STRENGTHS AND LIMITATIONS OF THIS STUDY

This pilot trial will provide a comprehensive assessment of the feasibility and acceptability of methods and procedures intended for use in a definitive trial of Responding to Cognitive Concerns, a web-based cognitive rehabilitation programme, in people who have received chemotherapy for aggressive lymphoma.

This study will address an evidence gap in interventions to improve cognitive outcomes for people experiencing cancer-related cognitive impairment.

The web-based intervention will increase equity of access to cognitive rehabilitation for people with lymphoma, regardless of geographical location, and has the potential to provide a new therapeutic option for those with low perceived cognitive function.

Introduction

Many people living after a cancer diagnosis report cancer-related cognitive impairment (CRCI), which can be a distressing and disabling side effect.1 2 Reported rates of CRCI vary, but recent studies of people living with solid tumours (other than blood cancers) suggest that up to 75% of people self-report some degree of cognitive impairment.1 2 The cognitive domains most commonly affected are memory, concentration, information processing speed and executive function.1 Cognitive impairment may be transient for some people; however, for others, these symptoms can be long-lasting and impact the quality of life and ability to function.3

Lymphoma is the sixth most common cancer in adults and the most common cancer in people aged 15–29 years in Australia.4 Current treatments, consisting of combination chemotherapy with or without radiation therapy, provide a 5-year progression-free survival rate of between 65% and 92% and potential cure in around 50% of people.5 This growing population of lymphoma survivors is at risk of side effects from the long-term toxicity associated with their cancer treatments, including cognitive dysfunction.6 The detrimental effects of cancer and related treatments on cognitive function have emerged as a focus of cancer survivorship research.7

Persistent changes in cognitive function are frequently reported by lymphoma survivors.8–12 Our previous research demonstrated that CRCI is a concern for people with aggressive lymphoma and showed very high recruitment rates, retention and compliance with comprehensive assessments.10 13 Our findings highlighted for the first time that cognitive impairment was readily apparent both before and after chemotherapy on objective tests in patients with newly diagnosed aggressive lymphoma undergoing standard treatment with curative intent.10 13–15 This burden is compounded by a lack of evidence for CRCI management.16 There have been a few randomised controlled trials to guide how best to help cancer survivors reporting CRCI to cope with their cognitive functioning, and more evidence is needed.17–20 Cognitive rehabilitation interventions and training programmes have the potential to mitigate changes in cognitive function through strategy and skills training; however, to date, most research has been undertaken in samples that are largely or exclusively composed of people with solid tumours.18 21–23 To date, most interventions have been implemented face-to-face, which may impact accessibility and dissemination. Web-based interventions offer several advantages to face-to-face programmes as they reach a wider demographic group, are cost-effective, provide participants with the flexibility to complete tasks individually in their home and offer anonymity when discussing personal information.17 Web-based cognitive rehabilitation interventions, such as Responding to Cognitive Concerns (eReCog), have been evaluated in people self-reporting cognitive impairment following treatment for solid tumours.24 25 The programme has been adapted from the original face-to-face format and has demonstrated improvements in attention and executive function on objective testing using the WebNeuro online cognitive test battery with small to medium effects.26 Significant improvements were also demonstrated in perceived cognitive functioning measured by the Functional Assessment of Cancer Therapy-Cognitive Function V.3 with small to medium effects.17 21 27

Aims

This study has two aims. The main aim is to test the feasibility and acceptability of methods and procedures intended for use in a definitive trial of a web-based cognitive rehabilitation programme (eReCog) in people who have received chemotherapy for aggressive lymphoma. The secondary aim is to obtain preliminary evidence of efficacy potential.

Objectives

Trial objectives are to determine the feasibility of recruitment and retention at follow-up assessment (primary outcomes); adherence to, usability of and intrinsic motivation to engage with eReCog; compliance with study measures; and potential efficacy of eReCog.

MethodsDesign and setting

This study is a single-site, parallel-group, pilot randomised controlled trial, with one baseline and one follow-up (or postintervention) assessment (figure 1). It will be conducted in the clinical haematology service at a specialist cancer centre in metropolitan Melbourne, Australia. Participants will be recruited over a 12-month period, beginning July 2023. All study methods and procedures were approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/97384/PMCC).

Figure 1

Schematic overview of study design. eReCog, Responding to Cognitive Concerns.

