Aim and objectives
The overall aim of the study is to examine if MBI can improve cognitive functioning and quality of life for cancer patients after chemotherapy.
The objectives are as follows:
- Investigate whether MBI improves cognitive functioning in comparison with both control conditions;
- Determine the differences in both structural and functional changes in the brain within (longitudinal) and between the groups; and
- Explore whether changes in behavioral, psychological and biological outcomes, are associated with improvements in cognitive functioning.
Our hypotheses are:
- Both MBI and the physical training (active control condition) improve cognitive impairment compared to the TAU-control condition.
- MBI is more effective than the active control condition for improving cognitive impairment.
- A mechanistic difference will exist between MBI and the active control condition based on brain imaging. More specifically, we expect a stronger impact in the salience and dorsal attention networks, the frontoparietal network and default mode network. These networks have been associated before with aspects of cognitive changes after chemotherapy treatment.
This is a single-centre RCT with three study-arms and stratified random allocation. Participants in the control condition will receive care from the treatment centre as usual, participants in the intervention groups will receive MBI or a physical training as well as their usual care. The intervention format is equivalent in both intervention conditions. Study evaluation will be done by comparing within and between the 3 groups. The potential effect will be assessed on a series of outcome measures. Measurements will take place at baseline (i.e. 1 to 3 weeks before randomization), 1 to 3 weeks after the intervention and 3 months after the intervention. Participants are allowed to withdraw without giving a reason at any time. There will be no follow-up assessments of these participants. The development of the study protocol followed the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (29). The planned flow diagram of this trial is presented in Figure 1. The protocol is reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT; Fig. 2 and additional file 1). This study was approved by the Medical Ethics Committee of UZ/KU Leuven on 9th July 2018 (S59396). This study was registered with ClinicalTrials.gov (NCT03736460) on 8th November 2018.
Participants will be included if they had a diagnosis of breast cancer at an early stage with or without solitary metastases (except solitary brain metastases), and completed their treatment (surgery and chemotherapy) minimum 6 months and maximum 5 years before. Participants have significant cognitive complaints as measured by the Cognitive Failure questionnaire (CFQ total score > mean study Ponds + 1 SD or on 2 or more of the CFQ extra questions (T/E) > mean study Ponds + 1 SD; (30)), are between 18 and 65 years old, and have sufficient understanding of Dutch.
Patients with a history of mental retardation, psychiatric and or neurological disorder will be excluded. Patients will also be excluded if they report a previous participation in a mindfulness-based training or have a regular meditation practice.
Setting and recruitment process
Recruitment will take place in the multidisciplinary breast cancer centre (MBC), UZ Leuven. Patients will be identified through the outpatient database and study eligibility determined using medical records. Potential candidates will receive a letter with a general outline of the study and will be contacted by phone in order to evaluate their interest. Patients that are interested will be sent the informed consent and the Cognitive Failure Questionnaire (CFQ). The researcher will follow up by phone to answer any questions related to the study. Only patients with a total score > mean study Ponds + 1 SD will be recruited for the study (see also eligibility criteria).
Participants are randomized (1:1:1) to the control group or intervention groups stratified by time since chemotherapy completion, age and hormone therapy (Y/N). The randomization will be carried out by an independent researcher using random number lists created in MinimPy, a free open-source application (http://minimpy.sourceforge.net/). Participants will be randomized by minimization, a covariate-adaptive randomization technique which balances the allocation to groups across specified covariates without compromising randomization (31).
After randomization, participants will be unblinded to group assignment, as the interventions do not allow for blinding. Assessors and statisticians will be blinded.
