Effect of Physical Exercise on MRI-Assessed Brain Perfusion in Chemotherapy-Treated Breast Cancer Patients: A Randomized Controlled Trial.

BACKGROUND: Exercise is a promising intervention to alleviate cognitive problems in breast cancer patients, but studies on mechanisms underlying these effects are lacking. PURPOSE: Investigating whether an exercise intervention can affect cerebral blood flow (CBF) in cognitively impaired breast cancer patients and to determine if CBF changes relate to memory function. STUDY TYPE: Prospective. POPULATION: A total of 181 chemotherapy-treated stage I-III breast cancer patients with cognitive problems and relatively low physical activity levels (≤150 minutes moderate to vigorous physical activity per week), divided into an exercise (N = 91) or control group (N = 90). FIELD STRENGTH/SEQUENCE: Two-dimensional echo planar pseudo-continuous arterial spin labeling CBF sequence at 3 T. ASSESSMENT: The 6-month long intervention consisted of (supervised) aerobic and strength training, 4 × 1 hour/week. Measurements at baseline (2-4 years post-diagnosis) and after 6 months included gray matter CBF in the whole brain, hippocampus, anterior cingulate cortex, and posterior cingulate cortex. Physical fitness and memory function were also assessed. Subgroup analyses were performed in patients with high fatigue levels at baseline. STATISTICAL TESTS: Multiple regression analyses with a two-sided alpha of 0.05 for all analyses. RESULTS: There was a significant improvement in physical fitness (VO2peak in mL/minute/kg) in the intervention group (N = 53) compared to controls (N = 51, ß = 1.47 mL/minute/kg, 95% CI: 0.44-2.50). However, no intervention effects on CBF were found (eg, whole brain: P = 0.565). Highly fatigued patients showed larger but insignificant treatment effects on CBF (eg, whole brain: P = 0.098). Additionally, irrespective of group, a change in physical fitness was positively associated with changes in CBF (eg, whole brain: ß = 0.75, 95% CI: 0.07-1.43). There was no significant relation between CBF changes and changes in memory performance. DATA CONCLUSION: The exercise intervention did not affect CBF of cognitively affected breast cancer patients. A change in physical fitness was associated with changes in CBF, but changes in CBF were not associated with memory functioning. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study.

INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.

Effects and moderators of exercise on muscle strength, muscle function and aerobic fitness in patients with cancer: a meta-analysis of individual patient data.

OBJECTIVE: To optimally target exercise interventions for patients with cancer, it is important to identify which patients benefit from which interventions. DESIGN: We conducted an individual patient data meta-analysis to investigate demographic, clinical, intervention-related and exercise-related moderators of exercise intervention effects on physical fitness in patients with cancer. DATA SOURCES: We identified relevant studies via systematic searches in electronic databases (PubMed, Embase, PsycINFO and CINAHL). ELIGIBILITY CRITERIA: We analysed data from 28 randomised controlled trials investigating the effects of exercise on upper body muscle strength (UBMS) and lower body muscle strength (LBMS), lower body muscle function (LBMF) and aerobic fitness in adult patients with cancer. RESULTS: Exercise significantly improved UBMS (ß=0.20, 95% Confidence Interval (CI) 0.14 to 0.26), LBMS (ß=0.29, 95% CI 0.23 to 0.35), LBMF (ß=0.16, 95% CI 0.08 to 0.24) and aerobic fitness (ß=0.28, 95% CI 0.23 to 0.34), with larger effects for supervised interventions. Exercise effects on UBMS were larger during treatment, when supervised interventions included ≥3 sessions per week, when resistance exercises were included and when session duration was >60 min. Exercise effects on LBMS were larger for patients who were living alone, for supervised interventions including resistance exercise and when session duration was >60 min. Exercise effects on aerobic fitness were larger for younger patients and when supervised interventions included aerobic exercise. CONCLUSION: Exercise interventions during and following cancer treatment had small effects on UBMS, LBMS, LBMF and aerobic fitness. Demographic, intervention-related and exercise-related characteristics including age, marital status, intervention timing, delivery mode and frequency and type and time of exercise sessions moderated the exercise effect on UBMS, LBMS and aerobic fitness.

Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy.

