2.2.1. Specific quantitative research questions and hypotheses.

How do changes in the EF of individuals with cancer impact their performance of daily activities pre- and post-chemotherapy?

1. Daily functioning and performance pre-chemotherapy will be largely explained by emotional symptoms and fatigue.
2. Objective and perceived EF, as well as emotional symptoms and fatigue, will significantly worsen post- compared with pre-chemotherapy.
3. The performance of individuals’ daily activities post-chemotherapy will be largely explained by the objective and perceived EF impairments.

2.2.2. Qualitative research questions.

Through the open-ended questions we aimed to better understand how individuals with cancer perceive how changes in EF impact their performance of daily activities pre- and post-chemotherapy. The specific qualitative questions are as follows:

1. Do individuals with cancer perceive changes in their ability to perform complex cognitive tasks?
2. What cognitive difficulties do individuals with cancer experience?
3. What do individuals with cancer think causes these difficulties?
4. How do individuals with cancer perceive that these difficulties can impact their performance of daily activities?
5. What other factors are thought to affect their performance of daily activities?

2.4.1. Intervention.

The chemotherapy protocol includes the standard adjuvant or neoadjuvant treatment for different types of solid malignancies, as defined by the oncologist. Such chemotherapy protocols are widely used in the early stages of different types of cancer [30]. Adjuvant chemotherapy is used after a definitive treatment, either surgery or radiotherapy; it is aimed to eradicate any residual micro-metastatic disease in order to reduce recurrences and improve long-term survival. Neoadjuvant chemotherapy was applied before definitive treatment and was primarily used in locally advanced diseases, where a downstaging procedure is mandatory before definitive treatment [31]. Chemotherapy protocols vary according to the chemotherapeutic agent, dose density, and intensity, but are typically administered weekly, biweekly, or tri-weekly for up to six months [30]. The most commonly used agents are 5 Flourouracil, Anthracyclines, Platinum salts, and Taxanes [30]. Participants will come to the oncology department for chemotherapy treatment.

2.4.2. Outcome measures.

The following quantitative and qualitative outcome measures will be used for a comprehensive assessment, considering the individual’s personal context, environment, culture and community concerns, valued activities, routines, roles, and previous lifestyle [32].