Intervention group - MBI
The MBI adheres to a standardized protocol developed from the MBSR curriculum (32) and the mindfulness-based cognitive therapy for cancer (33). The program was adjusted for women, who have an active life, combining job activities with (often) motherhood, and consists of four 3h group sessions spread over 8 weeks. Each session consists of guided experiential mindfulness exercises (e.g., focus on the breath, body scan, breathing space, mindful movement, sitting meditation), sharing of experiences of these exercises, reflection in small groups, psycho-education (e.g., on topics such as stress, fatigue, fear of cancer recurrence, self-care) and review of homework exercises. The program aims to: (1) increase present moment awareness and recognize entanglement with one's thoughts and emotions; (2) teach acceptance and mindfulness as an alternative strategy for dealing with problematic thoughts and feelings, and how these may be used to facilitate values-based actions. The program is led by two clinical psychologists who are skilled trainers following standardized procedures. In between the group sessions participants are contacted by phone or mail for a short check-up and a kind reminder to continue their daily practice. The training is supported by the use of homework exercises and audio material. Daily home practice will be strongly encouraged.
Attendance to the group sessions will be monitored as well as daily home practice (see further).
The MBI will be delivered by two clinical psychologists with experience in delivering MBIs to breast cancer patients. Treatment fidelity and trainer adherence will be established using randomly selected video-recordings of the sessions who will be analyzed by independent raters. This will be done using the Mindfulness-Based Intervention – Teaching Assessment Criteria (34).
Active control group - Physical training
This intervention is based on the recommended levels of physical activity for adults aged 18 - 64 years from the World Health Organization. These recommendations are the same for women after a breast cancer treatment (35). This program will consist of four 2h group sessions spread over 8 weeks. Each session will consist of psycho-education (e.g., on topics such as the basics of movement, advantages of physical activity, and training-principles), endurance and resistance training, stretching, balance and relaxation exercises, sharing of experiences of these exercises and review of homework exercises. The goal of the program is: (1) to improve physical functioning, physical fitness, strength, flexibility and balance, and (2) to increase knowledge about physical activity. Participants will receive exercise material and homework assignments which they are expected to follow daily. The physical training is led by a physiotherapist experienced in oncology revalidation.
Attendance to the group sessions will be monitored as well as daily home practice.
The specific elements of each session in both programs are described in Table 1.
For both programs daily home practice will be assessed using a practice journal made by the instructor. The practice journal has the same format for both intervention conditions with indications for the duration, the frequency and type of exercise. At the end of the eight-week training program, participants hand in the practice journal to the trainer.
TAU control group – usual care
Participants in the TAU control group will continue to receive their usual care. They will complete assessments at exactly the same time points as the intervention groups, i.e. at baseline (T0), post-intervention (T1) and at 3-months follow-up (T2). Upon completion of the final assessment, the control group will be offered the MBI.
Data to be collected at baseline include age, sex, marital status, education level, professional status.
Cognitive Failure Questionnaire
The Cognitive Failure Questionnaire (CFQ) is used to obtain information on subjective cognitive function (36). The CFQ consists of 25-items assessing self-reported cognitive failures in daily activities, such as forgetting what the person went into a room to do. Questions are rated on a five-point scale ranging from 0-‘never’ to 5-‘very often’. Subscales on distraction, distraction in social situations, names and word finding, orientation, and a total summary score are available. Four extra questions assess if complaints increased over the past 5 years. The scale has shown high internal consistency and good construct and criterion validity in groups of adult cancer patients (10, 37).
Emotional distress is measured using the Depression Anxiety Stress Scales (DASS-21) (38). DASS-21 consists of three 7 item scales designed to assess depression (DASS-21-D), anxiety (DASS-21-A), and stress symptoms (DASS-21-S). The total scale score is used as a measure of general distress. The scale is a valid and reliable measure for use among cancer patients (39).
Fatigue is measured with the fatigue severity subscale of the Checklist Individual Strength (CIS) (40). This subscale consists of eight items, each scored on a 7-point Likert scale, with higher scores reflecting more fatigue. The CIS has shown high internal consistency and good construct and criterion validity in a group of adults with different cancer types (18).