PURPOSE: Exercise has been shown to reduce fatigue during cancer treatment. Hypothesized mechanisms include inflammatory pathways. Therefore, we investigated effects of exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy. METHODS: We pooled data from two randomized controlled exercise intervention trials with breast cancer patients during adjuvant chemotherapy (n = 130), which had previously shown beneficial effects of exercise on fatigue. Exercise comprised a 12-week resistance training (BEATE study) or an 18-week combined resistance and aerobic training (PACT study). Serum IL-6, IL-1ra, and the IL-6/IL-1ra ratio were quantified at baseline, mid-intervention, post-intervention, and 6-9 months post-baseline. RESULTS: Mixed effect models showed significant increases in IL-6 and IL-6/IL-1ra ratio during chemotherapy and decreases afterwards. Differences between exercise and control group were not significant at any time point. Changes in total cancer-related fatigue were significantly correlated with changes in IL-6/IL-1ra ratio (partial correlation r = 0.23) and IL-6 (r = 0.21), and changes in physical cancer-related fatigue with changes in IL-6/IL-1ra ratio (r = 0.21). CONCLUSIONS: Changes in fatigue were slightly correlated with changes in inflammatory markers, and there was a strong inflammatory response to adjuvant chemotherapy. The supervised exercise training did not counteract this increase in inflammation, suggesting that beneficial effects of exercise on fatigue during adjuvant chemotherapy for breast cancer are not essentially mediated by IL-6, IL-1ra, or the IL-6/IL-1ra ratio.

Four-year effects of exercise on fatigue and physical activity in patients with cancer.

BACKGROUND: In the earlier randomized controlled Physical Activity during Cancer Treatment (PACT) study, we found beneficial effects of an 18-week supervised exercise program on fatigue in patients with newly diagnosed breast or colon cancer undergoing adjuvant treatment. The present study assessed long-term effects of the exercise program on levels of fatigue and physical activity 4 years after participation in the PACT study. METHODS: The original study was a two-armed, multicenter randomized controlled trial comparing an 18-week supervised exercise program to usual care among 204 breast cancer patients and 33 colon cancer patients undergoing adjuvant treatment. Of the 237 PACT participants, 197 participants were eligible and approached to participate in the 4-year post-baseline measurements, and 128 patients responded. We assessed fatigue and physical activity levels at 4 years post-baseline and compared this to levels at baseline, post-intervention (18 weeks post-baseline), and at 36 weeks post-baseline. RESULTS: Intention-to-treat mixed linear effects model analyses showed that cancer patients in the intervention group reported significantly higher moderate-to-vigorous total physical activity levels (141.46 min/week (95% confidence interval (CI) 1.31, 281.61, effect size (ES) = 0.22) after 4 years compared to the usual care group. Furthermore, cancer patients in the intervention group tended to experience less physical fatigue at 4 years post-baseline compared to the usual care group (- 1.13, 95% CI -2.45, 0.20, ES = 0.22), although the result was not statistically significant. CONCLUSION: Patients with breast or colon cancer who participated in the 18-week exercise intervention showed significant higher levels of moderate-to-vigorous total physical activity levels and a tendency towards lower physical fatigue levels 4 years post-baseline. Our result indicate that exercising during chemotherapy is a promising strategy for minimizing treatment-related side effects, both short and long term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571 , Dutch Trial Register NTR2138 . Trial registered on 9 December 2009.

Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial.

BACKGROUND: Exercise started shortly after breast cancer diagnosis might prevent or diminish fatigue complaints. The Physical Activity during Cancer Treatment (PACT) study was designed to primarily examine the effects of an 18-week exercise intervention, offered in the daily clinical practice setting and starting within 6 weeks after diagnosis, on preventing an increase in fatigue. METHODS: This multi-centre controlled trial randomly assigned 204 breast cancer patients to usual care (n = 102) or supervised aerobic and resistance exercise (n = 102). By design, all patients received chemotherapy between baseline and 18 weeks. Fatigue (i.e., primary outcome at 18 weeks), quality of life, anxiety, depression, and physical fitness were measured at 18 and 36 weeks. RESULTS: Intention-to-treat mixed linear model analyses showed that physical fatigue increased significantly less during cancer treatment in the intervention group compared to control (mean between-group differences at 18 weeks: -1.3; 95 % CI -2.5 to -0.1; effect size -0.30). Results for general fatigue were comparable but did not reach statistical significance (-1.0, 95%CI -2.1; 0.1; effect size -0.23). At 18 weeks, submaximal cardiorespiratory fitness and several muscle strength tests (leg extension and flexion) were significantly higher in the intervention group compared to control, whereas peak oxygen uptake did not differ between groups. At 36 weeks these differences were no longer statistically significant. Quality of life outcomes favoured the exercise group but were not significantly different between groups. CONCLUSIONS: A supervised 18-week exercise programme offered early in routine care during adjuvant breast cancer treatment showed positive effects on physical fatigue, submaximal cardiorespiratory fitness, and muscle strength. Exercise early during treatment of breast cancer can be recommended. At 36 weeks, these effects were no longer statistically significant. This might have been caused by the control participants' high physical activity levels during follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on December 9th, 2009.

