Exercise Dose and Type During Breast Cancer Chemotherapy
Neither HIGH nor COMB were superior to STAN for the primary outcome of the SF-36 physical functioning subscale. Previous trials have shown that aerobic exercise and resistance exercise are superior to no exercise for improving patient-reported physical functioning in cancer patients receiving treatments. It is possible that additional aerobic exercise or weight training does not provide further benefit to patient-reported physical functioning during breast cancer chemotherapy. It is also possible, however, that the SF-36 physical functioning subscale is not sensitive to higher volumes of exercise in breast cancer patients receiving chemotherapy because of irrelevant items or ceiling effects related to their younger age and higher functioning. The SF-36 physical functioning subscale includes several low-level functioning items that are common activities of daily living that are not likely problematic for most breast cancer patients or may be adequately addressed by standard aerobic exercise. The SF-36 physical functioning subscale may be more sensitive to lifestyle interventions in older cancer survivors with lower functioning. The optimal patient-reported physical functioning scale for exercise trials in cancer patients is still unclear.
HIGH was superior to STAN for the more comprehensive SF-36 measure, the physical component summary, and trended toward superiority for the cancer-specific trial outcome index–fatigue scale. These data suggest the possibility of a dose–response effect for aerobic exercise. The mean group differences of 1.6 on the physical component summary and 3.4 on the trial outcome index–fatigue scale fall below the suggested meaningful group differences of two to three points and five points, respectively; however, these modest effects were obtained over and above a standard aerobic exercise program. The comparison of higher-dose exercise programs with standard aerobic exercise provides the most rigorous test of the causal effects of exercise because it controls for the many nonexercise-related factors that may improve patient-reported outcomes, such as travel to the fitness center, interactions with the trainer or other participants, expectation of benefit, and cognitive dissonance.
Interestingly, HIGH even trended toward superiority over COMB for the SF-36 physical component summary scale, suggesting the possibility of an exercise type effect as well. It is unclear why additional aerobic exercise may have beneficial effects on patient-reported physical functioning but not additional weight training. It is possible that aerobic exercise better addresses central and leg fatigue, which may influence activities of daily living in breast cancer patients more so than upper-body (arm) fatigue. Previous trials in breast cancer survivors and lymphoma patients have found improvements in patient-reported physical functioning to be mediated by improved aerobic fitness.
HIGH was also superior to both STAN and COMB for bodily pain. Pain is a common symptom in breast cancer patients and is associated with anxiety, sleep disturbance, and poor quality of life. Few exercise trials in breast cancer patients have examined pain as an outcome. The mean group differences of 2.0 and 2.3 are within the suggested meaningful group differences of two to three points on SF-36 bodily pain scale. These results suggest both an exercise dose and type effect for aerobic exercise. Mechanisms for pain reduction from aerobic exercise may include endorphin production, weight loss, improved functioning, and mood.
Both HIGH and COMB were superior to STAN for managing endocrine symptoms. Endocrine symptoms are common and distressing in breast cancer patients, yet no previous exercise study has examined endocrine symptoms in breast cancer patients. Exercise may manage endocrine symptoms by increasing hypothalamic and peripheral β-endorphin production, which may stabilize the thermoregulatory center and reduce the risk of hot flashes. The endocrine symptom subscale has no minimal important difference, but the mean group differences of 2.5 and 2.2 translate into about 0.33 standard deviations. Our results suggest a dose–response effect of exercise regardless of exercise type. This finding may portend an even more powerful effect of exercise on endocrine symptoms when compared with no exercise and may be particularly important given the reluctance to prescribe hormone replacement therapy for menopausal symptoms in breast cancer patients.
Higher dose aerobic exercise partially blunted a substantial decline in maximal oxygen consumption in STAN and COMB by about 1.0mL/mg/kg or 3% to 4%. These declines, despite aerobic exercise training, are even larger than previously reported in our Supervised Trial of Aerobic versus Resistance Training (START). These differences may be the result of changing chemotherapy protocols. During the START Trial (2002 to 2005), about 30% of patients received taxane-based chemotherapies, whereas in the CARE Trial (2008 to 2011), 90% of patients received such therapies.
Weight training improved muscular fitness compared with the aerobic exercise groups by approximately 10% to 30%. Again, in the START Trial we found that a similar weight training protocol improved muscular strength by approximately 35% compared with no exercise. The more modest improvements in the CARE trial may be the result of the aerobic exercise comparison groups or the changing chemotherapy protocols. In subgroup analyses from the START Trial, we found a strength improvement of 40% in patients not receiving taxane-based chemotherapies compared with 15% in patients receiving taxane-based chemotherapies. These data highlight the importance of tracking chemotherapy protocols in exercise trials because they may influence the exercise response.
There were no exercise dose or type effects on chemotherapy completion rate. We previously reported that weight training improved chemotherapy completion rate compared with usual care in breast cancer patients receiving chemotherapy. It is possible that the addition of weight training did not improve chemotherapy completion in the CARE trial because of the marginal beneficial effects of aerobic exercise or because the chemotherapy protocols have changed. Nevertheless, the CARE data suggest that even higher volumes of aerobic or combined exercise do not interfere with breast cancer patients' ability to complete their chemotherapy.
