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.

Effects of Exercise Therapy Dosing Schedule on Impaired Cardiorespiratory Fitness in Patients With Primary Breast Cancer: A Randomized Controlled Trial.

BACKGROUND: Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40-50 minutes per session), and volume (120-160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer. METHODS: Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VO2peak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO2peak (mL O2·kg-1·min-1) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety. RESULTS: No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VO2peak increased 0.6±1.7 mL O2·kg-1·min-1 (P=0.05) and 0.8±1.8 mL O2·kg-1·min-1 (P=0.07) in LET and NLET, respectively, compared with attention control. Change in VO2peak ranged from -2.7 to 4.1 mL O2·kg-1·min-1 and from -3.6 to 5.1 mL O2·kg-1·min-1 in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VO2peak responders (ie, Δ ≥1.32 mL O2·kg-1·min-1). NLET improved all patient-reported outcomes compared with attention control. CONCLUSIONS: Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01186367.

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.

Prognostic Importance of Pretransplant Functional Capacity After Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: The purpose of this study was to investigate the prognostic importance of functional capacity in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for hematological malignancies. PATIENTS AND METHODS: Using a retrospective design, 407 patients completed a 6-minute walk distance (6 MWD) test to assess functional capacity before HCT; 193 (47%) completed a 6 MWD test after hospital discharge. Cox proportional hazards regression was used to estimate the risk of nonrelapse mortality (NRM) and overall survival (OS) according to the 6 MWD category (<400 m vs. ≥ 400 m) and the change in 6 MWD (before HCT to discharge) with or without adjustment for Karnofsky performance status (KPS), age, and other prognostic markers. RESULTS: Compared with <400 m, the unadjusted hazard ratio for NRM was 0.65 (95% confidence interval, 0.44-0.96) for a 6 MWD ≥ 400 m. A 6 MWD of ≥ 400 m provided incremental information on the prediction of NRM with adjustment for age (p = .032) but not KPS alone (p = .062) or adjustment for other prognostic markers (p = .099). A significant association was found between the 6 MWD and OS (p = .027). A 6 MWD of ≥ 400 m provided incremental information on the prediction of OS with adjustment for age (p = .032) but not for other prognostic markers (p > .05 for all). Patients presenting with a pre-HCT 6 MWD of <400 m and experiencing a decline in 6 MWD had the highest risk of NRM. CONCLUSION: The 6 MWD is a significant univariate predictor of clinical outcomes but did not provide prognostic information beyond that of traditional prognostic markers in HCT. IMPLICATIONS FOR PRACTICE: The pretransplant 6-minute walk test is a significant univariate predictor of clinical outcomes in hematological patients beyond age but not beyond that of performance status. On this basis, 6-minute walk distance testing should not be considered part of the standard battery of assessments for risk stratification before hematopoietic cell transplantation.

Cardiorespiratory Fitness in Patients With Early-Stage Breast Cancer and Radiation Therapy-Related Fatigue: A Prospective Pilot Study.

PURPOSE: Fatigue is among the most common but most poorly understood radiation therapy-associated toxicities. This prospective study sought to investigate whether cardiorespiratory fitness, an integrative measure of whole-body cardiopulmonary function, is associated with patient-reported fatigue in women with early-stage breast cancer undergoing radiation therapy. METHODS AND MATERIALS: Patients with stage Tis-T2N0M0 breast cancer and an Eastern Cooperative Oncology Group performance status of 0 to 1 undergoing breast radiation therapy performed a symptom-limited cardiopulmonary exercise test (CPET) on a motorized treadmill to assess cardiorespiratory fitness as measured by peak oxygen uptake (VO2peak). Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale. Both assessments were performed during or immediately after radiation therapy completion. All patients were treated with an opposed tangent technique to a dose of 4240 cGy in 16 fractions with or without a lumpectomy bed boost. Patients receiving cytotoxic chemotherapy were excluded. Pearson correlation coefficients and univariate linear regression were used to assess associations amongVO2peak, fatigue, and patient characteristics. RESULTS: Twenty-eight patients (median age, 52 years; range, 31-71) completed a CPET and FACIT-Fatigue assessment. Median VO2peak was 25.1 mL O2.kg-1.min-1 (range, 16.7-41.7). The majority of patients (78.6%) displayed a VO2peak lower than their age-predicted VO2peak. Both age and body mass index were significantly associated with VO2peak levels. The median FACIT-Fatigue score was 41.5 (range, 10-52), with lower values indicating more fatigue. VO2peak was not significantly associated with FACIT-Fatigue score (P = .20). CONCLUSIONS: VO2peak was not a significant predictor of radiation therapy-related fatigue. Most patients with breast cancer had marked impairments in cardiorespiratory fitness as determined by VO2peak. Larger prospective studies are needed to further investigate this novel finding and evaluate the effects of interventions aimed at improving cardiorespiratory fitness and their ability to potentially prevent fatigue.

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.

Validity of Estimated Cardiorespiratory Fitness in Patients With Primary Breast Cancer.