Moderators of exercise effects on self-reported cognitive functioning in cancer survivors: an individual participant data meta-analysis.

PURPOSE: This individual participant data meta-analysis (IPD-MA) assesses exercise effects on self-reported cognitive functioning (CF) and investigates whether effects differ by patient-, intervention-, and exercise-related characteristics. METHODS: IPD from 16 exercise RCTs, including 1987 patients across multiple types of non-metastatic cancer, was pooled. A one-stage IPD-MA using linear mixed-effect models was performed to assess exercise effects on self-reported CF (z-score) and to identify whether the effect was moderated by sociodemographic, clinical, intervention- and exercise-related characteristics, or fatigue, depression, anxiety, and self-reported CF levels at start of the intervention (i.e., baseline). Models were adjusted for baseline CF and included a random intercept at study level to account for clustering of patients within studies. A sensitivity analysis was performed in patients who reported cognitive problems at baseline. RESULTS: Minimal significant beneficial exercise effects on self-reported CF (ß=-0.09 [-0.16; -0.02]) were observed, with slightly larger effects when the intervention was delivered post-treatment (n=745, ß=-0.13 [-0.24; -0.02]), and no significant effect during cancer treatment (n=1,162, ß=-0.08 [-0.18; 0.02]). Larger effects were observed in interventions of 12 weeks or shorter (ß=-0.14 [-0.25; -0.04]) or 24 weeks or longer (ß=-0.18 [-0.32; -0.02]), whereas no effects were observed in interventions of 12-24 weeks (ß=0.01 [-0.13; 0.15]). Exercise interventions were most beneficial when provided to patients without anxiety symptoms (ß=-0.10 [-0.19; -0.02]) or after completion of treatment in patients with cognitive problems (ß=-0.19 [-0.31; -0.06]). No other significant moderators were identified. CONCLUSIONS: This cross-cancer IPD meta-analysis observed small beneficial exercise effects on self-reported CF when the intervention was delivered post-treatment, especially in patients who reported cognitive problems at baseline. IMPLICATIONS FOR CANCER SURVIVORS: This study provides some evidence to support the prescription of exercise to improve cognitive functioning. Sufficiently powered trials are warranted to make more definitive recommendations and include these in the exercise guidelines for cancer survivors.

Fear of movement in cancer survivors: validation of the modified Tampa scale of kinesiophobia-fatigue.

OBJECTIVE: To date, there is no validated questionnaire to assess fear of movement in cancer survivors. We aim to validate the modified Tampa scale of kinesiophobia-fatigue (TSK-F) in Dutch cancer survivors participating in a rehabilitation programme. We first select the optimal model for cancer survivors. Subsequently, stability, internal consistency, and construct validity of the optimal model is tested. METHODS: A sample of 658 cancer survivors participating in a rehabilitation programme was included. Out of nine models derived in chronic pain and chronic fatigue patients, the optimal model of the TSK-F was selected in a calibration sample (n1 = 329) using confirmatory factor analysis. Stability of the derived optimal model was confirmed in a validation sample (n2 = 329). Internal consistency and construct validity were assessed in the full sample. RESULTS: The 11-item two-factor model of the TSK-F was the best-fitting model for cancer survivors and it seemed to be invariant for sex and cancer diagnosis. Internal consistency of the model was acceptable (Cronbach's alpha between 0.62 and 0.74). Construct validity was illustrated by significant associations between TSK-F total and TSK-F somatic focus with perceived global health status (EORTC-QOL-C30) and fatigue (FACT-F) (p<0.001). CONCLUSIONS: The adjusted 11-item TSK-F consisting of two subscales 'somatic focus' and 'activity avoidance' seems to be a robust and valid tool in measuring fear of movement in cancer survivors with an acceptable internal consistency. Further psychometric testing of the TSK-F in cancer survivors is recommended. In the future, TSK-F scores may be used to customise rehabilitation programmes in cancer survivors.

