Search Weight Loss Topics:

Home » Uncategorized » Supervised, structured and individualized exercise in metastatic breast cancer: a randomized controlled trial – Nature.com

Study design and participants

The PREFERABLE-EFFECT study design and methods have been published previously, and the full protocol is provided in the Supplementary information37. In brief, this multinational randomized controlled trial was undertaken at eight hospitals and study centers in Germany, the Netherlands, Poland, Spain, Sweden and Australia.

Eligible patients were 18years of age or older, diagnosed with stage IV breast cancer, had an Eastern Cooperative Oncology Group performance status of 2, and were able and willing to participate in the exercise program and wear an activity tracker. Exclusion criteria were unstable bone metastases as determined by the local treating physician; untreated symptomatic brain metastases; estimated life expectancy of <6months; serious active infection; excessive physical activity (>210min per week of moderate-intensity to vigorous-intensity exercise) or current participation in an exercise training program comparable to the EFFECT exercise program; severe neurologic or cardiac impairment according to the ACSM criteria38; uncontrolled severe respiratory insufficiency or dependency on oxygen supplementation at rest or during exercise; uncontrolled severe pain; any other contraindications for exercise; any circumstances that would impede adherence to study requirements or the ability to give informed consent; or pregnancy. Patients were enrolled regardless of sex, which was collected according to the identity information provided by the patients. Patients were recruited by their clinical care or study teams or through social media (for example, national patient organizations). Medical eligibility criteria were assessed by a physician at the treating hospital.

The study was conducted in accordance with standards of good clinical practice and the Declaration of Helsinki. The study was approved by the institutional review board of the University Medical Center Utrecht, the Netherlands (19-524/M), and by the local ethical review boards of all participating institutions. The study was registered with ClinicalTrials.gov on 9 October 2019 (NCT04120298). All patients provided written informed consent before enrollment.

Patients who met the eligibility criteria and provided informed consent were randomly assigned (1:1), after completion of the baseline measurements, to participate in a 9-month structured and individualized exercise program in addition to usual care (exercise group) or to receive general physical activity advice in addition to usual care, but no structured exercise program (control group). All participants received an activity tracker. Randomization was performed centrally using a blocked computer-generated sequence and was stratified by study center and therapy line (first-line or second-line vs. third-line treatment or a later line of treatment). Owing to the nature of the intervention, participants, local clinicians and study nurses, and investigators were not blinded to group assignment after randomization.

A 9-month structured and individualized exercise program was offered to participants randomized to the exercise group. Details of the exercise program have been published elsewhere37. In brief, the exercise program included supervised, multimodal exercise sessions of 1h, two times per week for the first 6months. For the last 3months, one supervised session was replaced by one unsupervised session. Supervision was performed by qualified exercise professionals (for example, physiotherapists and exercise physiologists) in a community-based or hospital-based fitness center, or a physical therapy practice close to the participants home address. In addition to the in-person supervised exercise sessions, we offered live remote exercise sessions to participants using videoconferencing software (Zoom) if training facilities were closed owing to local COVID-19 regulations or if previously enrolled participants felt unsafe exercising at a local training facility because of the COVID-19 threat.

The multimodal exercise program consisted of resistance, aerobic and balance exercises (Extended Data Table 6). Resistance exercise intensity was individualized using 12-repetition maximum muscle strength testing. For participants with bone metastases, 12-repetition maximum testing was not performed for exercises that loaded the parts of the skeleton with bone metastases (see Extended Data Table 7). During the exercise sessions, resistance exercises that loaded the affected region were either omitted or performed according to the start low (that is, low weight and more repetitions), go slow (that is, gradual increase) principle25, depending on patient characteristics and the experience of the involved exercise professional. Aerobic exercise intensity was tailored to the participants fitness levels using the maximal short exercise capacity (MSEC) and estimated peak power output (Wpeak) with the steep ramp test at baseline. The intensity of both the aerobic and resistance exercises gradually increased during the exercise program; however, the intensity was continuously adjusted, depending on the health status of the participant and the participant's perceived exertion.

In addition to the supervised exercise program, participants were encouraged to be physically active for at least 30min per day on all remaining days of the week. To support this, participants received an activity tracker (that is, Fitbit Inspire HR) and an exercise app specifically designed for the PREFERABLE-EFFECT study. The app included exercises that participants learned during the supervised exercise program and that could be performed at home. All exercises were illustrated with simple animations and contained clear instructions (see Supplementary Fig. 1 for screenshots of the app). The exercise app was also used to support the unsupervised sessions during the last 3months of the intervention period.

Participants randomized to the control group received care as usual, supplemented with written information on the current physical activity guidelines (that is, 150min of aerobic exercise and resistance exercise two to three times per week). They were advised to avoid inactivity and to be as physically active as their health status allowed11. They also received an activity tracker and an explanation of the basic functions of the tracker. The control group did not receive a structured exercise intervention, as this is not yet part of routine care.