Quantitative Outcome Measures Pre- and Post-Chemotherapy

1. The primary outcome measure is the Canadian Occupational Performance Measure (COPM) [33], which is an individualized semi-structured interview that assesses performance and satisfaction with one’s performance of daily activities (i.e., self-care, productive, leisure, and social activities). Pre-chemotherapy participants will identify three to five daily activities that they prioritize as meaningful for them; for one person, the performance might be cooking, for another person, it might be walking the dog, and for a third person, it might be participating in a course online [34]. Each of these activities will then be rated on a 10-point scale for perceived performance (1 = not able to do at all, 10 = able to do extremely well) and similarly for satisfaction with performance. The performance and the satisfaction scores represent the average scores for all activities. Post-chemotherapy, participants will rate the same activities they prioritized in the pre-chemotherapy assessment. The COPM has been widely tested in various target groups and its responsiveness (sensitivity to change) is supported in many studies [35–38]. The internal consistency (Cronbach Alpha) in a sample of women after breast cancer was between 0.67–0.79 for performance and between 0.73–0.77 for satisfaction from performance [39].
2. Secondary outcome measures:
   1. The Reintegration to Normal Living Index (RNL) [40] will assess participants’ general participation. The RNL consists of 11 statements of participation in recreational and social activities, movement within the community, and the degree of comfort the individuals have in their role in the family and with other relationships. The responses are given on a 1–10-point Likert scale (1, highly do not agree, to 10 highly agree). The adjusted score is calculated as the (Total Score/110) × 100, and ranges from 10–100 points, with a higher score indicating more participation. The RNL has previously been used with patients undergoing surgery and treatment for rectal cancer [41]. It showed acceptable test–retest reliability in different populations (intraclass correlation coefficients (ICCs) ranging between 0.71 and 0.87) [42,43].
   2. Objective EF assessments:
      • The Backward Digit Span (BDS) [44] will assess working memory. Participants will be asked to repeat a series of numbers (read out by the examiner) in the reverse order. The number of correct sequences will be recorded. The mean (across age groups) internal consistency reliability of the BDS scores was reported at 0.82 [45].
      • Dual-task assessment will assess the ability to perform multi-tasking. This will include a motor task performed using the hands—the Box and Blocks Test (BBT) [46] and a cognitive task—repetitively counting backwards by subtracting threes. Participants will perform the tasks as single tasks and the two tasks concurrently (motor and cognitive) in order to assess the interference (cost) of the motor task on the cognitive task (cognitive cost) and the impact of the cognitive task on the motor task (motor cost). The BBT is a standardized, reliable, and valid assessment tool used to assess manual dexterity; its test–retest reliability is high (intraclass correlations coefficients of 0.89 to 0.97) [47,48]. Participants will be asked to transfer wooden blocks from one side, over a wooden partition, to the other side of a box within one minute. The number of blocks transferred in 1 minute will be registered. This test will first be performed by the dominant and then by the non-dominant hand. More blocks indicate greater upper-extremity manual dexterity. For the single cognitive task, participants will be asked to count backwards by subtracting the number 3 from a three-digit number (i.e., 399) and then to keep subtracting 3 from their answer for 1 minute. The number of correct answers will be recorded. The motor/cognitive cost calculation is: (single task—dual task)/single task ×100.
      • The Color Trail Test (CTT) [49] is a paper and pencil test. This visual attention timed neuropsychological test will assess cognitive flexibility. The CTT1 consists of 25 circled numbers from 1 to 25 (even numbers are in a yellow background and odd numbers are in a pink background). The participants will be asked to connect the circles in consecutive order, which assesses visual attention and perceptual tracking. The CTT 2 consists of double the stimuli; two sets of 25 numbers in each color (pink and yellow); this part requires divided attention, cognitive flexibility, and more complex perceptual tracking. The participants will be asked to connect the numbers alternating between the two-color sets (1-pink, 2-yellow, 3-pink, 4-yellow…). The completion time will be recorded for CTT1 and CTT2 (up to 240 seconds). In addition, the score of the Interference Index will be calculated as follows: (CTT2 time raw score—CTT1 time raw score)/CTT1 time raw score. The Interference Index score reflects the difference in the participant’s performance between CTT1 and CTT2. Its retest reliability among healthy adults was 0.909 for the CCT-A and 0.912 for CTT-B [50,51].
   3. The Weekly Calendar Planning Activity (WCPA) [32], a performance-based assessment tool, will assess the impact of EF on the participant’s ability to perform a multiple-step activity. A list of 10 appointments is presented to the participant, who is asked to schedule them in a 1-weekly calendar while adhering to five rules. The scores include accuracy, the number of appointments entered, planning time, total time, efficiency, error types, the number of rules followed, and the number of strategies used. Interrater reliability ranges between 0.64 to 0.98 supported in a number of studies across ages, cultures, and clinical populations [52,53]. To our knowledge, this is the first study to use WCPA in cancer.
   4. The perceived cognitive and executive functioning abilities:
      • Cognitive Self Abilities Scale CogPCA (FACT-Cognitive Function Version 3) [53] (https://www.facit.org/ (accessed on 1 July 2022)) will assess perceived cognitive abilities, including those related to EF. The CogPCA scale includes seven statements with responses given on a 5-point Likert scale (from 0, never, to 4, very much, several times a day). The score ranges from 0 to 28, with higher scores indicating greater difficulties. The CogPCA reliability was found (Cronbach’s alpha coefficient = 0.93) in patients with non-CNS cancers [54].
      • The Perceived Cognitive Impairment scale—PCI (FACT-Cognitive Function Version 3) [54] (https://www.facit.org/ (accessed on 1 July 2022)) will assess the perceived cognitive abilities, including those related to EF. The PCI scale includes 18 statements with responses given on a 5-point Likert scale (from 0, never; to 4, very much, several times a day). The score ranges from 0 to 72, with higher scores indicating greater difficulties. The CogPCI reliability is high (Cronbach’s alpha coefficient = 0.97) in patients with non-CNS cancers [55].
   5. The Emotional Well-Being subscale (EWB) [56] from the FACT-G (General) questionnaire (https://www.facit.org/ (accessed on 1 July 2022)) will assess the participants’ emotional status. The EWB scale includes six statements with responses given on a 5-point Likert scale (from 0, not at all, to 4, very much). The score ranges from 0 to 24, with higher scores indicating greater emotional deficits. The EWB subscale was found to be sensitive to change in patients with cancer. Its test-retest reliability within 3–7 days was 0.82 [55].
   6. The Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-F) (Version 4 https://www.facit.org/ (accessed on 1 July 2022)) [57] will assess the participants’ fatigue. The FACT Fatigue includes 13 statements with responses given on a 5-point Likert scale (from 0, not at all, to 4, very much). The score ranges from 0 to 52, with higher scores indicating more fatigue. Internal consistency (Cronbach’s alpha = 0.84) and test–retest reliability (intraclass correlation coefficient = 0.92) was good in a mixed population [58].
   7. Demographic and medical data will be collected using a questionnaire with the following details: age, education, sex, marital status, the number of children, the years of education, work status, dominant hand, socioeconomic level (income level), the type/stage of cancer, disease characteristics (e.g., the size of the tumor, the number of affected lymph nodes), the details of the treatments received (e.g., the types of surgery chemotherapy regimens, the date of chemo commencement, and the number of cycles completed).