Role of fear of movement in cancer survivors participating in a rehabilitation program: a longitudinal cohort study.

OBJECTIVE: To study the relationship between fear of movement and perceived global health status and the role of rehabilitation with graded activity in cancer survivors. DESIGN: Longitudinal cohort study. SETTING: Rehabilitation centers. PARTICIPANTS: Cancer survivors (N=1236). INTERVENTION: Twelve-week graded activity rehabilitation program. MAIN OUTCOME MEASURES: Fear of movement (Modified Tampa Scale for Kinesiophobia-Fatigue), fatigue (Functional Assessment of Cancer Therapy-Fatigue), and perceived global health status (European Organisation Research and Treatment of Cancer Quality of Life Questionnaire C30) were measured at baseline and after rehabilitation. We performed multiple linear regression analyses to examine the association between fear of movement and perceived global health status at baseline. Differences between baseline and postintervention scores were assessed with a paired t test and effect sizes (ESs). Hierarchical multiple regression analyses were used to investigate whether changes in fear of movement were associated with perceived global health status. RESULTS: Fear of movement was associated with perceived global health status prior to rehabilitation (P=.001). Only participants with high scores on baseline fear of movement showed a considerable decrease in fear of movement after rehabilitation (ES=-.69; 95% confidence interval [CI], -.80 to -.57); the reduction was largest for fears because of a somatic focus (ES=-.57; 95% CI, -.68 to -.45). Changes in fear of movement because of a somatic focus were related to perceived global health status postintervention (P=.001). CONCLUSIONS: Fear of movement is associated with the perceived global health status of cancer survivors. Fear of movement decreases after rehabilitation with graded activity in high scorers on baseline fear of movement.

Physical Fitness and Chemotherapy Tolerance in Patients with Early-Stage Breast Cancer.

INTRODUCTION: An optimal relative dose intensity (RDI) of adjuvant chemotherapy is associated with better survival in patients with breast cancer. Little is known about the role of physical fitness in attaining an adequate RDI in patients with early-stage breast cancer. We investigated the association between pretreatment physical fitness and RDI in this population. METHODS: We pooled individual patient data from two randomized exercise trials that studied exercise programs in early breast cancer: the Physical Exercise During Adjuvant Chemotherapy Effectiveness Study (n = 230) and the Physical Activity during Chemotherapy Treatment (n = 204) study. Logistic regression models were used to evaluate the association between pretreatment fitness and achieving an optimal RDI (≥85%). In addition, we added an interaction term to the model to explore the potential moderating effect of participating in an exercise program. RESULTS: Data were available for 419 patients (mean age at diagnosis, 50.0 ± 8.6 yr). In the total sample, lower pretreatment physical fitness was associated with significantly lower odds of achieving ≥85% RDI: age-adjusted odds ratio (OR) of 0.66 (95% confidence interval (CI), 0.46-0.94). In patients allocated to the supervised exercise intervention during chemotherapy (n = 173), the association between pretreatment physical fitness and RDI was almost completely mitigated (OR, 0.95 (95% CI, 0.54-1.56)), whereas it was more pronounced in patients who received care as usual (n = 172; OR, 0.31 (95% CI, 0.13-0.63); Pinteraction = 0.022). CONCLUSIONS: Early-stage breast cancer patients with relatively lower levels of pretreatment physical fitness have lower odds of achieving an optimal dose of chemotherapy. Given that physical fitness is modifiable and our results suggest that following a moderate-to-high intensity exercise training during chemotherapy could improve treatment completion, clinicians should not refrain from referring patients to supportive exercise programs because of low fitness.

Loss of Paid Employment up to 4 Years after Colorectal Cancer Diagnosis-A Nationwide Register-Based Study with a Population-Based Reference Group.