The 37-item Comprehensive Inventory of Mindfulness Experiences (CHIME) is used to measure mindfulness (41). Items are rated on a 6-point scale ranging from 1 to 6, with higher scores indicating higher levels of mindfulness. The CHIME provides eight subscales: awareness of internal experiences, awareness of external experiences, acting with awareness, accepting and non-judgmental orientation, decentering and non-reactivity, openness to experiences, relativity of thoughts, and insightful understanding. In the present study the total score and scores of the subscales will be used. The CHIME is a valid and reliable measure for use among adults (42, 43).
Health related Quality of Life
Health-related quality of life will be assessed using the Quality of Life Questionnaire (QLQ‐C30) (44). This is a multidimensional, cancer‐specific quality‐of‐life questionnaire developed by the European Organization for Research and Treatment of Cancer (EORTC) Study Group on Quality of Life for use in international clinical trial settings. It includes 5 functional scales (physical, role, emotional, social and cognitive functioning), 3 symptom scales (fatigue, pain, nausea and vomiting) and a global health status/quality of life scale. In this study we will only use the global health status/quality of life scale.
Objective cognitive performance is evaluated using a neurocognitive test battery, covering several domains: (1) Attention and concentration [Bourdon-Wiersma Dot Cancellation Test (45, 46), Trail Making Test (TMT) (46, 47, 48, 49)]; (2) Memory [Auditory Verbal Learning Test (AVLT), part A and B (46), WAIS III forward digit span (50); (3) Executive functioning [Stroop Color Word Test (51, 52), Controlled Oral Word Association Test (COWAT) (46, 53), Trail Making Test (TMT), form B (46, 47, 48, 49), WAIS III backward digit span, and WAIS III letter-number sequencing (50)] and (4) Cognitive/Psychomotor processing speed [WAIS III digit symbol-coding (50), Nine-hole Peg Test (9HPT) (54, 55) and Trail Making Test (TMT), form A (46, 47, 48, 49)]. Additionally, verbal IQ is estimated by the Dutch Adult Reading test (DART) (56). The neuropsychological test battery has high reliability and good validity in our study population (9-11).
Structural and functional changes in the brain
Non-invasive MRI imaging of the brain (High-resolution anatomical T1-w imaging, Multi-shell diffusion imaging (DWI) and functional MRI (fMRI) will be used to study both structural and functional changes in the brain. All subjects are imaged on a 3 Tesla scanner (Achieva, Philips, the Netherlands) with a 32 channel phased-array head coil.
High-resolution 3D T1-weighted image (3D-T1-w, duration ± 5 min)
The 3D T1-weighted anatomical image will be acquired using a 3D-turbo field echo (TFE) sequence and is used to assess volumetric changes in the brain and as anatomical reference for both functional and diffusion MRI.
Resting-state functional MRI (rs-fMRI, duration ± 7 min)
Whole brain T2*‐weighted echo planar images (EPIs), sensitive to blood oxygenation level dependent (BOLD) contrast will be used to acquire functional MRI (fMRI) scans during “Resting state”. Participants are asked to close their eyes, lay still and not to fall asleep.
Active functional MRI (afMRI, duration ± 8 min)
Whole brain T2*‐weighted echo planar images (EPIs), sensitive to blood oxygenation level dependent (BOLD) contrast will be used to acquire functional MRI (fMRI) scans while participants perform a memory task in the scanner. The fMRI task consists of a visual N-back sequential letter task used to assess working memory brain activation (57, 58). Four conditions are tested: 0-back, 1- back, 2-back, and 3-back in a blocked design. The 0-back control condition has a minimal working memory load; participants need to decide if the current letter matches a single target letter that was specified before. In the 1-back condition, participants need to asses if the current letter matches the previous letter. During the 2-back (3-back) condition, participants need to assess whether the current letter matches the letter that has been presented two back (three back) in the sequence. Participants practice the task before the scanning session. During the MRI scanning session, participants respond by pressing a button to indicate whether the item matches the target condition.
Diffusion-weighted imaging (DWI, duration ± 20 30 min)
Whole-brain multi-shell diffusion weighted echoplanar imaging will be acquired with low and high b-values, ranging from 0 to 4000 and with number of directions ranging from 20 to 60. Diffusion images will be used to assess microscopic white matter microstructural differences.