2.4.3. Qualitative outcome measures.

Qualitative data will be collected through open-ended questions pre- and post-chemotherapy. The questions will be printed, and participants will be asked by the assessor to answer in writing (see the questions in Table 1). At the pre-chemotherapy assessment, participants will be asked to describe whether they recognize any changes or difficulties in their cognitive functioning since the cancer diagnosis, whether they feel or recognize the impact of these changes on their performance of daily activities, and how these changes are reflected. Post-chemotherapy, participants will be asked to address the same questions by comparing their condition to the pre-chemotherapy assessment.

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Table 1. Flow chart of the qualitative open-ended questions pre- and post-chemotherapy.

https://doi.org/10.1371/journal.pone.0314551.t001

2.6.1. Quantitative data analysis.

At the pre- and post-chemotherapy assessments, data analysis will be performed using SPSS version 27 [59] (https://www.ibm.com/products/spss-statistics (accessed on 16 March 2023)). Descriptive statistics will be used to describe the study population and the outcome measures. Normal distribution of the variables will be verified using the Shapiro–Wilk test. For variables found to be non-normally distributed, appropriate non-parametric tests will be applied. In order to handle error variance in explanatory variables (e.g., demographics), we will consider the transformation of each of these variables into dummy variables where necessary, allowing for more accurate regression modelling. To identify the variables that best explain the daily performance (COPM), multiple linear regression analysis (Enter method) will be used pre- and post-chemotherapy. The enter method will enable us to explore how each independent variable contributes to the model, which is particularly valuable in our study due to the exploratory nature of the research when there are no theoretical reasons to enter the variables stepwise or hierarchically [60]. By treating all variables equally, it will help avoid missing important predictors, which is crucial given the novel context of our study [61]. Given that the sample might not be the same (due to attrition), to confirm that differences in explaining variables are not due to the composition of the sample (but rather to the impairments caused by the chemotherapy), we can also run this analysis, for only participants who have pre- and post-assessments. Three variables that will be significantly correlated with daily performance (pre/post) will be entered into the model. Scatter plots of residuals against the model data will be inspected, as well as outliers and influential data points, along with the variance inflation factor for multicollinearity.

To compare the pre- and post-chemotherapy assessments, for normally distributed variables, paired t-tests will be used; when data are not distributed normally and the scales of measurements are ordinal, non-parametric tests will be used; for the primary outcome (COPM, an ordinal scale), the Wilcoxon Signed Ranks test will be used.

2.6.2. Qualitative data analysis.

The qualitative data include the participants’ answers to the open-ended questions at pre- and post-chemotherapy and additional data during the administration of the semi-structured interview of the COPM. Qualitative data will be analyzed using deductive coding, which is particularly relevant for explanatory case studies [62] methods while ensuring the participants’ anonymity by using pseudonyms (e.g., in their quotations). Data will be coded and categorized into four main categories, which have been determined in advance for the coding protocol in accordance with the literature review and quantitative outcome measures (Fig 3): perceived performance in daily activities and related difficulties; perceived changes in cognitive functioning; perceived difficulties in cognitive functioning; and perceived additional factors that may affect performance in daily activities. First, we will revise and/or confirm that the codes do appear in the data by finding examples; we added codes to the codebook if additional codes are identified in the data; finally, we identified the main themes that will arise [63]. Two authors will perform the text analysis deductively and undertake a thorough description and validation by a few participants to ensure its trustworthiness [26].

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Fig 3. Mixed methods study design for pre- and post-chemotherapy.

Abbreviations: BDS = Backward Digit Span; COPM = Canadian Occupational Performance Measure; CogPCA = Cognitive Self Abilities; CTT = Color Trail Test; FACT = Functional Assessment of Cancer Therapy; FACIT = Functional Assessment of Chronic Illness Therapy—Fatigue; EWB = Emotional Well-Being subscale; PCI = Perceived Cognitive Impairment; RNL = Reintegration to Normal Living Index; WCPA = Weekly Calendar Planning Activity.

https://doi.org/10.1371/journal.pone.0314551.g003

2.6.3. Mixed methods/merging the data.

At pre- and post-chemotherapy, the quantitative results will be reported, followed by qualitative quotes or themes that either support or refute the quantitative results. We will identify qualitative content areas to expand our understanding of the main quantitative results, specifically to those areas that explain how the EF difficulties impact the participants’ performance of daily activities pre-chemotherapy.

Post-chemotherapy, we will divide the sample into two groups (with and without perceived difficulties) according to the participants’ Yes/No answers to the question: “Have you experienced any cognitive changes since you began the chemotherapy?”. The dichotomy of group classification will be performed according to participant’s answers (Yes/No). The changes in EF and performance of daily activities will be compared between groups. In addition, we will build a study diagram to illustrate the results post-chemotherapy.