Effects of Aerobic and Resistance Exercise in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Multicenter Randomized Controlled Trial
Kerry S. Courneya,
Roanne J. Segal,
John R. Mackey,
Robert D. Reid,
Christine M. Friedenreich,
Aliya B. Ladha,
Jeffrey K.H. Vallance,
Yutaka Yasui and
Donald C. McKenzie
From the University of Alberta; Cross Cancer Institute, Edmonton; Alberta Cancer Board, Calgary, Alberta; Ottawa Hospital Regional Cancer Center; University of Ottawa Heart Institute, Ottawa, Ontario; British Columbia Cancer Agency; and the University of British Columbia, Vancouver, British Columbia, Canada
Address reprint requests to Kerry S. Courneya, PhD, Faculty of Physical Education and Recreation, University of Alberta, E-488 Van Vliet Center, Edmonton, Alberta, Canada T6G 2H9; e-mail: email@example.com
Purpose Breast cancer chemotherapy may cause unfavorable changes in physical functioning, body composition, psychosocial functioning, and quality of life (QOL). We evaluated the relative merits of aerobic and resistance exercise in blunting these effects.
Patients and Methods We conducted a multicenter randomized controlled trial in Canada between 2003 and 2005 that randomly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care (n = 82), supervised resistance exercise (n = 82), or supervised aerobic exercise (n = 78) for the duration of their chemotherapy (median, 17 weeks; 95% CI, 9 to 24 weeks). Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy–Anemia scale. Secondary end points were fatigue, psychosocial functioning, physical fitness, body composition, chemotherapy completion rate, and lymphedema.
Results The follow-up assessment rate for our primary end point was 92.1%, and adherence to the supervised exercise was 70.2%. Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem (P = .015), aerobic fitness (P = .006), and percent body fat (adjusted P = .076). Resistance exercise was superior to usual care for improving self-esteem (P = .018), muscular strength (P < .001), lean body mass (P = .015), and chemotherapy completion rate (P = .033). Changes in cancer-specific QOL, fatigue, depression, and anxiety favored the exercise groups but did not reach statistical significance. Exercise did not cause lymphedema or adverse events.
Conclusion Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy, but they did improve self-esteem, physical fitness, body composition, and chemotherapy completion rate without causing lymphedema or significant adverse events.
Adjuvant combination chemotherapy for early-stage breast cancer improves survival, but it may also cause unfavorable changes in quality of life (QOL),1 fatigue,2physical functioning,3 and body composition.4 Few interventions have been shown to prevent these declines. Although exercise training has been considered, few studies have focused on breast cancer patients receiving chemotherapy, and the quality of the evidence is modest.5-7 In particular, study samples have been small and/or clinically heterogeneous (ie, mixed cancer sites on mixed treatment modalities), and no study has compared aerobic with resistance exercise. Moreover, few studies have examined body composition end points or lymphedema rates, and no study has documented chemotherapy completion rates. Consequently, the safety, efficacy, and optimal mode of exercise training in breast cancer patients receiving chemotherapy are still unknown.
Here, we report results from the Supervised Trial of Aerobic Versus Resistance Training (START), which examined the independent effects of aerobic and resistance exercise on QOL, fatigue, psychosocial functioning, physical fitness, body composition, chemotherapy completion rates, and lymphedema rates in breast cancer patients receiving adjuvant chemotherapy. We hypothesized that both aerobic exercise training (AET) and resistance exercise training (RET) would be superior to usual care (UC) for the patient-rated outcomes. For the objective outcomes, we hypothesized that AET would have beneficial effects on aerobic fitness and body fat levels, whereas RET would have beneficial effects for muscular strength and lean body mass. We did not expect either exercise intervention to cause lymphedema or interfere with chemotherapy completion rates.
Participants were recruited from the Cross Cancer Institute (Edmonton, Alberta, Canada), the Ottawa Hospital Integrated Cancer Program (Ottawa, Ontario, Canada), and the British Columbia Cancer Agency (Vancouver, British Columbia, Canada). The trial received ethical approval from all three centers and written informed consent from all participants. Eligibility criteria included English- or French-speaking nonpregnant women ≥ 18 years old with stage I to IIIA breast cancer who were beginning first-line adjuvant chemotherapy. Women were excluded if they had incomplete axillary surgery, transabdominal rectus abdominus muscle reconstructive surgery, uncontrolled hypertension, cardiac illness, psychiatric illness, or if they were otherwise not approved by their oncologist.
