Longitudinal associations of bioelectrical phase angle and fatigue in breast cancer patients.

Cancer-related fatigue is commonly treated in an undifferentiated manner, because its pathophysiology is still not well understood. Therefore, we investigated if bioelectrical phase angle (PhA), a non-invasive marker of cell integrity, could help to single out specific fatigue subtypes. In a randomized controlled strength training intervention trial, PhA was measured by bioelectrical impedance analysis in 158 breast cancer patients. Fatigue was assessed with the multidimensional 20-item Fatigue Assessment Questionnaire. Multiple regression analyses considering changes in PhA and fatigue from baseline to post-intervention and ANCOVA models investigating the strength training effect on PhA were conducted. Further, explorative mediation and moderation analyses were performed. Decrease (=worsening) in PhA was significantly associated with increase in physical (P = .010) and emotional (P = .019) fatigue. These associations were markedly stronger in patients with normal BMI (interaction P = .059 and .097) and with low pre-diagnosis exercise level (interaction P = .058 and .19). Among patients with normal BMI strength training was associated with an increase in PhA (ANCOVA P = .059), but not among overweight/obese patients (interaction P = .035). Chemotherapy was a major determinant for low PhA, but PhA did not mediate the effect of chemotherapy on fatigue. In conclusion, PhA has a significant inverse association with physical and emotional fatigue. This association is moderated by BMI and previous exercise. Significant relationships of PhA were also observed with chemotherapy and strength training. Thus, PhA might be a marker that could help in the classification of subtypes of fatigue with different pathophysiology, which may require specifically tailored treatment. Further research on this is warranted.

Muscle strength in breast cancer patients receiving different treatment regimes.

BACKGROUND: Muscle dysfunction and sarcopenia have been associated with poor performance status, an increased mortality risk, and greater side effects in oncologic patients. However, little is known about how performance is affected by cancer therapy. We investigated muscle strength in breast cancer patients in different adjuvant treatment settings and also compared it with data from healthy individuals. METHODS: Breast cancer patients (N = 255) from two randomized controlled exercise trials, staged 0-III and aged 54.4 ± 9.4 years, were categorized into four groups according to their treatment status. In a cross-sectional design, muscle function was assessed bilaterally by isokinetic dynamometry (0°, 60°, 180°/s) as maximal voluntary isometric contraction (MVIC) and maximal isokinetic peak torque (MIPT) in shoulder rotators and knee flexors and extensors. Additionally, muscular fatigue index (FI%) and shoulder flexibility were evaluated. Healthy women (N = 26), aged 53.3 ± 9.8 years, were tested using the same method. Analysis of covariance was used to estimate the impact of different cancer treatments on skeletal muscle function with adjustment for various clinical and socio-demographic factors. RESULTS: Consistently, lower muscle strength was measured in shoulder and knee strength in patients after chemotherapy. On average, patients had up to 25% lower strength in lower extremities and 12-16% in upper extremities in MVIC and MIPT during cancer treatment compared with healthy women. No substantial difference between patient groups in shoulder strength, but significantly lower shoulder flexibility in patients with radical mastectomy was measured. Chemotherapy-treated patients had consistently higher FI%. No serious adverse events were reported. CONCLUSIONS: Breast cancer patients showed markedly impaired muscle strength and joint dysfunctions before and after anticancer treatment. The significant differences between patients and healthy individuals underline the need of exercise therapy as early as possible in order to prevent or counteract the loss of muscle function after curative surgery as well as the consequences of neo-/adjuvant chemotherapy.

Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial.

PURPOSE: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. METHODS AND MATERIALS: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R(2) effect-size measures for mediation were calculated. RESULTS: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. CONCLUSIONS: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast cancer patients. This effect was counteracted by progressive resistance exercise training. Interleukin-6 and the IL-6/IL-1ra ratio seemed to mediate the beneficial effect of exercise on physical fatigue and pain but only to a small extent.

Factors influencing participation in a randomized controlled resistance exercise intervention study in breast cancer patients during radiotherapy.

BACKGROUND: Over the past years knowledge about benefits of physical activity after cancer is evolving from randomized exercise intervention trials. However, it has been argued that results may be biased by selective participation. Therefore, we investigated factors influencing participation in a randomized exercise intervention trial for breast cancer patients. METHODS: Non-metastatic breast cancer patients were systematically screened for a randomized exercise intervention trial on cancer-related fatigue. Participants and nonparticipants were compared concerning sociodemographic characteristics (age, marital status, living status, travel time to the training facility), clinical data (body-mass-index, tumor stage, tumor size and lymph node status, comorbidities, chemotherapy), fatigue, and physical activity. Reasons for participation or declination were recorded. RESULTS: 117 patients (52 participants, 65 nonparticipants) were evaluable for analysis. Multiple regression analyses revealed significantly higher odds to decline participation among patients with longer travel time (p=0.0012), living alone (p=0.039), with more comorbidities (0.031), previous chemotherapy (p=0.0066), of age≥70 years (p=0.025), or being free of fatigue (p=0.0007). No associations were found with BMI or physical activity. By far the most frequently reported reason for declination of participation was too long commuting time to the training facility. CONCLUSIONS: Willingness of breast cancer patients to participate in a randomized exercise intervention study differed by sociodemographic factors and health status. Neither current physical activity level nor BMI appeared to be selective for participation. Reduction of personal inconveniences and time effort, e.g. by decentralized training facilities or flexible training schedules, seem most promising for enhancing participation in exercise intervention trials. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01468766 (October 2011).

Exercise training intensity prescription in breast cancer survivors: validity of current practice and specific recommendations.