Background: Estimated peak oxygen consumption (Vo2peak) is widely used in oncology; however, estimated Vo2peak equations were developed in noncancer settings. Objectives: The aim of this study was to evaluate the validity of estimated Vo2peak in women with primary breast cancer and to develop oncology-specific estimated Vo2peak equations. Methods: Vo2peak was directly measured (TrueOne 2400, Parvo Medics) during 380 cardiopulmonary exercise tests in women previously treated for breast cancer (mean age: 59 ± 10 years; 3.1 ± 1.2 years post-therapy). The American College of Sports Medicine (ACSM), the Fitness Registry and the Importance of Exercise National Database (FRIEND), and heart failure (HF)-FRIEND equations were used to estimate Vo2peak. New equations were developed using patient and peak (Oncpeak) or submaximal (Oncsub) exercise test characteristics. Results: The median differences between measured and estimated Vo2peak were 7.0 mL O2·kg-1·min-1, 3.9 mL O2·kg-1·min-1, and -0.2 mL O2·kg-1·min-1 for ACSM, FRIEND, and HF-FRIEND, respectively. The number of estimated Vo2peak values within ±3.5 mL O2·kg-1·min-1 of the measured values was 70 (18%), 164 (43%), and 306 (81%) for ACSM, FRIEND, and HF-FRIEND, respectively. The Oncpeak and OncSub models included body mass index, age, a history of chemotherapy or radiation, the peak measured heart rate, and the treadmill grade and/or speed. The median differences between measured and estimated Vo2peak were 0.02 mL O2·kg-1·min-1 (Oncpeak) and -0.2 mL O2·kg-1·min-1 (Oncsub). Eighty-six percent (n = 325) and 76% (n = 283) estimated Vo2peak values were within ±3.5 mL O2·kg-1·min-1 of the measured Vo2peak values for Oncpeak and Oncsub, respectively. Conclusions: HF-FRIEND or oncology-specific equations could be applied to estimate Vo2peak in patients previously treated for breast cancer in settings where cardiopulmonary exercise tests are not available. (Trial Comparing the Effects of Linear Versus Nonlinear Aerobic Training in Women With Operable Breast Cancer [EXCITE]; NCT01186367.

A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND).

BACKGROUND: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide. METHODS: We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO2peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values. RESULTS: The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (-0.31 L/min, -10.9%; p < 0.01) and relative CRF (-3.2 mL/kg/min, -8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17. CONCLUSIONS: This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity. GOV IDENTIFIER: NCT02256111.

Effects and tolerability of exercise therapy modality on cardiorespiratory fitness in lung cancer: a randomized controlled trial.

BACKGROUND: Poor cardiorespiratory fitness (CRF) is a cardinal feature of post-treatment primary lung cancer. The most effective exercise therapy regimen to improve CRF has not been determined. METHODS: In this parallel-group factorial randomized controlled trial, lung cancer survivors with poor CRF (below age-sex sedentary values) were randomly allocated to receive 48 consecutive supervised sessions thrice weekly of (i) aerobic training (AT)-cycle ergometry at 55% to >95% of peak oxygen consumption (VO2 peak); (ii) resistance training (RT)-lower and upper extremity exercises at 50-85% of maximal strength; (iii) combination training (CT)-AT plus RT; or (iv) stretching attention control (AC) for 16 weeks. The primary endpoint was change in CRF (VO2 peak, mL O2 ·kg-1 ·min-1 ). Secondary endpoints were body composition, muscle strength, patient-reported outcomes, tolerability (relative dose intensity of exercise), and safety. Analysis of covariance determined change in primary and secondary endpoints from baseline to post-intervention (Week 17) with adjustment for baseline values of the endpoint and other relevant clinical covariates. RESULTS: Ninety patients (65 ± 9 years; 66% female) were randomized (AT, n = 24; RT, n = 23; CT, n = 20; and AC, n = 23) of the planned n = 160. No serious adverse events were observed. For the overall cohort, the lost-to-follow-up rate was 10%. Mean attendance was ≥75% in all groups. In intention-to-treat analysis, VO2 peak increased 1.1 mL O2 ·kg-1 ·min-1 [95% confidence interval (CI): 0.0, 2.2, P = 0.04] and 1.4 mL O2 ·kg-1 ·min-1 (95% CI: 0.2, 2.5, P = 0.02) in AT and CT, respectively, compared with AC. There was no difference in VO2 peak change between RT and AC (-0.1 mL O2 ·kg-1 ·min-1 , 95% CI: -1.2, 1.0, P = 0.88). Favourable improvements in maximal strength and body composition were observed in RT and CT groups compared with AT and AC groups (Ps < 0.05). No between-group changes were observed for any patient-reported outcomes. Relative dose intensity of exercise was lower in RT and CT compared with AT (Ps < 0.05). CONCLUSIONS: In the context of a smaller than planned sample size, AT and CT significantly improved VO2 peak in lung cancer survivors; however, the tolerability-to-benefit ratio was superior for AT and hence may be the preferred modality to target impaired CRF in post-treatment lung cancer survivors.

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.