Study design
A multicenter, three-armed randomized controlled trial will be conducted to evaluate the effectiveness of an online cognitive rehabilitation program. Two intervention groups (i.e., a basic and an extensive cognitive rehabilitation program) and one waitlist control group will be included. An economic evaluation will be conducted to assess cost-effectiveness of the cognitive rehabilitation program. Furthermore, a process evaluation will be performed to evaluate the procedures regarding recruitment, execution and implementation of the cognitive rehabilitation program. This study will be conducted by the Netherlands Cancer Institute, Amsterdam, the Netherlands. Participants will be cancer survivors who are treated for cancer in several (university) hospitals in the Netherlands. The study has been approved by the Medical Ethic Committee at the Netherlands Cancer Institute and is registered at ClinicalTrials.gov (registration number NCT03900806).
Study sample
The study sample will be composed of 261 men and women of working age (18 – 65 years) with histologically confirmed non-CNS cancer. Eligible participants should have been treated with chemotherapy, targeted agents and/or immunotherapy, which should have been completed a minimum of six months before study entry. Patients who are still receiving hormonal therapy can be included in the trial. Since it is expected that cognitive problems affect work in the first period after RTW most prominently, cancer diagnosis can be at the utmost 42 months ago at study entry. Eligible patients should self-report cancer and/or cancer treatment-related cognitive problems. This will be assessed by the study team during a screening. Both patients with and without cognitive impairment according to neuropsychological tests (i.e., a z-score of 1 under or above the mean score of a control group, on at least two tests of the different cognitive domains compared to the normative data of a healthy population by age), will be included in the study. Furthermore, eligible participants should be occupationally active for a minimum of 12 working hours per week and have a fixed or temporary employment contract (with at least six months left of their contract).
Patients will be excluded from the trial if they lack basic proficiency in Dutch, have a serious overt psychiatric or neurological disorder that can interfere with the study aims, or have no internet access. In addition, patients will be excluded if they participate in comparable studies or programs focused on the reduction of cognitive problems and/or on the support of patients to retain work.
Recruitment and randomization
Cancer patients will be identified through the Netherlands Cancer Registry, and recruited via treating physicians of several (university) hospitals in the Netherlands. Potentially eligible patients will receive a personalized letter from their treating physician, informing them about the study and the cognitive rehabilitation program. Patients will be asked to respond via post (response card), email or phone whether or not they are interested in participation. In case a patient does not respond, a reminding letter will be sent after three weeks. Patients who express interest in participation will receive a phone call from the study team for further screening (e.g., a check of their employment status) and to provide additional information about the trial. Patients will be invited by e-mail to complete the baseline measurement (i.e., an online questionnaire and an online neuropsychological assessment) in case they fulfil all criteria, are motivated and willing to comply to the trial procedures. After completion of this baseline measurement, a session (face-to-face or using videoconference) with a therapist (e.g., neuropsychologist, occupational therapist) will be planned to discuss outcomes of the neuropsychological assessment, followed by collaborative treatment goal setting.
Upon receipt of all baseline information and after the session with the therapist, patients will be randomly allocated to the basic intervention arm (N=87), the extensive intervention arm (N = 87), or the waitlist control group (N = 87), using randomized design in the computerized program ALEA. Minimization will be applied for presence of cognitive impairment on the neuropsychological assessment to equalize group sizes. Blinding of participants and professionals is not possible for this type of intervention. Further, blinding for assessment is not applicable since measurements will be computer-based. A flow diagram of the recruitment procedure is outlined in Figure 1. Figure 2 shows a schedule of enrolment, interventions, and assessments.
Intervention
The cognitive rehabilitation program will be based on the protocol of a frequently used meta-cognitive strategy approach applied in many rehabilitation centers in the Netherlands (i.e., ‘Niet Rennen Maar Plannen’). In cooperation with the creators of this protocol, we will adapt it for work-related cognitive problems and for online use. Patients and professionals will evaluate the adapted version of the protocol in several stages throughout its development. Both individual sessions and focus group interviews will be organized to obtain feedback, which will be used to evaluate and improve both content and user-friendliness of the adapted version of the intervention. The program will consist of several modules that can be used in a flexible way, depending on the specific individual problems and goals. As part of this study, therapists have undergone additional training in issues related to cancer-related cognitive impairment and problems occupationally active cancer survivors might experience at work. In both intervention arms, participants will receive access to a secured personal webpage, where all content relevant to the treatment sessions can be obtained. Table 1 shows an outline of the intervention content of both the basic and the extensive cognitive rehabilitation program.