PURPOSE: Cancer survivors are recommended to perform 150 min/week of moderate or 75 min/week of vigorous aerobic exercise, but it remains unclear how moderate and vigorous intensities can be prescribed. Therefore, it was investigated whether and how intensity prescriptions for healthy adults by the American College of Sports Medicine (ACSM) need to be adapted for breast cancer survivors. METHODS: Fifty-two breast cancer survivors (stage 0-III, age 52 ± 9 years, BMI 25.4 ± 3.5 kg/m2) performed cardiopulmonary exercise tests at the end of primary therapy. Intensity classes defined as percentages of maximal heart rate (HRmax), heart rate reserve (HRR), and maximal oxygen uptake (VO2max) were compared to the ACSM's intensity classes using oxygen uptake reserve as reference. RESULTS: The prescriptions for moderate and vigorous exercise intensities were significantly different between breast cancer survivors and healthy adults when using VO2max (moderate 50-66 vs. 46-63 and vigorous 67-91 vs. 64-90% VO2max) or HRR (moderate 26-50 vs. 40-59 and vigorous 51-88 vs. 60-89 % HRR), but not when using HRmax (moderate 65-76 vs. 64-76 and vigorous 77-94 vs. 77-95% HRmax). CONCLUSIONS: In breast cancer survivors, intensity prescriptions for healthy adults result in considerably too intense training if HRR is used as guiding factor. Prescriptions using VO2max result in a slightly too low exercise intensity, whereas recommendations in percentages of HRmax appear valid. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors should not uncritically adopt exercise intensity prescriptions for healthy adults. Specific prescriptions for the studied population are provided.

Cardiorespiratory fitness in breast cancer patients undergoing adjuvant therapy.

PURPOSE: The aim of this work was to investigate cardiorespiratory fitness in breast cancer patients at different time points of anti-cancer treatment. PATIENTS AND METHODS: Non-metastatic breast cancer patients (n = 222, mean age 55 years) were categorized into four subgroups according to their treatment status. Cardiopulmonary exercise testing (CPET) was used to measure patients' cardiorespiratory fitness, including oxygen delivery and metabolic muscle function. Testing was performed by bicycle ergometry, and maximal oxygen uptake (VO2peak) was measured. Heart rate during exercise at 50 watts (HR50) was assessed as a cardiocirculatory parameter and ventilatory threshold (VT) was used as an indicator of the O2 supply to muscle. Analysis of covariance was used to estimate the impact of different cancer treatments on cardiorespiratory fitness with adjustment for clinical factors. RESULTS: Submaximal measures were successfully assessed in 220 (99%) and 200 (90%) patients for HR50 and VT, while criteria for maximal exercise testing were met by 176 patients (79%), respectively. The mean VO2peak was 20.6 ± 6.7 ml/kg/min, mean VT 10.7 ± 2.9 ml/min/kg and mean HR50 112 ± 16 beats/min. Chemotherapy was significantly associated with decreased VO2peak, with significantly lower adjusted mean VO2peak among patients post adjuvant chemotherapy compared to patients with no chemotherapy or those who just started chemotherapy regime (all p < 0.01). Patients post adjuvant chemotherapy reached only 63% of the VO2peak level expected for their age- and BMI-category (mean VO2peak 15.5 ± 4.8 ml/kg/min). Similarly, HR50 was significantly associated with treatment. However, VT was not associated with treatment. CONCLUSION: Breast cancer patients have marked and significantly impaired cardiopulmonary function during and after chemotherapy. Hereby, chemotherapy appears to impair cardiorespiratory fitness by influencing the oxygen delivery system rather than impacting metabolic muscle function. Our findings underline the need of exercise training in breast cancer patients to counteract the loss of cardiorespiratory fitness during the anti-cancer treatment.

Randomized controlled trial to evaluate the effects of progressive resistance training compared to progressive muscle relaxation in breast cancer patients undergoing adjuvant radiotherapy: the BEST study.

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common and distressing side effects of cancer and its treatment. During and after radiotherapy breast cancer patients often suffer from CRF which frequently impairs quality of life (QoL). Despite the high prevalence of CRF in breast cancer patients and the severe impact on the physical and emotional well-being, effective treatment methods are scarce.Physical activity for breast cancer patients has been reported to decrease fatigue, to improve emotional well-being and to increase physical strength. The pathophysiological and molecular mechanisms of CRF and the molecular-biologic changes induced by exercise, however, are poorly understood.In the BEST trial we aim to assess the effects of resistance training on fatigue, QoL and physical fitness as well as on molecular, immunological and inflammatory changes in breast cancer patients during adjuvant radiotherapy. METHODS/DESIGN: The BEST study is a prospective randomized, controlled intervention trial investigating the effects of a 12-week supervised progressive resistance training compared to a 12-week supervised muscle relaxation training in 160 patients with breast cancer undergoing adjuvant radiotherapy. To determine the effect of exercise itself beyond potential psychosocial group effects, patients in the control group perform a group-based progressive muscle relaxation training. Main inclusion criterion is histologically confirmed breast cancer stage I-III after lumpectomy or mastectomy with indication for adjuvant radiotherapy. Main exclusion criteria are acute infectious diseases, severe neurological, musculosceletal or cardiorespiratory disorders. The primary endpoint is cancer-related fatigue; secondary endpoints include immunological and inflammatory parameters analyzed in peripheral blood, saliva and urine. In addition, QoL, depression, physical performance and cognitive capacity will be assessed. DISCUSSION: The BEST study is the first randomized controlled trial comparing progressive resistance training with muscle relaxation training in breast cancer patients during adjuvant radiotherapy. Based on the analysis of physiological, immunological and inflammatory parameters it will contribute to a better understanding of the physiological and psychosocial effects and the biological mechanisms of resistance training. The ultimate goal is the implementation of optimized intervention programs to reduce fatigue, improve quality of life and potentially the prognosis after breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01468766.