Cancer survivors consider work as a key aspect of cancer survivorship while previous research indicated that cancer survivors have a higher risk of unemployment. The objectives were to assess: (1) whether colorectal cancer survivors less often have paid employment at diagnosis compared to a population-based reference group, (2) whether colorectal cancer survivors with paid work have a higher risk of loss of employment up to 4 years after diagnosis compared to a population-based reference group and (3) which colorectal cancer survivors are at highest risk of loss of paid employment. In a nationwide register-based study, persons diagnosed with colorectal cancer (N = 12,007) as registered in the Netherlands Cancer Registry, were compared on loss of paid employment with a sex and age-matched population-based reference group (N = 48,028) from Statistics Netherlands. Cox regression analyses were conducted. Colorectal cancer survivors had a higher risk of loss of paid employment (HR 1.56 [1.42, 1.71]). Within the group of colorectal cancer survivors, risk of loss of paid employment was lower for older survivors (>60 vs. 45-55) (HR 0.64 [0.51, 0.81]) and higher for those with a more advanced cancer stage (IV vs. I) (HR 1.89 [1.33, 2.70]) and those receiving radiotherapy (HR 1.37 [1.15, 1.63]). Colorectal cancer survivors at high risk of loss of paid employment may benefit from work support interventions as part of cancer survivorship.

Physical Activity during Cancer Treatment (PACT) Study: design of a randomised clinical trial.

BACKGROUND: Fatigue is a major problem of cancer patients. Thirty percent of cancer survivors report serious fatigue three years after finishing treatment. There is evidence that physical exercise during cancer treatment reduces fatigue. This may also lead to an improvement of quality of life. Such findings may result in a decrease of healthcare related expenditures and societal costs due to sick leave. However, no studies are known that investigated these hypotheses. Therefore, the primary aim of our study is to assess the effect of exercise during cancer treatment on reducing complaints of fatigue and on reducing health service utilisation and sick leave. METHODS/DESIGN: The Physical Activity during Cancer Treatment study is a multicentre randomised controlled trial in 150 breast and 150 colon cancer patients undergoing cancer treatment. Participants will be randomised to an exercise or a control group. In addition to the usual care, the exercise group will participate in an 18-week supervised group exercise programme. The control group will be asked to maintain their habitual physical activity pattern. Study endpoints will be assessed after 18 weeks (short term) and after 9 months (long term). Validated questionnaires will be used. PRIMARY OUTCOME: fatigue (Multidimensional Fatigue Inventory and Fatigue Quality List) and cost-effectiveness, health service utilisation and sick leave. Secondary outcome: health related quality of life (European Organisation Research and Treatment of Cancer-Quality of Life questionnaire-C30, Short Form 36 healthy survey), impact on functioning and autonomy (Impact on functioning and autonomy questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), physical fitness (aerobic peak capacity, muscle strength), body composition and cognitive-behavioural aspects. To register health service utilisation and sick leave, participants will keep diaries including the EuroQuol-5D. Physical activity level will be measured using the Short Questionnaire to Assess Health-Enhancing Physical Activity and will be monitored with an exercise log and a pedometer. DISCUSSION: This study investigates the (cost)-effectiveness of exercise during adjuvant treatment of patients with breast or colon cancer. If early physical exercise proves to be (cost) effective, establishing standardised physical exercise programmes during cancer treatment will be planned. TRIAL REGISTRATION: Current Controlled trials ISRCTN43801571, Dutch Trial Register NTR2138.

Socio-ecological correlates of physical activity in breast and colon cancer survivors 4 years after participation in a randomized controlled exercise trial (PACT study).

BACKGROUND: Having a physically active lifestyle after cancer diagnosis is beneficial for health, and this needs to be continued into survivorship to optimize long-term benefits. We found that patients, who participated in an 18-week exercise intervention, reported significant higher physical activity (PA) levels 4 years after participation in a randomized controlled trial of supervised exercise delivered during chemotherapy (PACT study). This study aimed to identify social-ecological correlates of PA levels in breast and colon cancer survivors 4 years after participation in the PACT study. METHODS: Self-reported PA levels and potential correlates (e.g. physical fitness, fatigue, exercise history, and built environment) were assessed in 127 breast and colon cancer survivors shortly after diagnosis (baseline), post-intervention and 4 years later. Multivariable linear regression analyses were performed to identify social-ecological correlates of PA 4 years post-baseline. RESULTS: The final model revealed that lower baseline physical fatigue (ß = -0.25, 95% CI -0.26; -0.24) and higher baseline total PA (0.06, 95% CI, 0.03; 0.10) were correlated with higher total PA levels 4 years post-baseline. Higher baseline leisure and sport PA (0.02, 95% CI 0.01; 0.03), more recreational facilities within a buffer of 1 km (4.05, 95% CI = 1.28; 6.83), lower physical fatigue at 4-year follow-up (-8.07, 95% CI -14.00; -2.13), and having a positive change in physical fatigue during the intervention period (0.04, 95% CI 0.001; 0.07) were correlates of sport and leisure PA levels 4 years post-baseline. CONCLUSIONS: This study suggests that baseline and 4-year post-baseline physical fatigue, and past exercise behaviour, were significant correlates of PA 4 years after participation in an exercise trial. Additionally, this study suggests that the built environment should be taken into account when promoting PA. Understanding of socio-ecological correlates of PA can provide insights into how future exercise interventions should be designed to promote long-term exercise behaviour. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on 9 December 2009, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2138.