Table 1 Outline intervention content
Modules
|
Content
|
Basic cognitive rehabilitation
|
Extensive cognitive rehabilitation
|
|
- Review current knowledge about cancer related cognitive impairment
- Learning how to identify ‘at risk’ situations (at work) where cognitive failures arise
|
X
X
|
X
X
|
|
- Coping with fatigue (at work)
|
X
|
X
|
- Cognitive behavioral therapy
|
- Coping with behavioral and emotional consequences of cognitive impairment (at work)
|
X
|
X
|
|
- Learning how to disclose your cognitive problems to colleagues
|
X
|
X
|
- Strategy training: memory
|
- Learn and practice memory strategies at the workplace
|
|
X
|
- Strategy training: information processing
|
- Learn and practice information processing strategies at the workplace
|
|
X
|
- Strategy training: executive function
|
- Learn and practice planning and problem solving, flexibility and self- control strategies at the workplace
|
|
X
|
Therapy guidance
|
|
|
X
|
Basic cognitive rehabilitation program
The basic arm will consist of a brief cognitive training program without individual guidance throughout the intervention, which has to be completed in a period of 12 weeks.
Extensive cognitive rehabilitation program
The extensive arm will consist of a comprehensive training program, which has to be completed in a period of 12 weeks. The extensive cognitive rehabilitation program involves tailored therapy guidance in which the patients’ in-session reflection and homework assignments will be discussed. Cognitive strategy modules will be assigned by the therapist depending on the participants’ cognitive profile and personal treatment goals.
Waiting list control group
Participants in the waiting list control group will be offered the opportunity to follow the basic cognitive rehabilitation program after completion of the 26-week follow-up measurement.
Data collection
Participants will be followed for six months in total, and will be invited to complete measurements at three time points (at baseline (T0), treatment endpoint at 12 weeks post-randomization (T1) and at 26 weeks post-baseline (T2)). Measurements will be performed via a secured website, for which a link will be sent by email. Intervention effectiveness will be measured in terms of work-related goal attainment and secondary outcome measures. Secondary analyses will be performed to explore moderating and mediating processes. An overview of measures, mediating and moderating processes in treatment is presented in Figure 3. Detailed descriptions of these secondary study measures are provided in Table 2.
Table 2 Study measures and corresponding instrument
Variable
|
Instrument
|
Details
|
Primary outcome
|
|
|
Goal Attainment Scaling
|
GAS
|
- 3 personalized treatment goals
- 6-points scale
|
Secondary outcomes
|
|
|
Cognitive problems
|
CSC-W DV
|
- 19 items, 5-point scale
- Score range: 0 (never) - 4 (always)
- Cronbach’s alpha: 0.95
|
Work ability
|
WAI
|
- 1 item, 10-point Likert scale
|
Work functioning
|
WRFQ
|
- 27 items
- Range 0 to 100; higher scores indicate better work functioning.
- Subscales: work scheduling demands, mental demands, social demands, physical demands, and output demands
- Cronbach’s alpha: 0.91–0.96
|
Absenteeism and presenteeism
|
iPCQ
|
- 6 items
- Subscales: absenteeism, presenteeism
|
Need for recovery
|
VBBA
|
|
Health-Related Quality of Life
|
SF-36
|
- 36 items, dichotomous and 3- to 6-point Likert scales
- Subscales: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, mental health, emotional role functioning, and social role functioning
- Score range: 0-100; higher score indicates higher levels of functioning/ well-being.
- Time frame: past week
- Cronbach’s alpha: 0.66-0.91 (mean 0.84)
|
Fatigue
|
SF-36
|
|
Coping
|
CERQ
|
- 36 items, 5-point Likert scale
- Score range: 0 (never) – 5 (always)
- Subscales: self-blame, acceptance, rumination, positive refocusing, refocus of planning, positive reappraisal, putting in to perspective, catastrophizing and other blame
|
Neuropsychological function
|
ACS
|
- 7 different neuropsychological tasks
- Online assessment
- Cognitive domains: executive functioning, information processing speed, attention, working memory, verbal learning and memory, psychomotor speed.
- The ASC is usable a reliable for the oncology setting, with test–retest correlations in the range 0.29 up to 0.78, which is comparable with traditional tests.