All participants visited the study center for measurements at baseline, and at 3 and 6months post baseline. This included the assessment of functional performance and physical fitness. At all visits as well as at 9months post baseline, PROs were assessed using online questionnaires. Participants were asked to complete them without conferring with others. For participants undergoing intravenous chemotherapy, the measurements took place at least 3days after chemotherapy administration. PROs, including HRQOL and fatigue, were assessed using the EORTC QLQ-C30 and the EORTC QLQ-FA12, respectively39,40. The QLQ-C30 is a 30-item questionnaire, including a global HRQOL score, five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea and vomiting, and pain) and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). A summary HRQOL score can be calculated using 13 subscales, excluding the global QOL and financial difficulties items41. The QLQ-FA12 is a 12-item questionnaire that assesses different dimensions of fatigue (physical, emotional, cognitive and total fatigue). For both EORTC questionnaires, scores range from 0 to 100. For the summary score, global QOL score and functional scales, higher scores indicate a higher HRQOL or a higher function, whereas for symptom scales, higher scores indicate a greater symptom burden. To assess higher levels of physical functioning, four items from the EORTC questionnaire item bank were added to the physical function scale (see Supplementary Table 2). Subsequently, a domain-specific T-score was calculated for physical functioning using EORTC software. This T-score reflects the score of the participant relative to an age-matched and a gender-matched European reference population, with 50 representing average physical functioning.

Self-reported physical activity levels were assessed using a modified version of the GodinShephard Leisure-Time Exercise Questionnaire42,43. The Godin questionnaire is a four-item questionnaire that includes questions about the average frequency and duration of mild-, moderate- and vigorous-intensity aerobic exercise and resistance exercise in bouts of at least 10min performed during leisure time in a typical week. In addition, the Fitbit Inspire HR was used to measure daily step count and minutes of physical activity (that is, minutes per day being sedentary or lightly, fairly or very active, as classified by the FitBit software), throughout the study period. For Fitbit data, only data were used for participants who had >4 valid wear days (defined as 10h of activity registration) around the measurement timepoints (that is, baseline and 3, 6 and 9months post baseline).

As a measure of physical fitness, the MSEC was assessed with the steep ramp test using a cycle ergometer44. After 3min of unloaded cycling, the test started at 25W and was increased by 2.5Ws1 or 25W per 10s, depending on the available settings of the cycle ergometer used, until exhaustion. Participants were instructed to cycle between 70 and 90r.p.m. The test ended when the cycling cadence dropped below 60r.p.m. or when the participant experienced pain or discomfort. After termination, the participant was asked to continue cycling at an easy cadence and with minimal load to promote recovery. The outcome was recorded as the highest achieved output in W and is referred to as the MSEC. From the MSEC, peak power output (Wpeak) was estimated using a regression equation45. Before physical fitness testing, resting heart rate and blood pressure were measured for safety reasons.

Body weight and height were measured in light clothing without shoes. Demographic and clinical data were extracted from questionnaires and medical records, respectively. Adherence to the supervised exercise program was recorded by the exercise professional in a case report form. Safety was assessed by the reporting of AEs and SAEs related to exercise or physical fitness testing. Participants in both groups were asked by the study personnel about exercise-related and physical fitness testing-related AEs and SAEs in a standardized manner during all follow-up visits. In addition, for participants allocated to the exercise group, the exercise professionals assessed any potential exercise-related AEs and SAEs that had occurred since the previous exercise session or during the current session and recorded this on standardized training documentation forms.

Adherence to the supervised exercise program was measured in terms of attendance and compliance. Attendance rates were computed as the number of supervised exercise sessions attended divided by the number of sessions offered. Compliance rates were calculated as the number of supervised exercise sessions in which participants performed all prescribed balance, resistance and aerobic exercises, divided by the number of sessions prescribed.

The study had two primary outcomes: HRQOL and cancer-related physical fatigue, which were assessed using the summary score of the QLQ-C30 and the physical fatigue dimension of the QLQ-FA12, respectively. We assessed the primary outcomes at the fully supervised intervention period (that is, at 6months) and defined the period from 6 to 9months as the maintenance period.

Secondary outcomes reported in this paper include the primary outcomes assessed at 3 and 9months, as well as a range of other variables: the QLQ-C30 global QOL score, and all other QLQ-C30 function and symptom scales and single items, all other QLQ-FA12 fatigue dimensions, self-reported and measured physical activity, and the MSEC.