Our detailed exercise adherence data provide important information for the design of future exercise trials and clinical interventions. Although both of the higher-dose exercise groups completed more exercise than the standard group, relative adherence to the frequency and volume (minutes) of aerobic exercise was higher for STAN compared with HIGH and COMB. Moreover, STAN and COMB achieved slightly better adherence to the intensity component of aerobic exercise than HIGH. Finally, COMB adhered better to their aerobic exercise prescription than strength exercise prescription because of the possibility of completing aerobic exercise at home. These relative adherence differences may partly explain the modest effects of our higher-dose exercise interventions, especially the COMB intervention, compared with the standard dose. Moreover, these differences also suggest that the higher-dose interventions are more challenging and may not achieve their full effects in clinical practice because of feasibility issues.
Our trial's strengths include the innovative design that simultaneously examined exercise dose and type effects, the clinical utility of these comparisons, the largest sample size to date, the well-defined population, the multicenter recruitment, the supervised exercise, the good adherence rates, the validated measures at multiple time points, and trivial loss-to-follow-up.
Limitations include the 41% recruitment rate, the demographically homogenous sample, the failure to collect data on decliners to determine selection biases and generalizability, and the adherence differences across groups that may have partly diluted the effects of the higher-dose interventions. Finally, given the 27 comparisons we made for the secondary patient-reported outcomes without adjustment for multiple testing, we would expect one or two false discoveries by chance if all of these comparisons were actually null.
In summary, a higher dose of aerobic or combined exercise compared with a standard dose of aerobic exercise did not dampen the impact of chemotherapy on patient-reported physical functioning as assessed by the SF-36 physical functioning subscale. The CARE Trial did demonstrate that higher doses of aerobic or combined exercise of up to 50 to 60 minutes per session are safe and feasible and do not interfere with chemotherapy completion or exacerbate any symptoms. Moreover, a higher dose of aerobic exercise curbs some of the negative impact of chemotherapy on aerobic fitness, patient-reported physical functioning, bodily pain, fatigue, and endocrine symptoms, whereas combined exercise improves muscular fitness and partly mitigates the worsening of endocrine symptoms. Additional exercise dose and type trials targeting these specific outcomes are warranted. Cancer care professionals can safely recommend higher doses of exercise during breast cancer chemotherapy in appropriately supervised settings.
Discussion
Neither HIGH nor COMB were superior to STAN for the primary outcome of the SF-36 physical functioning subscale. Previous trials have shown that aerobic exercise and resistance exercise are superior to no exercise for improving patient-reported physical functioning in cancer patients receiving treatments. It is possible that additional aerobic exercise or weight training does not provide further benefit to patient-reported physical functioning during breast cancer chemotherapy. It is also possible, however, that the SF-36 physical functioning subscale is not sensitive to higher volumes of exercise in breast cancer patients receiving chemotherapy because of irrelevant items or ceiling effects related to their younger age and higher functioning. The SF-36 physical functioning subscale includes several low-level functioning items that are common activities of daily living that are not likely problematic for most breast cancer patients or may be adequately addressed by standard aerobic exercise. The SF-36 physical functioning subscale may be more sensitive to lifestyle interventions in older cancer survivors with lower functioning. The optimal patient-reported physical functioning scale for exercise trials in cancer patients is still unclear.
HIGH was superior to STAN for the more comprehensive SF-36 measure, the physical component summary, and trended toward superiority for the cancer-specific trial outcome index–fatigue scale. These data suggest the possibility of a dose–response effect for aerobic exercise. The mean group differences of 1.6 on the physical component summary and 3.4 on the trial outcome index–fatigue scale fall below the suggested meaningful group differences of two to three points and five points, respectively; however, these modest effects were obtained over and above a standard aerobic exercise program. The comparison of higher-dose exercise programs with standard aerobic exercise provides the most rigorous test of the causal effects of exercise because it controls for the many nonexercise-related factors that may improve patient-reported outcomes, such as travel to the fitness center, interactions with the trainer or other participants, expectation of benefit, and cognitive dissonance.
Interestingly, HIGH even trended toward superiority over COMB for the SF-36 physical component summary scale, suggesting the possibility of an exercise type effect as well. It is unclear why additional aerobic exercise may have beneficial effects on patient-reported physical functioning but not additional weight training. It is possible that aerobic exercise better addresses central and leg fatigue, which may influence activities of daily living in breast cancer patients more so than upper-body (arm) fatigue. Previous trials in breast cancer survivors and lymphoma patients have found improvements in patient-reported physical functioning to be mediated by improved aerobic fitness.