- Concurrent validity with traditional tests is medium to large.
|
Work involvement
|
WIS
|
- 6 items, 5-point scale
- Score range: 1 (totally disagree) to 5 (totally agree). High scores indicate a high work involvement
|
Job characteristics
|
JCQ
|
- 35 items, ordinal 4-point scales
- Score range: 1 (totally disagree) to 4 (totally agree).
|
Depression and anxiety
|
HADS
|
- 14 items, 4-point Likert scale
- Subscales: depression, anxiety
- Score range: 0-42
- Time frame: past week
- Cronbach’s alpha: 0.68-0.93
- Cut off: a score of 11 and over indicates the possible presence of clinical depression.
|
Study measures
Sociodemographic and clinical data
Sociodemographic data including age, gender, marital status, number of children living at home, education, breadwinner status (sole/shared) will be obtained via questionnaire. Clinical information including cancer site, month/year of diagnosis, received (and future) treatment(s), (i.e., surgery, radiation, chemotherapy, immunotherapy, targeted treatment, hormonal therapy other medication), recurrence(s) of the disease and comorbidity will be obtained from the medical records, Netherlands Cancer Registry and via self-report. Information on general employment issues and on work accommodation, including employment sector, type of employment (fixed/temporary), years of work experience, and working hours and days per week according to employment contract, will be acquired via questionnaire.
Primary outcome measure
The primary outcome for this study will be individually defined work-related treatment goals, using the 6-point Goal Attainment Scale (GAS) on personal outcome (-3, achievement of the goal after training is worse; -2, achievement of the goal is the same; 1, partial achievement of the goal; 0, achievement of the goal; 1, exceeding the goal, and 2, greatly exceeding the goal) (33). Patients will formulate three treatment goals and define the six outcome levels at baseline, in collaboration with their therapist. Attainment of the goals is measured in a standardized way, i.e., an overall GAS T-score will be computed for each participant on basis of aggregated GAS scores involving attainment of multiple personal treatment goals, according a summary scoring algorithm that calculates the extent to which patients’ goals are met. (see Equation 1 in the Supplmental Files)
T is the composite score, wᵢ is the weight assigned to goalᵢ (based on the patients prioritisation), xᵢ is the original score for goalᵢ ranging from −3 to +2, and ρ is the estimated correlation between goal scores. The T-score has a mean of 50 and a standard deviation of 10. wᵢ is considered as equally relevant for each goal and thus assigned 1. Based on previous studies, correlation between the goal scores is constant and can be set at 0.3 (33). Goals will be set at baseline (T0), and evaluated by patients (of all study arms) in collaboration with the cognitive therapist at T1 and T2. Due to practical reasons, this scoring of the level of attainment will be done by telephone. An independent assessor will perform quality checks on the use and scoring of GAS during the initial phase of the trial, to assure fidelity of the GAS-protocol.
Secondary outcome measures
Secondary outcome measures include standardized self-report questionnaires assessing cognitive complaints (CSC-W DV) (34), work ability (WAI) (35, 36), work functioning (WRFQ) (37), absenteeism and presenteeism (iPCQ) (38), need for recovery after a working day (VVBA) (39, 40), and health-related quality of life (SF-36) (41).
Mediation and moderating measures
Fatigue (SF-36) and coping (CERQ) are considered mediators and will be assessed through self-report questionnaires (42, 43). Neuropsychological functioning is considered a moderator and will be measured using a self-administered online neuropsychological test battery (ACS) (44). Other moderators are: work involvement (WIS) (45), job characteristics (JCQ) (46), depression and anxiety (HADS) (47), and treatment utilization (Log-data of the online program).
Cost-effectiveness
An economic evaluation will be conducted alongside the trial to evaluate costs and patient outcomes of implementing the online cognitive rehabilitation program. Both a cost-utility analysis (CUA) and cost-effectiveness analysis (CEA) will be conducted. Quality adjusted life years (QALYs) will be measured using EQ-5D-5L (48). Intervention costs will be calculated, including health professional labor (time spent on treatment per patient), staff training, administration, and material costs. Unit prices (or appropriate tariffs) will be multiplied by volumes of use, following the Dutch costing guidelines (49). Health care costs will be assessed using self-reported questionnaires about participants’ use of health care services (e.g., general practitioner (GP), medical specialist, paramedical care). Productivity costs will be administered by questionnaires reporting on productivity losses due to sickness absence from work (absenteeism) and health-related diminished productivity at work (presenteeism). Presenteeism and sickness absence will be administered with the Productivity Costs Questionnaire (iPCQ). This questionnaire includes three questions for measuring absenteeism and three questions identifying the proportion of presenteeism (38). Full working days lost because of presenteeism are calculated according to following formula: P = (E − A)∗ p, in which E is total working days, A is sickness absence days, and p is the proportion of lost work performance due to presenteeism. Productivity loss will be valued using age-, gender-, and/or education-specific price weights.