The study included pre-planned modifier analyses for the following covariates: age (<50 vs. 50 years), baseline fatigue levels (QLQ-C30 fatigue scale score of <39 vs. 39)16, baseline depression levels (PHQ-4 depression subscore of <3 vs. 3), history of psychological disorders (any report vs. none), baseline insomnia (PSQI global score of 04, 58 or 9), baseline body mass index (<25 vs. 25 and <30 vs. 30), baseline fitness level (MSEC, continuous), type of therapy (chemotherapy vs. other), type of metastasis at baseline (bone only vs. mixed (visceral and non-visceral) vs. non-visceral only) and primary tumor receptor status (triple-negative vs. human epidermal growth factor receptor 2 (HER2)-positive vs. HER2-negative and hormone receptor-positive). In addition, the following subgroup analyses were prespecified: female patients only, all patients excluding those who never started the exercise program or dropped out within a month, all patients excluding those who did not adhere to the exercise program (that is, attendance of <80% of scheduled exercise sessions), all patients excluding those who began chemotherapy (intravenous or oral) between baseline and 6months post baseline. A subgroup analysis based on baseline pain levels (QLQ-C30 pain scale score of <25 vs. 25)16 was not prespecified but became of interest during the study.

An improvement in either or both primary outcomes in the exercise group from baseline to 6months post baseline relative to the control group was of primary relevance. Based on a pooled analysis of six randomized controlled exercise trials in patients with breast cancer receiving adjuvant treatment, we anticipated an ES of 0.35(ref. 46). With n=139 patients per group (n=278 in total), a mean standardized ES of at least 0.35 could be detected with a power of at least 78% or 82% at a nominal two-sided significance level of 2.5% for each outcome separately using an analysis of covariance adjusted for baseline values of the outcome variable, assuming a correlation between pre-invervention and post-intervention levels of =0.3 or =0.4, respectively47. To account for a potential drop-out rate of approximately 20%, the target sample size was 350 participants (n=175 per study arm).

A statistical analysis plan was written before the analysis was performed and included in the study protocol. Descriptive statistics were used to characterize the study population at baseline. Questionnaire scores were calculated according to published scoring manuals. All primary analyses were performed according to the intention-to-treat principle. For the primary outcomes, linear mixed-effects models were used to assess exercise effects on physical fatigue and HRQOL separately while taking the hierarchical structure of the data into account. Models were adjusted for the baseline value of the outcome and stratification factors (that is, center and therapy line) and included participants for whom the outcome was observed at two or more timepoints. Models with different covariance structures were compared on the basis of Akaikes information criterion. Modeling assumptions were examined and met. The same approach was used for the analysis of secondary outcomes.

Cohens standardized ESs were calculated by dividing the adjusted BGD of the 3-month, 6-month and 9-month post-intervention means by the pooled standard deviation at baseline. For the primary outcome, a two-tailed BonferroniHolm-adjusted P value was calculated to indicate statistical significance. For all secondary outcomes, ESs and 95% CIs are reported without P values. These confidence intervals are intended to express precision of the effect estimate and should not be used to infer statistical significance, as they do not account for multiple comparisons.

Prespecified intervention effect modifiers were individually added to the model as a covariate main effect and interaction effect with group allocation. Covariates that appeared to be intervention effect modifiers (Pinteraction0.10) gave rise to subgroup analyses. Prespecified subgroup analyses were performed, irrespective of interaction effects, to assess whether the intervention effect was consistent across subgroups. All modifier and subgroup analyses were treated as exploratory.

Missing values of the primary outcome variables as well as all other PROs were considered as missing at random and dealt with using linear mixed-effects models. A sensitivity analysis, using multiple imputation (m=100, R package MICE)48, was carried out to explore potential bias and demonstrate the robustness of our results.

All statistical analyses were performed using R v4.2.2.

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Here is the original post:
Supervised, structured and individualized exercise in metastatic breast cancer: a randomized controlled trial - Nature.com

Your Full Name
Your Email
Your Phone Number
Select your age (30+ only)	30313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120
Select Your US State	Select Your StateAlabamaAlaskaArizonaArkansasCaliforniaColoradoConnecticutDelawareFloridaGeorgiaHawaiiIdahoIllinoisIndianaIowaKansasKentuckyLouisianaMaineMarylandMassachusettsMichiganMinnesotaMississippiMissouriMontanaNebraskaNevadaNew HampshireNew JerseyNew MexicoNew YorkNorth CarolinaNorth DakotaOhioOklahomaOregonPennsylvaniaRhode IslandSouth CarolinaSouth DakotaTennesseeTexasUtahVermontVirginiaWashingtonWashington,DCWest VirginiaWisconsinWyoming
Program Choice	Select Your ProgramInjectable HGHInjectable TestoteroneInjectable SermorelinInjectable Weight LossInjectable HCG DietInjectable Vitamins
Confirm over 30 years old	Yes
Confirm that you resident in USA	Yes
This is a Serious Inquiry	Yes
Message:

Home » Uncategorized » Supervised, structured and individualized exercise in metastatic breast cancer: a randomized controlled trial – Nature.com