HIGH was also superior to both STAN and COMB for bodily pain. Pain is a common symptom in breast cancer patients and is associated with anxiety, sleep disturbance, and poor quality of life. Few exercise trials in breast cancer patients have examined pain as an outcome. The mean group differences of 2.0 and 2.3 are within the suggested meaningful group differences of two to three points on SF-36 bodily pain scale. These results suggest both an exercise dose and type effect for aerobic exercise. Mechanisms for pain reduction from aerobic exercise may include endorphin production, weight loss, improved functioning, and mood.
Both HIGH and COMB were superior to STAN for managing endocrine symptoms. Endocrine symptoms are common and distressing in breast cancer patients, yet no previous exercise study has examined endocrine symptoms in breast cancer patients. Exercise may manage endocrine symptoms by increasing hypothalamic and peripheral β-endorphin production, which may stabilize the thermoregulatory center and reduce the risk of hot flashes. The endocrine symptom subscale has no minimal important difference, but the mean group differences of 2.5 and 2.2 translate into about 0.33 standard deviations. Our results suggest a dose–response effect of exercise regardless of exercise type. This finding may portend an even more powerful effect of exercise on endocrine symptoms when compared with no exercise and may be particularly important given the reluctance to prescribe hormone replacement therapy for menopausal symptoms in breast cancer patients.
Higher dose aerobic exercise partially blunted a substantial decline in maximal oxygen consumption in STAN and COMB by about 1.0mL/mg/kg or 3% to 4%. These declines, despite aerobic exercise training, are even larger than previously reported in our Supervised Trial of Aerobic versus Resistance Training (START). These differences may be the result of changing chemotherapy protocols. During the START Trial (2002 to 2005), about 30% of patients received taxane-based chemotherapies, whereas in the CARE Trial (2008 to 2011), 90% of patients received such therapies.
Weight training improved muscular fitness compared with the aerobic exercise groups by approximately 10% to 30%. Again, in the START Trial we found that a similar weight training protocol improved muscular strength by approximately 35% compared with no exercise. The more modest improvements in the CARE trial may be the result of the aerobic exercise comparison groups or the changing chemotherapy protocols. In subgroup analyses from the START Trial, we found a strength improvement of 40% in patients not receiving taxane-based chemotherapies compared with 15% in patients receiving taxane-based chemotherapies. These data highlight the importance of tracking chemotherapy protocols in exercise trials because they may influence the exercise response.
There were no exercise dose or type effects on chemotherapy completion rate. We previously reported that weight training improved chemotherapy completion rate compared with usual care in breast cancer patients receiving chemotherapy. It is possible that the addition of weight training did not improve chemotherapy completion in the CARE trial because of the marginal beneficial effects of aerobic exercise or because the chemotherapy protocols have changed. Nevertheless, the CARE data suggest that even higher volumes of aerobic or combined exercise do not interfere with breast cancer patients' ability to complete their chemotherapy.
Our detailed exercise adherence data provide important information for the design of future exercise trials and clinical interventions. Although both of the higher-dose exercise groups completed more exercise than the standard group, relative adherence to the frequency and volume (minutes) of aerobic exercise was higher for STAN compared with HIGH and COMB. Moreover, STAN and COMB achieved slightly better adherence to the intensity component of aerobic exercise than HIGH. Finally, COMB adhered better to their aerobic exercise prescription than strength exercise prescription because of the possibility of completing aerobic exercise at home. These relative adherence differences may partly explain the modest effects of our higher-dose exercise interventions, especially the COMB intervention, compared with the standard dose. Moreover, these differences also suggest that the higher-dose interventions are more challenging and may not achieve their full effects in clinical practice because of feasibility issues.
Our trial's strengths include the innovative design that simultaneously examined exercise dose and type effects, the clinical utility of these comparisons, the largest sample size to date, the well-defined population, the multicenter recruitment, the supervised exercise, the good adherence rates, the validated measures at multiple time points, and trivial loss-to-follow-up.
Limitations include the 41% recruitment rate, the demographically homogenous sample, the failure to collect data on decliners to determine selection biases and generalizability, and the adherence differences across groups that may have partly diluted the effects of the higher-dose interventions. Finally, given the 27 comparisons we made for the secondary patient-reported outcomes without adjustment for multiple testing, we would expect one or two false discoveries by chance if all of these comparisons were actually null.
In summary, a higher dose of aerobic or combined exercise compared with a standard dose of aerobic exercise did not dampen the impact of chemotherapy on patient-reported physical functioning as assessed by the SF-36 physical functioning subscale. The CARE Trial did demonstrate that higher doses of aerobic or combined exercise of up to 50 to 60 minutes per session are safe and feasible and do not interfere with chemotherapy completion or exacerbate any symptoms. Moreover, a higher dose of aerobic exercise curbs some of the negative impact of chemotherapy on aerobic fitness, patient-reported physical functioning, bodily pain, fatigue, and endocrine symptoms, whereas combined exercise improves muscular fitness and partly mitigates the worsening of endocrine symptoms. Additional exercise dose and type trials targeting these specific outcomes are warranted. Cancer care professionals can safely recommend higher doses of exercise during breast cancer chemotherapy in appropriately supervised settings.
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