Many of the occupationally active cancer survivors experience cognitive problems.Both from an individual and a societal perspective, it is important to sustain cancer survivors' employability.The aim of the current study is to develop an internet-based cognitive intervention programme for occupationally active cancer survivors confronted with cognitive problems, and to evaluate the (cost-)effectiveness of this program. A three-armed randomized controlled trial will be conducted with six months of follow-up, including two intervention groups (i.e., basic and extensive cognitive rehabilitation program) and one waitlist control group. Primary and secondary outcomes will be measured at baseline (T0), at three months, upon completion of the intervention (T1), and at three months post-intervention (T2).In total, 261 cancer survivors (18 - 65 years) who have returned to work and who experience cognitive problems will be recruited.

The proposed study will evaluate the (cost-)effectiveness of an internet-based cognitive intervention program in achieving personal work-related rehabilitation goals in occupationally active cancer survivors confronted with cognitive problems. Secondary outcomes will be among others subjective cognitive function, work function and quality of life.

It is hypothesized that:

• both cancer survivors who undergo the basic or extensive cognitive rehabilitation program will achieve better their pre-set rehabilitation goals, both at baseline till treatment endpoint (T1) and follow-up (T2), compared to cancer survivors in the waitlist control group.
• cancer survivors with baseline cognitive deficits (measured with neuropsychological tests) will achieve better their pre-set rehabilitation goals after the extended cognitive rehabilitation program than after the basic cognitive rehabilitation program.

A three-armed randomized controlled trial with two intervention groups (i.e., an extensive and a basic cognitive rehabilitation program) and one waitlist control group will be conducted.

The cognitive rehabilitation program will be delivered online; either as a self-help intervention or as an online therapist-guided intervention. The therapists will be cognitive trainers who have undergone additional training in issues related to cancer-related cognitive decline.

Participants will be followed for six months in total, including three measurements time points (at baseline (T0), at three months (treatment endpoint; T1) and at 6 months follow-up (three months after completion of treatment; T2).

Cancer patients will be identified through the tumour registry, in case of the Netherlands Cancer Institute, or through the Netherlands Cancer Registry (IKNL), in all other centers. Patients will be recruited via their treating physician using an information letter of the study, including a response card. If patients are interested in participation, a member of the study team will call the patient to provide them with further information and to screen for eligibility.

Sample size calculation: This longitudinal study design will allow for testing of the main effect of the intervention (exposure to a cognitive rehabilitation programme) over time, with the GAS score as the primary outcome measure. With a sample size of 65, and 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 and the waitlist control group. To perform subgroup analysis, as indicated by our second aim, sample size should be inflated fourfold. Therefore, we strive for a sample size of 261, with 87 patients in each group.

The intervention arms differ with respect to therapy guidance and intensity of the cognitive rehabilitation part. Both programs involve psychoeducation, cognitive behavioural therapy and fatigue management. In both intervention arms, participants will receive access to a secured personal webpage where all content relevant to the treatment sessions can be obtained.

Prior to randomization, a face-to-face appointment with a therapist will be convened to discuss the results of the neuropsychological tests, to evaluate the self-perceived (cognitive) complaints and to define three primary work-related intervention goals.

Upon receipt of all baseline information and one face-to-face session with a cognitive therapist (involving feedback on baseline neuropsychological tests and personalized treatment goal setting) , patients will be randomly allocated to the basic arm (N=87), the extensive arm (N = 87) or the waitlist control group (N = 87), using the computerized randomization programme ALEA. Stratified randomization will be applied for cognitive impairment on tests (yes/no). Minimization will be applied with respect to cognitive impairment status to equalize group sizes. Blinding of participants and professionals is not possible for this type of intervention. Blinding for assessment is not applicable since measurements are computer-based.

Study procedures: All eligible patients will be asked to complete an online neuropsychological assessment and patient-reported outcomes regarding cognition, work-related functioning and overall health-related quality of life at baseline (T0). As noted previously, results of baseline information and subsequently intervention goals will be discussed with patients prior to randomisation. Upon completion of the intervention (T1) and at three months post-intervention (T2), primary and secondary outcomes will be assessed through online questionnaire and through a call with the cognitive therapist in case of goal attainment. Participants in the waitlist control group will be given the choice to undergo the online rehabilitation programme after T2. Finally, non-response will be measured by assessing the proportion of patients who participated in comparison with all eligible patients.

Intervention effectiveness will be measured in terms of work-related goal attainment and secondary outcome measures. Furthermore, secondary analysis will be performed to explore mediating and moderating processes.

Cost-effectiveness: An economic evaluation will be conducted alongside the randomized controlled trial to evaluate costs and patient outcomes of implementing the online cognitive rehabilitation programme. From a societal perspective, a cost-utility analysis (CUA) will be conducted, whereby all costs and consequences are taken into account irrespective of who pays or benefits from them. Furthermore, in order to sustain cost-effectiveness from an employer's point of view, we will conduct a cost-effectiveness analysis (CEA) to compare the difference in costs versus the difference in effects over the two intervention groups and the waitlist control group. The cost-effectiveness of the two interventions will be evaluated by incremental treatment costs for improving goal attainment by a clinically relevant degree.

STATISTICAL ANALYSIS Means and SDs will be presented for continuous normally distributed variables and median and regions for non-normally distributed variables.

Baseline characteristics: Analyses will first be performed to evaluate the comparability of the control and the intervention groups (basic and expanded cognitive rehabilitation) at baseline 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 randomization procedures, the groups are found not to be comparable on one or more background variables, those variables will be employed as covariates in subsequent analyses.

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. To evaluate the intra-individual difference 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. 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 (BIC; Schwarz, 1978) and the Akaike information criterion (AIC; Akaike, 1998). 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. The same approach will be used for secondary outcome measures.

All analyses will be done on an ´intention to treat´ basis. Differences in mean change scores over time between the intervention groups and the control group will be accompanied by effect sizes.

Inclusion Criteria:

1. Working age (18 - 65 years) at the time of study entry
2. Histologically confirmed cancer (all tumour types except for brain tumours).
3. Completed primary therapy including chemotherapy, targeted agents and/or immunotherapy 6 months ago. Patients who are still receiving hormonal therapy can be included in the trial.
4. Experience cancer/cancer treatment-related cognitive problems. Both patients with and without cognitive impairment assessed with neuropsychological tests, formally assessed with neuropsychological tests, will be included in the study.
5. Fixed or temporary employment contract (with at least six months left of their contract).
6. Being at work for a minimum of 12 working hours/week.

Exclusion Criteria:

1. Psychiatric or neurological disorder that can interfere with current study aims.
2. Lack basic proficiency in Dutch.
3. Participating in comparable studies or programmes.

Blinding of participants and professionals is not possible for this type of intervention. Blinding for assessment is not applicable since measurements are computer-based.