Study population

Individuals will be considered eligible to participate if they meet all of the following criteria: aged 18 years or older, completed chemotherapy for aggressive lymphoma within the past 5 years, in remission at enrolment, low perceived cognitive functioning based on responses to the Cognitive Change Screen (CCS; details provided in methods section),28 have access to a computer with internet and an active email account, are able to read and comprehend English and have a documented Eastern Cooperative Oncology Group Performance Status score of ‘2’ or less.29

Individuals meeting any of the following criteria will be excluded: lymphomatous CNS involvement; prior cranial radiotherapy, received CAR (Chimeric Antigen Receptor) T-cell therapy or allograft; a life expectancy of less than 12 months; any medical condition that may compromise adherence with study procedures or lead to prolonged hospitalisation; and a documented history of past/current substance over use or poorly controlled psychiatric illness.

Recruitment and consent

Potential participants will be identified by the treating team in the clinical haematology clinic. Details of the study will be discussed, and potential participants will receive a copy of the participant information sheet/consent form. If, after understanding the requirements of project participation, the individual agrees to participate, informed consent will be obtained.

Randomisation

After baseline assessment, participants will be randomised one-to-one to the intervention (eReCog) or control (usual care) arm (figure 1). Randomisation will be performed using a computer-generated block allocation sequence and carried out by a member of the research team not involved in the assessment of participants or delivery of intervention.

Interventions

Usual care comprises the provision of a factsheet, ‘Understanding changes in thinking and memory: A guide for people affected by cancer’, produced by the Cancer Council.30 Participants randomised to the control arm (or usual care) will also receive a list of brain training websites on study completion, that is, during follow-up assessment for neuropsychological testing. Participants will not be routinely monitored if they access cognitive rehabilitation programmes independently of the study, as they will be receiving multidisciplinary usual care as per standard practice.

The intervention comprises the provision of the Cancer Council factsheet plus access to eReCog, a web-based cognitive rehabilitation programme based on the principles of cognitive behavioural therapy. The eReCog programme offers psychoeducation on cognitive impairment associated with cancer and its treatment, skills training for improving memory and attention, relaxation training, discussion questions and weekly homework tasks. The programme is supported by a clinician and participant manual to guide therapy.31 It comprises four modules: ageing, health, cancer and cognitive function; memory; attention; and fatigue, emotions and cognition. Each module has a fixed number of web pages, which participants progress through consecutively until reaching the end of the module. Modules take approximately 30–60 minutes to complete, and participants are expected to complete one module per week over 4 weeks. There is a tracking bar indicating the number of pages in the module enabling participants to monitor their progress. Progression through the modules will be tracked by the facilitator (JG) to ensure participants complete each module before access to the next module is enabled. Participants will be sent reminder emails if a task is not completed or discontinues during the module. Individualised feedback will also be emailed to participants on the goal setting activity from module 1 using the SMART approach to goal setting, to help with the management of everyday tasks.27 31

Outcomes, data sources and measurement

Study outcomes focus on the feasibility and acceptability of methods and procedures intended for use in a definitive trial of eReCog. Recruitment and retention were nominated as the primary outcomes, because together, slower-than-expected recruitment and a lower-than-expected recruitment rate would provide a clear indication of the lack of feasibility of a larger trial. Efficacy potential will also be considered; however, results will be interpreted cautiously as estimation is poor in small samples.32 Details of study outcomes are summarised in table 1. Additional information on data sources and measures is provided in the following sections.

Table 1

Study outcomes, objectives, data sources/measures and feasibility/acceptability criteria

Project operation data

Information of recruitment, retention, adherence and compliance will be recorded in a customised project operation database.

Demographic and clinical information

Demographic and clinical information will be gathered via a medical record review at baseline. This will include chemotherapy regimens, including agents delivered, dose intensity, duration and number of cycles. Performance status and current medications, including psychoactive and complementary medications, will also be documented.

