and heart rate (P = 0.03) decreased. Quadriceps force, relative to initial force, was higher at the end of the stimulation protocol posttraining (53.2 ± 9.1 vs. 46.8 ± 11.9%, P = 0.04). This study provides evidence that 4 wk of RT attenuates exertional dyspnea and improves exercise tolerance in individuals with COPD, which in part, is likely due to delayed ventilatory constraint and reduced intrinsic fatigability. A pulmonary rehabilitation program beginning with individualized lower-limb RT may help mitigate dyspnea before performing aerobic training in individuals with COPD.NEW & NOTEWORTHY This study presents the novel finding that 4-wk resistance training (RT) focused specifically on the lower limbs can reduce exertional dyspnea during constant-load cycling, improve exercise tolerance, and reduce intrinsic fatigability of the quadriceps in individuals with COPD.

Phenotyping Cardiopulmonary Exercise Limitations in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Exercise limitation in chronic obstructive pulmonary disease (COPD) is commonly attributed to abnormal ventilatory mechanics and/or skeletal muscle function, while cardiovascular contributions remain relatively understudied. To date, the integrative exercise responses associated with different cardiopulmonary exercise limitation phenotypes in COPD have not been explored but may provide novel therapeutic utility. This study determined the ventilatory, cardiovascular, and metabolic responses to incremental exercise in patients with COPD with different exercise limitation phenotypes. METHODS: Patients with COPD (n = 95, FEV1:23-113%pred) performed a pulmonary function test and incremental cardiopulmonary exercise test. Exercise limitation phenotypes were classified as: ventilatory [peak ventilation (VEpeak)/maximal ventilatory capacity (MVC) ≥ 85% or MVC-VEpeak ≤ 11 L/min, and peak heart rate (HRpeak) < 90%pred], cardiovascular (VEpeak/MVC < 85% or MVC-VEpeak > 11 L/min, and HRpeak ≥ 90%pred), or combined (VEpeak/MVC ≥ 85% or MVC-VEpeak ≤ 11 L/min, and HRpeak ≥ 90%pred). RESULTS: FEV1 varied within phenotype: ventilatory (23-75%pred), combined (28-90%pred), and cardiovascular (68-113%pred). The cardiovascular phenotype had less static hyperinflation, a lower end-expiratory lung volume and larger tidal volume at peak exercise compared to both other phenotypes (p < 0.01 for all). The cardiovascular phenotype reached a higher VEpeak (60.8 ± 11.5 L/min vs. 45.3 ± 15.5 L/min, p = 0.002), cardiopulmonary fitness (VO2peak: 20.6 ± 4.0 ml/kg/min vs. 15.2 ± 3.3 ml/kg/min, p < 0.001), and maximum workload (103 ± 34 W vs. 72 ± 27 W, p < 0.01) vs. the ventilatory phenotype, but was similar to the combined phenotype. CONCLUSION: Distinct exercise limitation phenotypes were identified in COPD that were not solely dependent upon airflow limitation severity. Approximately 50% of patients reached maximal heart rate, indicating that peak cardiac output and convective O2 delivery contributed to exercise limitation. Categorizing patients with COPD phenotypically may aid in optimizing exercise prescription for rehabilitative purposes.

Mechanical cardiopulmonary interactions during exercise in health and disease.

The heart and lungs are anatomically coupled through the pulmonary circulation and coexist within the sealed thoracic cavity, making the function of these systems highly interdependent. Understanding of the complex mechanical interactions between cardiac and pulmonary systems has evolved over the last century to appreciate that changes in respiratory mechanics significantly impact pulmonary hemodynamics and ventricular filling and ejection. Furthermore, given that the left and right heart share a common septum and are surrounded by the nondistensible pericardium, direct ventricular interaction is an important mediator of both diastolic and systolic performance. Although it is generally considered that cardiopulmonary interaction in healthy individuals at rest minimally affects hemodynamics, the significance during exercise is less clear. Adverse heart-lung interaction in respiratory disease is of growing interest as it may contribute to the pathogenesis of comorbid cardiovascular dysfunction and exercise intolerance in these patients. Similarly, heart failure represents a pathological uncoupling of the cardiovascular and pulmonary systems, whereby cardiac function may be impaired by the normal ventilatory response to exercise. Despite significant research contributions to this complex area, the mechanisms of cardiopulmonary interaction in the intact human and the clinical consequences of adverse interactions in common respiratory and cardiovascular diseases, particularly during exercise, remain incompletely understood. The purpose of this review is to present the key physiological principles of cardiopulmonary interaction as they pertain to resting and exercising hemodynamics in healthy humans and the clinical implications of adverse cardiopulmonary interaction during exercise in chronic obstructive pulmonary disease (COPD), pulmonary hypertension, and heart failure.

Novel Methods for Reporting of Exercise Dose and Adherence: An Exploratory Analysis.

PURPOSE: The purpose of this study was to explore whether methods adapted from oncology pharmacological trials have utility in reporting adherence (tolerability) of exercise treatment in cancer. METHODS: Using a retrospective analysis of a randomized trial, 25 prostate cancer patients received an aerobic training regimen of 72 supervised treadmill walking sessions delivered thrice weekly between 55% and 100% of exercise capacity for 24 consecutive weeks. Treatment adherence (tolerability) was assessed using conventional (lost to follow-up and attendance) and exploratory (e.g., permanent discontinuation, dose modification, and relative dose intensity) outcomes. RESULTS: The mean total cumulative "planned" and "completed" dose was 200.7 ± 47.6 and 153.8 ± 68.8 MET·h, respectively, equating to a mean relative dose intensity of 77% ± 24%. Two patients (8%) were lost to follow-up, and mean attendance was 79%. A total of 6 (24%) of 25 patients permanently discontinued aerobic training before week 24. Aerobic training was interrupted (missing ≥3 consecutive sessions) or dose reduced in a total of 11 (44%) and 24 (96%) patients, respectively; a total 185 (10%) of 1800 training sessions required dose reduction owing to both health-related (all nonserious) and non-health-related adverse events. Eighteen (72%) patients required at least one session to be terminated early; a total of 59 (3%) sessions required early termination. CONCLUSIONS: Novel methods for the conduct and reporting of exercise treatment adherence and tolerability may provide important information beyond conventional metrics in patients with cancer.

A framework for prescription in exercise-oncology research.

The field of exercise-oncology has increased dramatically over the past two decades, with close to 100 published studies investigating the efficacy of structured exercise training interventions in patients with cancer. Of interest, despite considerable differences in study population and primary study end point, the vast majority of studies have tested the efficacy of an exercise prescription that adhered to traditional guidelines consisting of either supervised or home-based endurance (aerobic) training or endurance training combined with resistance training, prescribed at a moderate intensity (50-75% of a predetermined physiological parameter, typically age-predicted heart rate maximum or reserve), for two to three sessions per week, for 10 to 60 min per exercise session, for 12 to 15 weeks. The use of generic exercise prescriptions may, however, be masking the full therapeutic potential of exercise treatment in the oncology setting. Against this background, this opinion paper provides an overview of the fundamental tenets of human exercise physiology known as the principles of training, with specific application of these principles in the design and conduct of clinical trials in exercise-oncology research. We contend that the application of these guidelines will ensure continued progress in the field while optimizing the safety and efficacy of exercise treatment following a cancer diagnosis.