Cancer-related Fatigue and Symptom Clusters - Effects of Virtual, Imagined and Real-life Nature-based Therapy in Cancer Survivors

The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) is a validated tool for the reliable measurement of fatigue in patients with cancer and other chronic diseases. The questionnaire has high internal consistency and validity and allows assessment of fatigue and its impact on quality of life and disease progression. 13 items to measure self-reported fatigue and its impact on daily activities and functions. In addition to the primary outcome (overall fatigue score), this secondary outcome will focus on specific FACIT-F items related to fatigue interference in daily activities. This aims to explore functional limitations due to fatigue beyond the global score. Scores range from 0 to 52, with higher scores indicating less fatigue (better outcome).

The Pittsburgh Sleep Quality Index (PSQI) measures subjective sleep quality. The 19-item questionnaire generates seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications, and daytime disturbances. The sum of the scores for these seven components gives a global score. Scores range from 0 to 21, with higher scores indicating worse sleep quality (worse outcome).

The Patient Health Questionnaire-9 (PHQ-9) is often used for the initial diagnosis of depression and for monitoring the course of the illness. The PHQ-9 consists of 9 questions that ask about the main and core symptoms of depression over the past two weeks, providing a structured and objective assessment of the severity of depression. Scores range from 0 to 27, with higher scores indicating more severe depressive symptoms (worse outcome).

The Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) is a 5-point Likert scale measure of chemotherapy-induced cognitive impairment in cancer patients. The questionnaire consists of 24 items covering four different domains: self-perceived cognitive impairment, feedback from others, perceived cognitive ability, and impact on quality of life. The assessment of these cognitive aspects indicates a relationship with objective symptoms and allows for a nuanced assessment of treatment-induced cognitive impairment. Scores range from 0 to 148, with higher scores indicating better cognitive function (better outcome).

The Brief Resilience Scale (BRS) is a instrument used to measure resilience, or an individual's ability to bounce back quickly from stress, adversity, or challenge. The BRS is known for its brevity and conciseness, with only a few items rated on a Likert scale. Scores range from 1 to 5, with higher scores indicating greater resilience (better outcome).

The Mindfulness Awareness Scale (MAAS) measures a person's level of mindfulness. The scale ranges from 1 to 6 and includes a total of 15 items. The items assess the extent to which a person invests his or her thoughts in the present moment by taking into account the extent to which he or she is aware of what is going on in his or her environment at any given moment. Scores range from 15 to 90, with higher scores indicating greater mindfulness (better outcome).

The Generalized Anxiety Disorder-7 (GAD-7) is a standardized screening questionnaire used to assess the severity of generalized anxiety disorder. It is used in both clinical practice and research to rapidly identify and assess the severity of anxiety symptoms. The questionnaire consists of 7 items that ask about typical symptoms of generalized anxiety disorder and focus on the last two weeks. Scores range from 0 to 21, with higher scores indicating more severe anxiety (worse outcome)

Functional Assessment of Cancer Therapy - (FACT-G) Quality of Life Questionnaire. The FACT-G was developed through a structured process to identify relevant content for a cancer-specific quality of life questionnaire. The instrument allows the calculation of a generic total quality of life scale (FACT-G) as well as subscales for physical, social, emotional, and functional quality of life. Scores range from 0 to 108, with higher scores indicating better quality of life (better outcome).

The Perceived Stress Scale (PSS) is the most frequently used psychological instrument for measuring the perception of stress. It measures the degree to which situations in a person's life are perceived as stressful. The scale also includes a series of direct questions about the current experience of stress. The items are easy to understand and the response alternatives are easy to record. The questionnaire consists of 10 items. Scores range from 0 to 40, with higher scores indicating greater perceived stress (worse outcome).

The Simulator Sickness Questionnaire (SSQ) is a standardised instrument designed to assess symptoms of simulator or motion sickness commonly experienced when using virtual reality (VR) and other simulated environments. The instrument consists of a series of questions divided into three subscales: Nausea, Disorientation and Oculomotor Stress.

The SSQ is widely used in VR research as it provides a means of quantifying symptoms and assessing their severity. Studies have shown that the SSQ is valid and reliable and has a high correlation with actual experienced symptoms. The results of the SSQ can be used to optimise VR experiences and improve usability. Total scores range from 0 to 235.62, with higher scores indicating greater simulator sickness (worse outcome).

Physical activity will be assessed using the Physical Activity and Sport Questionnaire (BSA), which records the frequency and type of physical activity in the past 4 weeks. Scores will be calculated in MET-minutes/week, based on self-reported duration and intensity of different physical activity domains (work, leisure, sport). Higher scores indicate higher levels of physical activity (better outcome).

To assess safety, participants will be asked whether they experienced any adverse events (AEs) during the 8-week intervention period. All reported AEs will be documented and classified by type and severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

The outcome will be the number of participants with at least one treatment-related adverse event recorded from baseline through the end of the 8-week intervention.

Physical activity will be monitored continuously during the 8-week intervention using a commercially available wearable device (e.g., Fitbit or Garmin).

The tracker will record daily step counts, active minutes and movement intensity.

The outcome will be the average number of steps per day during Week 8, as a marker of overall movement behavior. This complements patient-reported activity recorded in the physical activity diary.

Heart Rate Variability (HRV) is measured to assess autonomic nervous system activity and stress recovery. HRV will be recorded using a wearable chest strap sensor (e.g., Polar H10) or equivalent device, over a 5-minute resting period.

Outcome will be RMSSD (Root Mean Square of Successive Differences) in milliseconds.

Natural killer (NK) cell activity will be assessed by blood sampling at baseline and Week 8. Cytotoxic activity will be measured by flow cytometry based on CD107a expression and IFN-gamma production.

Outcome will be the percentage of NK cells expressing CD107a after stimulation.

Serum cytokines (IL-6, IL-10, TNF-alpha) will be measured using multiplex ELISA from venous blood samples collected at baseline, Week 4 and Week 8.

Outcomes will be reported as individual changes in cytokine concentrations (pg/mL) from baseline to Week 4 and Week 8.Outcomes will be reported as individual changes in cytokine concentrations (pg/mL); no composite score will be calculated.