Moderators of Exercise Effects on Cancer-related Fatigue: A Meta-analysis of Individual Patient Data.

PURPOSE: Fatigue is a common and potentially disabling symptom in patients with cancer. It can often be effectively reduced by exercise. Yet, effects of exercise interventions might differ across subgroups. We conducted a meta-analysis using individual patient data of randomized controlled trials (RCT) to investigate moderators of exercise intervention effects on cancer-related fatigue. METHODS: We used individual patient data from 31 exercise RCT worldwide, representing 4366 patients, of whom 3846 had complete fatigue data. We performed a one-step individual patient data meta-analysis, using linear mixed-effect models to analyze the effects of exercise interventions on fatigue (z score) and to identify demographic, clinical, intervention- and exercise-related moderators. Models were adjusted for baseline fatigue and included a random intercept on study level to account for clustering of patients within studies. We identified potential moderators by testing their interaction with group allocation, using a likelihood ratio test. RESULTS: Exercise interventions had statistically significant beneficial effects on fatigue (ß = -0.17; 95% confidence interval [CI], -0.22 to -0.12). There was no evidence of moderation by demographic or clinical characteristics. Supervised exercise interventions had significantly larger effects on fatigue than unsupervised exercise interventions (ßdifference = -0.18; 95% CI -0.28 to -0.08). Supervised interventions with a duration ≤12 wk showed larger effects on fatigue (ß = -0.29; 95% CI, -0.39 to -0.20) than supervised interventions with a longer duration. CONCLUSIONS: In this individual patient data meta-analysis, we found statistically significant beneficial effects of exercise interventions on fatigue, irrespective of demographic and clinical characteristics. These findings support a role for exercise, preferably supervised exercise interventions, in clinical practice. Reasons for differential effects in duration require further exploration.

Attendance and compliance with an exercise program during localized breast cancer treatment in a randomized controlled trial: The PACT study.

PURPOSE: Maintaining high adherence rates (session attendance and compliance) in exercise programs during breast cancer treatment can be challenging. We aimed to identify adherence rates and predictors to an exercise program during adjuvant breast cancer treatment. METHODS: Ninety-two patients with localized breast cancer undergoing chemotherapy were randomly assigned to an 18-week supervised moderate-to-high intensity aerobic and resistance exercise program, including two 1-hour sessions/week. Additionally, participants were asked to be physically active for at least 30 minutes/day on at least three other days. We report median percentages for attendance, compliance with the prescribed duration and intensity of aerobic and muscle strength exercises, and the exercise advice given. Predictors included in univariate and multivariable linear regression models were demographical, tumor- and treatment-related factors, constructs of the theory of planned behavior, psychological and physical factors. RESULTS: Patients attended 83% (interquartile range: 69-91%) of the supervised sessions. Compliance with the duration of aerobic exercise, high-intensity aerobic exercise (cycling at the ventilatory threshold), muscle strength exercises and the exercise advice were 88%(64-97%), 50%(22-82%), 84%(65-94%) and 61%(33%-79%), respectively. Education, radiotherapy, BMI and physical fatigue were important predictors of adherence to supervised exercise. Beliefs about planned behaviors were important predictors, especially for compliance with the exercise advice. CONCLUSIONS: Attendance to and compliance with an 18-week aerobic and strength exercise program were high. The lowest compliance was found for high-intensity supervised aerobic exercise. The identified predictors should be considered when designing or adapting exercise programs for patients with localized breast cancer to increase adherence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571 Dutch Trial Register NTR2138.

