Longitudinal Neurocognitive, Psychosocial and Health-related Quality of Life Assessment in Advanced Cancer Survivors Treated With Immunotherapy and the Efficacy of Integrative Neurocognitive Remediation Therapy

To measure neurocognitive functioning (attention, memory and executive functioning), with the computerized neuropsychological test battery COGBAT. This battery gives an overall degree of objective neurocognitive functioning, in addition to the specific test performance per subtest. The test performance will be measured in raw scores and z-scores. This test battery will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. Improvement in test performance after the therapy program, compared to baseline, will indicate efficacy of the integrative neurocognitive remediation therapy program.

To measure subjective cognitive functioning as assessed by the Cognitive Failures Questionnaire, values ranging from 0 to 100. Higher values mean more cognitive complaints. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. A cut-off score of 44 will be used to define elevated levels of cognitive complaints, a score higher than 54 indicates severe cognitive complaints. Improvement in subjective cognitive complaints after the therapy program, compared to baseline, will indicate efficacy of the integrative neurocognitive remediation therapy program.

To identify emotional distress, the Hospital Anxiety and Depression Scale will be used, with values ranging from 0 to 42. Higher scores mean more emotional distress. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. A cut-off score of 8 will be used to define elevated levels of emotional distress, a score higher than 10 corresponds to moderate emotional distress, a score higher than 14 corresponds to severe emotional distress.

To identify fatigue, the Fatigue Severity Scale will be used. Mean scores will be calculated, leading to a score between 1 and 7. Higher values indicate more fatigue. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. A cut-off score of 4 will be used to define elevated levels of fatigue.

To identify fear of cancer recurrence, the Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF). will be used. Values range from 0 to 36 and higher values indicate more fear of cancer recurrence. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. A cut-off score of 13 will be used to define significant fear of cancer recurrence. A score higher than 15 equals clinically significant fear of cancer recurrence, a score higher than 21 equals a pathological fear of cancer recurrence.

To measure health-related quality of life, the EORTC Quality of Life Questionnaire (EORTC-QLQ-C30) will be used. Transformed scores range between 0 and 100, higher scores indicate better health-related quality of life. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. The scores will be compared to the Threshold of Clinical Importance, developed by Giesinger et al. (2020). To evaluate change over time, the changes of at least 10 points are regarded, which are supported to be clinically meaningful changes (Snyder et al., 2014).

To document baseline demographic data, prior disease history, nature of immunotherapy therapy, the investigators will look into the patient medical record and a general questionnaire will be used.

To explore the feasibility of the implementation in a larger scale of this clinical program will be assessed by the care need of the patients and the possibility to implement the therapy program in other hospitals (resources needed, cost of the program for the patient).

Psychological distress will be measured by the sum scores of the Hospital Anxiety and Depression Scale. Subjective cognitive functioning will be measured by the sum scores of the Cognitive Failures Questionnaire. To measure the relation between the two variables, the investigators will conduct a statistical correlation of these outcomes. The outcome will be a correlation coefficient (r).

Psychological distress will be measured by the sum scores of the Hospital Anxiety and Depression Scale. Objective cognitive functioning will be measured by the COGBAT neuropsychological battery. To measure the relation between the two variables, the investigators will conduct a statistical correlation of these outcomes. The outcome will be a correlation coefficient (r).

Subjective cognitive functioning will be measured by the sum scores of the Cognitive Failures Questionnaire. Objective cognitive functioning will be measured by the COGBAT neuropsychological battery. To measure this relation, the investigators will conduct a statistical correlation of these outcomes. The outcome will be a correlation coefficient (r).

This will be assessed through two open questions asked to the patient, more specifically: 1) if the patient has interest in personalized nutritional advice, 2) what the specific nutritional care need is of the patient.

To identify rumination, the Brooding items of the Ruminative Response Scale (RRS) will be used. Values range from 5 to 20, higher values indicate more tendency of 'Brooding', a maladaptive type of rumination. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter.

To measure visuo-spatial memory span, with the computerized version of the Corsi Block Tapping Test by the Vienna Test System. The test performance will be measured in raw scores and z-scores. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter.

To measure verbal long-term memory measured by the California Verbal Learning Test. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and six months thereafter. The test performance will be measured in raw scores and z-scores.

To measure information processing speed measured by the WAIS-IV Symbol Search and Coding. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and six months thereafter. The test performance will be measured in raw scores and Weschler subscale scores. The Weschler subscale scores range from 0-20 and have a mean of 10.

To measure verbal short-term memory by the WAIS-IV Digit Span Forwards. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and six months thereafter. The test performance will be measured in raw scores and z-scores.

To measure working memory by the WAIS-IV Digit Span Backwards. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and six months thereafter. The test performance will be measured in raw scores and z-scores.

Anxiety will be measured by the State-Trait Anxiety Inventory. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and 6 months thereafter. Values range from 20 to 80. Higher values indicate more anxiety. STAI scores classified as "no or low anxiety" (20-37), "moderate anxiety" (38-44), and "high anxiety" (45-80).

Self-esteem will be measured by the Rosenberg Self-Esteem Scale. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and 6 months thereafter. Values range from 0 to 30. Higher values indicate a higher self-esteem. Scores between 15 and 25 are within normal range; scores below 15 correspond to low self-esteem.

Tendency for procrastination will be measured by the Pure Procrastination Scale. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and six months thereafter. Values range from 11 to 55. Higher values indicate more tendency for procrastination. A score lower than 28 indicate a low level of procrastination, a score between 28-39 indicate a moderate level of procrastination, and a score higher than 39 indicate a high level of procrastination.

Metacognition will be measured by the Metacognition Questionnaire. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and six months thereafter. Values range from 30 to 120. Higher values indicate more metacognitive beliefs.

Tendency for perfectionism will be measured by the Frost Multidimensional Perfectionism Scale. This will be tested only in the intervention group, i.e. the patients that will follow the integrative neurocognitive remediation therapy. It will be repeated after completion of the therapy program and six months thereafter. Values range from 35 to 210, higher values indicate more tendency for perfectionism.

To identify post-traumatic stress disorder (PTSD) symptoms, the PTSD checklist for DSM-5 (PCL-5) will be used. Values range from 0 to 80, and higher values indicate more symptoms of post-traumatic stress. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. A cut-off score of 33 indicates PTSD.

To measure subjective cognitive functioning as assessed by the EORTC QLQ-C30, cognitive functioning subscale. Transformed scores range from 0 to 100, with higher scores meaning better cognitive functioning. This will be repeated during follow-up for the non-intervention group. For the intervention group, the scores will be compared before and after the integrative neurocognitive remediation therapy, and 6 months thereafter. The scores will be compared to the Threshold of Clinical Importance, developed by Giesinger et al. (2020). To evaluate change over time, the changes of at least 10 points are regarded, which are supported to be clinically meaningful changes (Snyder et al., 2014).