Biomarkers of inflammation
Blood samples will be collected from all participants at the 3 time points, on the same day as completion of the other assessments. Levels of pro-inflammatory cytokines such as IL-1, IL-6, IL-8, TNF-α, IFNγ and MCP-1 and C-reactive protein (CRP) will be determined with bead-based multiplex immunoassays and compared between groups and timepoints.
Primary outcome measures:
- Changes in subjective cognitive impairment scores; and
- Changes in brain functional connectivity in the attention network.
Secondary outcome measures:
- Changes in neurocognitive test scores;
- Changes in emotional distress, fatigue, and mindfulness skills;
- Changes in brain white and gray matter structure;
- Changes in functional brain activity during N-back task;
- Changes in functional connectivity during resting-state; and
- Changes in biomarkers of inflammation.
Analyses will be done both per protocol and intention to treat. Analyses are based on general linear modelling and multilevel mixed effects modelling. The impact of the intervention will be tested via a multilevel model with two levels (time points nested within persons). Predictors are time (level 1 predictor), condition (level 2 predictor) and cross-level interactions. To evaluate the process of change a mediation analysis will be performed. Mediation will be tested by adding potential mediators (e.g., different mindfulness facets) and their interaction with condition and time in the intervention model. Time practicing will be tested as a potential moderator. Models are based on the procedure described in Bauer et al. (2006) (59).
State of the art image processing techniques will be used to analyse the MRI images and study both structural and functional differences longitudinal within groups and between the groups. Voxel-based morphometry (VBM) will be used to study structural changes in the brain. Additionally, advanced Multi-shell diffusion images will be processed and analysed using exploreDTI/Mrtrics (DTI, fixel-based analysis, CSD tractography), NODDI modelling software and in-house developed software. This will include head-motion and eddy-current correction and will use inverse phase encoding images and B0 maps for optimizing correction procedures. Seed-based analysis, independent component analysis (ICA) and graph theory will be applied to analyse the resting state fMRI data and assess brain connectivity. From the MRI data we will generate maps reflecting grey matter volume, white matter properties (e.g. fractional anisotropy, neurite density index, orientation dispersion index) and brain connectivity. Voxel-based statistical analysis using the general linear model and non-parametric statistics will be used to find significant differences (p<0.05) in imaging parameter maps between time-points and groups. Statistical parametric mapping on a voxel-by-voxel basis will be conducted by using a general linear model approach to assess brain activation during the N-back memory task. Contrast images comparing pairs of working memory load conditions (e.g., 3-back > 0-back) will be created for each patient and will be used in second-level to assess differences between time-points and groups.
The association between the obtained outcomes, psychological and behavioural outcomes based on the scores of retrospective questionnaires, neuroimaging parameter maps, the performance on neurocognitive tests and biomarkers of inflammation will be investigated using correlation analysis.
The number of patients in this study (40 patients in each group) is based on: (1) Earlier studies (9, 10) in which differences in the WM microstructure after chemotherapy could be observed with effect sizes varying between 0.03 and 0.05 in different brain regions and SD varying between 0.02 and 0.06 (power>85% with 40 patients); (2) Earlier studies that investigated the effects of MBI on the brain in which effects where shown after MBI in groups of n=20 (longitudinal design (60) and n=13 (cross-sectional design) (61, 62); (3) The one study that already investigated the impact of MBI on cognitive impairment after cancer treatment. This study reported an impact of MBI on cognitive functioning with a design of n < 40 in the different study arms (63).
Data are collected by the research staff and will be stored in a database in an in-house protected server at KU Leuven. Confidentiality of participants’ data is ensured by using participants’ IDs rather than identifiable information in the data set (i.e., coding) and by storing the document linking the IDs to the identifiable information separately and securely. Only researchers directly involved in the analysis of the RCT will have access to the final trial data set, which will only contain coded data. After data collection and before data storage, all outcomes are manually double checked by the research staff. The safety, progress, study integrity and design aspects will be monitored at various meetings by the research team involved in this study.