Effect of physical exercise on cognitive function and brain measures after chemotherapy in patients with breast cancer (PAM study): protocol of a randomised controlled trial.

INTRODUCTION: After treatment with chemotherapy, many patients with breast cancer experience cognitive problems. While limited interventions are available to improve cognitive functioning, physical exercise showed positive effects in healthy older adults and people with mild cognitive impairment. The Physical Activity and Memory study aims to investigate the effect of physical exercise on cognitive functioning and brain measures in chemotherapy-exposed patients with breast cancer with cognitive problems. METHODS AND ANALYTICS: One hundred and eighty patients with breast cancer with cognitive problems 2-4 years after diagnosis are randomised (1:1) into an exercise intervention or a control group. The 6-month exercise intervention consists of twice a week 1-hour aerobic and strength exercises supervised by a physiotherapist and twice a week 1-hour Nordic or power walking. The control group is asked to maintain their habitual activity pattern during 6 months. The primary outcome (verbal learning) is measured at baseline and 6 months. Further measurements include online neuropsychological tests, self-reported cognitive complaints, a 3-tesla brain MRI, patient-reported outcomes (quality of life, fatigue, depression, anxiety, work performance), blood sampling and physical fitness. The MRI scans and blood sampling will be used to gain insight into underlying mechanisms. At 18 months online neuropsychological tests, self-reported cognitive complaints and patient-reported outcomes will be repeated. ETHICS AND DISSEMINATION: Study results may impact usual care if physical exercise improves cognitive functioning for breast cancer survivors. TRIAL REGISTRATION NUMBER: NTR6104.

Targeting Exercise Interventions to Patients With Cancer in Need: An Individual Patient Data Meta-Analysis.

Background: Exercise effects in cancer patients often appear modest, possibly because interventions rarely target patients most in need. This study investigated the moderator effects of baseline values on the exercise outcomes of fatigue, aerobic fitness, muscle strength, quality of life (QoL), and self-reported physical function (PF) in cancer patients during and post-treatment. Methods: Individual patient data from 34 randomized exercise trials (n = 4519) were pooled. Linear mixed-effect models were used to study moderator effects of baseline values on exercise intervention outcomes and to determine whether these moderator effects differed by intervention timing (during vs post-treatment). All statistical tests were two-sided. Results: Moderator effects of baseline fatigue and PF were consistent across intervention timing, with greater effects in patients with worse fatigue (Pinteraction = .05) and worse PF (Pinteraction = .003). Moderator effects of baseline aerobic fitness, muscle strength, and QoL differed by intervention timing. During treatment, effects on aerobic fitness were greater for patients with better baseline aerobic fitness (Pinteraction = .002). Post-treatment, effects on upper (Pinteraction < .001) and lower (Pinteraction = .01) body muscle strength and QoL (Pinteraction < .001) were greater in patients with worse baseline values. Conclusion: Although exercise should be encouraged for most cancer patients during and post-treatments, targeting specific subgroups may be especially beneficial and cost effective. For fatigue and PF, interventions during and post-treatment should target patients with high fatigue and low PF. During treatment, patients experience benefit for muscle strength and QoL regardless of baseline values; however, only patients with low baseline values benefit post-treatment. For aerobic fitness, patients with low baseline values do not appear to benefit from exercise during treatment.

Cost-effectiveness analysis of an 18-week exercise programme for patients with breast and colon cancer undergoing adjuvant chemotherapy: the randomised PACT study.