Process evaluation
A process evaluation will be conducted to evaluate strategy fidelity, satisfaction and facilitators or barriers for implementation of the cognitive rehabilitation program. Six components will be assessed, namely: recruitment, reach, dosage, differentiation, implementation and experiences (of both participants and therapists). We define recruitment as the result of all procedures to recruit eligible cancer survivors for participation. Reach is defined as the percentage and characteristics of persons who receive the intervention program. The extent to which the participants actually were exposed to the intervention will account as treatment dosage. Furthermore, differentiation is regarded as the identification of unique and essential intervention features. Implementation refers to the qualitative aspects of the manner in which the intervention program was delivered. Participants’ and therapists’ experiences with the intervention activities will be evaluated. To gather data for the process evaluation, periodic self-report questionnaires for participants will be provided at the end of every module (for an overview of modules see table 1) and at T1. A self-report questionnaire for the therapists will be provided at the end of the trial.
Sample size calculation
This longitudinal study design will allow for testing of the main effect of the intervention over time, with the GAS score as the primary outcome measure. With a sample size of 65, and an alpha=0.05, the study will allow for an attrition rate of approximately 20% and have 80% power to detect an effect size of f=0.2 (equivalent to Cohens d=0.4) for the main effect of the intervention between both the basic and extended cognitive rehabilitation treatment group versus the waitlist control group (first hypothesis). To perform subgroup analysis, used to test our second hypothesis, sample size should be inflated fourfold (50). Therefore, we strive for a sample size of 261, with 87 patients in each group.
Statistical analysis
All data will be pseudo-anonymized prior to data analyses. The data set will not contain any personal identifiers. The information that is given online by patients is accessible to the study staff only, via a secured code. Means and SDs will be presented for continuous, normally distributed variables, and median and ranges for non-normally distributed variables. First, analyses will be performed to evaluate the comparability of the three study arms (i.e., the basic and extensive cognitive rehabilitation groups and the waiting list control group) at study entry, in terms of sociodemographic and clinical characteristics. ANOVA tests or appropriate non-parametric statistics will be used, depending on the level of measurement. If, despite the stratified block randomization procedure, the groups are found not to be comparable on one or more background variables, then those variables will be employed as covariates in subsequent analyses.
In this study, GAS will be used as the primary study endpoint, evaluating between-group differences over time in GAS scores. The GAS scores will be calculated according to published scoring algorithms (see: Method section). To evaluate intra-individual differences in the trajectory of change over time for the primary outcome, we will use a growth curve modeling approach with random intercept and slope. This approach takes into account the within and between person variability, and deals adequately with missing data (51). Both linear and quadratic effect of time will be modeled to determine if an initial improvement or deterioration in the outcome was followed by a deceleration of this change over time. Appropriateness of the final model (with or without quadratic effect) will be determined based on model fit statistics: the Bayesian information criterion (52) and the Akaike information criterion (53). In all analyses, the control group will be the reference group. Furthermore, moderation analysis will be conducted to determine whether the interventions have a differential effect among the subgroups classified as cognitive impaired yes or no (measured by ACS) at baseline. Baseline differences will be accounted for in the model. In case of non-ignorable dropout we will correct the model for different patterns of missing values (54). All analyses will be done on an intention-to-treat basis. Furthermore, as a secondary analysis, per-protocol analyses will be performed on patients who met criteria for minimal compliance (i.e., at least 4 logins into the online program) with the intervention(s). Differences in mean change scores over time between the intervention groups and the control group will be accompanied by effect sizes. Effect sizes of 0.2 are considered small, 0.5 moderate, and 0.8 large (55). Effect sizes of approximately 0.5 are considered to be clinically relevant (56).
Secondary study parameter(s)
We will calculate questionnaire scores according to published scoring algorithms. Missing values will be replaced by the average score of the completed items in the same scale for each participant, provided that at least 50% of the items in that scale have been completed. For the CSC-W DV, WAI, WRFQ, iPCQ, VBBA, and SF-36, the same growth curve modeling approach as described in the primary study parameter section will be used to evaluate between-group differences over time. In addition, we will test whether intervention effects are moderated by baseline scores on the ACS, WIS, JCQ, and HADS. Finally, we will explore the mediating effect of the (anticipated time-variant) variables fatigue (SF-36) and coping (CERQ) on the secondary outcomes.
Cost-effectiveness
Incremental cost will be calculated and, by using incremental QALYs and GAS scores, expressed as the incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratio (ICER), respectively. The ICUR and ICER will be measured for both intervention groups. ICUR represents the costs required for the particular intervention to generate one additional QALY in comparison with care as usual (control group). ICER represents incremental costs per relevant achievement of work-related treatment goals (GAS) over a time period of 6 months. Both ratios will be estimated by bootstrap analyses. As an indication of whether an intervention will be considered cost-effective, the ICUR is compared to a range of ceiling ratios varying from €20k per QALY to €80k per QALY in the Netherlands, with €30k per QALY commonly accepted as the prevailing ceiling ratio. In addition, cost-effectiveness acceptability curves will be used to inform decision-makers on the probability that the cognitive rehabilitation program is cost effective.