Design and Procedures
The study was a prospective, three-armed, randomized controlled trial. Eligible participants were identified by their treating oncologist before chemotherapy. Interested participants completed a questionnaire, physical fitness test, and dual x-ray absorptiometry scan (added after the first 23 participants were randomly assigned).
Participants were stratified by center and chemotherapy protocol (taxane based vnon–taxane based) and randomly assigned to AET, RET, or UC in a 1:1:1 ratio using a computer-generated program. The allocation sequence was generated in Edmonton and concealed from the project directors at each site who assigned participants to groups.
Exercise Training Interventions
Participants exercised for the duration of their chemotherapy, including delays, beginning 1 to 2 weeks after starting chemotherapy and ending 3 weeks after chemotherapy. Warm-up and cool-down periods were 5 minutes of light aerobic activity and stretching. The AET group was asked to exercise three times per week on a cycle ergometer, treadmill, or elliptical beginning at 60% of their maximal oxygen consumption, or VO2max, for weeks 1 to 6 and progressing to 70% during weeks 7 to 12 and 80% beyond week 12.8 Exercise duration began at 15 minutes for weeks 1 to 3 and increased by 5 minutes every 3 weeks until the duration reached 45 minutes at week 18. The RET group were asked to exercise three times per week performing two sets of eight to 12 repetitions of nine different exercises at 60% to 70% of their estimated one-repetition maximum.9 The exercises were leg extension, leg curl, leg press, calf raises, chest press, seated row, triceps extension, biceps curls, and modified curl-ups. Resistance was increased by 10% when participants completed more than 12 repetitions. The UC group was asked not to initiate an exercise program and was offered a 1-month exercise program after postintervention assessments.
Assessment of Primary and Secondary End Points
Patient-rated outcomes were assessed at baseline (1 to 2 weeks after starting chemotherapy), midpoint (middle of chemotherapy), after the intervention (3 to 4 weeks after chemotherapy), and the 6-month follow-up (data not presented). Cancer-specific QOL and fatigue were assessed by the Functional Assessment of Cancer Therapy–Anemia scale.10 Psychosocial functioning was assessed by the Rosenberg Self-Esteem Scale,11 the Center for Epidemiological Studies Depression Scale,12 and the Spielberger State Anxiety Inventory.13
Objectively measured outcomes were assessed at baseline and after intervention. Aerobic fitness was evaluated using a maximal incremental exercise protocol on a treadmill.14 Expired gases were analyzed using a metabolic measurement cart (CPX-D; Medical Graphics, St Paul, MN). Peak oxygen consumption was determined by taking the highest values during a 15-second period. Muscular strength was assessed by an eight-repetition maximum on the horizontal bench press and leg extension.15 The maximum weight and number of repetitions were used to estimate the one-repetition maximum.15 Body weight to the nearest 0.1 kg and standing height to the nearest 0.5 cm were assessed without shoes using a balance beam scale (Health-o-Meter; Jarden Corporation, Rye, NY). A dual x-ray absorptiometry scan was obtained for the assessment of whole body fat and lean tissue using the Hologic QDR-4500 (Hologic, Bedford, MA) in Vancouver and the General Electric LUNAR EXPERT (GE, Piscataway, NJ) in Ottawa and Edmonton. Lymphedema was assessed using standard volumetric arm measurements based on water displacement.16 Chemotherapy completion rate was assessed as the average relative dose-intensity (RDI) for the originally planned regimen based on standard formulas.17,18
Demographic and behavioral data were collected by self-report, and medical data were abstracted from records. Exercise trainers monitored adherence and adverse events. Nonprotocol exercise was assessed by self-report.19
Statistical Analyses and Sample Size Calculation
With 80 participants per group, our trial had 0.80 power to detect a difference in change scores of 7 points (standard deviation = 16) on the Functional Assessment of Cancer Therapy–Anemia scale10 with a loss-to-follow-up of 10%, a two-tailed α < .05, and no adjustment for multiple testing. Baseline comparisons were performed using univariate analysis of variance for continuous variables and χ2 analyses for categoric variables. Mixed-model analysis was used to model each outcome measure at three (or two) time points and compare the differences across groups in changes over time.20 Our primary analysis was unadjusted, but we also performed adjusted analyses controlling for baseline value of the outcome, age, marital status, employment status, disease stage, chemotherapy protocol, exercise status, and smoking status, using baseline propensity scores21 for being assigned to the RET and AET groups. We provide descriptive data and 95% CIs for all possible comparisons but provide significance tests (P values) only for hypothesized comparisons. For all analyses, we used the intent-to-treat principle. Available data for participants with missing data were included under the missing at random assumption of the mixed-model analysis.