OBJECTIVE: Meta-analyses show that exercise interventions during cancer treatment reduce cancer-related fatigue. However, little is known about the cost-effectiveness of such interventions. Here we aim to assess the cost-effectiveness of the 18-week physical activity during cancer treatment (PACT) intervention for patients with breast and colon cancer. The PACT trial showed beneficial effects for fatigue and physical fitness. DESIGN: Cost-effectiveness analyses with a 9-month time horizon (18 weeks of intervention and 18 weeks of follow-up) within the randomised controlled multicentre PACT study. SETTING: Outpatient clinics of 7 hospitals in the Netherlands (1 academic and 6 general hospitals) PARTICIPANTS: 204 patients with breast cancer and 33 with colon cancer undergoing adjuvant treatment including chemotherapy. INTERVENTION: Supervised 1-hour aerobic and resistance exercise (twice per week for 18 weeks) or usual care. MAIN OUTCOME MEASURES: Costs, quality-adjusted life years (QALY) and the incremental cost-effectiveness ratio. RESULTS: For colon cancer, the cost-effectiveness analysis showed beneficial effects of the exercise intervention with incremental costs savings of €4321 and QALY improvements of 0.03. 100% of bootstrap simulations indicated that the intervention is dominant (ie, cheaper and more effective). For breast cancer, the results did not indicate that the exercise intervention was cost-effective. Incremental costs were €2912, and the incremental effect was 0.01 QALY. At a Dutch threshold value of €20 000 per QALY, the probability that the intervention is cost-effective was 2%. CONCLUSIONS: Our results suggest that the 18-week exercise programme was cost-effective for colon cancer, but not for breast cancer. TRIAL REGISTRATION NUMBER: ISRCTN43801571.

Effects and moderators of exercise on quality of life and physical function in patients with cancer: An individual patient data meta-analysis of 34 RCTs.

This individual patient data meta-analysis aimed to evaluate the effects of exercise on quality of life (QoL) and physical function (PF) in patients with cancer, and to identify moderator effects of demographic (age, sex, marital status, education), clinical (body mass index, cancer type, presence of metastasis), intervention-related (intervention timing, delivery mode and duration, and type of control group), and exercise-related (exercise frequency, intensity, type, time) characteristics. Relevant published and unpublished studies were identified in September 2012 via PubMed, EMBASE, PsycINFO, and CINAHL, reference checking and personal communications. Principle investigators of all 69 eligible trials were requested to share IPD from their study. IPD from 34 randomised controlled trials (n=4519 patients) that evaluated the effects of exercise compared to a usual care, wait-list or attention control group on QoL and PF in adult patients with cancer were retrieved and pooled. Linear mixed-effect models were used to evaluate the effects of the exercise on post-intervention outcome values (z-score) adjusting for baseline values. Moderator effects were studies by testing interactions. Exercise significantly improved QoL (ß=0.15, 95%CI=0.10;0.20) and PF (ß=0.18, 95%CI=0.13;0.23). The effects were not moderated by demographic, clinical or exercise characteristics. Effects on QoL (ßdifference_in_effect=0.13, 95%CI=0.03;0.22) and PF (ßdifference_in_effect=0.10, 95%CI=0.01;0.20) were significantly larger for supervised than unsupervised interventions. In conclusion, exercise, and particularly supervised exercise, effectively improves QoL and PF in patients with cancer with different demographic and clinical characteristics during and following treatment. Although effect sizes are small, there is consistent empirical evidence to support implementation of exercise as part of cancer care.

Effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of cancer-related fatigue: A meta-analysis.

Cancer-related fatigue has a multidimensional nature and complaints typically increase during adjuvant treatment for breast cancer. Physical exercise might prevent or reduce cancer-related fatigue. So far, no meta-analysis has investigated the effects of physical exercise on different dimensions of fatigue. The aim of the present meta-analysis was to investigate the effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of fatigue. We performed a systematic literature search in PubMed, Embase and the Cochrane Library in June 2015. Randomised controlled trials reporting the effects of physical exercise during adjuvant breast cancer treatment on different dimensions of fatigue were included. Pooled effects of 6 exercise programmes (including 784 patients) showed significant beneficial exercise effects on general fatigue (ES: -0.22, 95% CI -0.38; -0.05) and physical fatigue (ES: -0.35, 95% CI -0.49; -0.21). Effects on fatigue subscales 'reduced activity' (ES: -0.22, 95% CI -0.38; -0.05) and 'reduced motivation' (ES: -0.18, 95% CI -0.35; -0.01) were also in favour of physical exercise. No effects were found on cognitive and affective fatigue. Including only the supervised exercise programmes (n=4 studies), slightly larger pooled effect estimates were found on general fatigue (ES: -0.25, 95% CI -0.47; -0.04) and physical fatigue (-0.39, 95% CI -0.56; -0.23). In conclusion, physical exercise during adjuvant breast cancer treatment has beneficial effects on general fatigue, physical fatigue, 'reduced activity' and 'reduced motivation', but did not show effects on cognitive and affective fatigue. Largest effect sizes are found for physical fatigue, suggesting that this is the fatigue dimension most sensitive to physical exercise.