Clinical neuropsychological assessment

A series of neuropsychological tests will be administered to participants at two times: baseline (before randomisation) and follow-up (approximately 8 weeks postbaseline) (figure 1). All tests will be administered face-to-face in one sitting in the clinical haematology service. Selected tests include those recommended as part of a core battery of tests by the International Cognition and Cancer Task force.16 They assess cognitive domains most commonly impaired in cancer survivors, are widely used, with normative data available, and have robust measurement properties. We have demonstrated the feasibility of conducting these assessments in a population of people being treated for aggressive lymphoma.10 Estimated testing time is 45 minutes.10 14

Executive function will be measured using the Stroop colour and word test.33 It is based on the observation that individuals can read words much faster than they can identify and name colours. Information processing speed and task switching will be measured using the Trail Making A and B tests.34 Participants draw lines connecting consecutively numbered circles in part A and then in part B connect circles with consecutively numbered alternating numbers and letters. Participants are asked to do the task as rapidly as possible. Verbal memory will be measured using the Hopkins Verbal Learning test.35 Participants are asked to remember a list of 12 words with 3 semantic categories. Three learning trials are followed by a 24-word list in which participants are asked which words are the target words and which are distractors. Verbal fluency will be measured using the Controlled Oral Word Association Test,36 which measures the spontaneous production of words belonging to the same category or beginning with the same designated letter. Auditory-focused attention and working memory will be measured using the Digit Span Wechsler Adult Intelligence Scale.37 The participant remembers a series and repeats them in the same order or in reverse order.

Patient-reported outcomes measures

Measures of cognitive function, fatigue and emotional distress will be administered to all willing participants at the same time as the neuropsychological tests (table 2). All measures are appropriate for use in cancer populations and meet minimum standards for use in patient-centred outcomes and comparative effectiveness research. Measures of usability and intrinsic motivation will be administered to intervention participants only at follow-up (table 2). All patient-reported outcome measures will be administered online via REDCap. Customised links will be distributed via email. Estimated completion time is 30–40 minutes.

Table 2

Schedule of events

Perceived changes in cognitive function will be measured by the CCS.28 This consists of a single item: ‘How much change have you noticed in your memory and concentration since you started chemotherapy?’ Respondents use a 10-cm visual analogue scale, ranging from ‘0’ (no change) to ‘100’ (much worse), to record their responses. A score of ‘28.5’ or higher is used to identify cases of low perceived cognitive functioning.28

Perceived changes in cognitive function of different cognitive domains, including mental acuity, concentration, verbal and non-verbal memory, and verbal fluency in the past week will be measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function-Abilities- short-form 8a.38 Respondents use a 5-item Likert scale ranging from ‘1’ (not at all) to ‘5’ (very much) to rate each item. Responses are summed, pro-rated (if required) and then converted to a t-score (possible range: 23.27–67.09), and higher scores reflect higher levels of perceived cognitive abilities.

Given that fatigue and anxious and depressive symptomatology are thought to be contributors to cognitive dysfunction, fatigue will be measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (QLQ) cancer-related fatigue module (EORTC QLQ-FA12).39 This 12-item questionnaire assesses physical, cognitive and emotional aspects of cancer-related fatigue in the past week. Respondents use a 4-item Likert scale ranging from ‘1’ (not at all) to ‘4’ (very much) to rate each item. Responses are summed, pro-rated (if required), then rescaled to provide a total score (possible range: 0–100); higher scores reflect higher levels of fatigue. The EORTC QLQ-FA12 has undergone extensive validation and is very sensitive to changes in fatigue in previous studies of patients with cancer.40

The frequency of emotions such as worthlessness, hopelessness and sadness in the last 7 days will be measured using the PROMIS Emotional Distress-Depression 8b.41 Respondents use a 5-point Likert-type scale ranging from ‘1’ (never) to ‘5’ (always) to rate each item. Item review involved patients and psychometric evidence supports its use in patients with cancer.42 Responses are summed, pro-rated (if required) and then converted to a t-score (possible range: 35.2–82.4); higher scores reflect higher levels of depression. The frequency of emotions such as fear, stress and anxiety in the last 7 days will be measured using the 7-item PROMIS Anxiety 7a short form.43 Respondents use a 5-point Likert-type scale ranging from ‘1’ (never) to ‘5’ (always) to rate each item. Item review involved patients and psychometric evidence supports its use in patients with cancer.42 Again, responses are summed, pro-rated (if required) and then converted to a t-score (possible range: 36.3–82.7); higher scores reflect higher levels of anxiety.

The ease of use and satisfaction of the eReCog will be measured using the mHealth App Usability Questionnaire44 by intervention participants only at follow-up (table 2). The 18-item scale will assess ease of use and satisfaction, system information arrangement and usefulness of the intervention. Respondents use a 7-point Likert-type scale ranging from ‘1’ (disagree) to ‘7’ (agree) to rate each item. The tool has demonstrated reliability and validity.44 Item responses are summed and pro-rated, if required, to calculate a total score (possible range: 18–126); higher scores reflect higher levels of usability. Intrinsic motivation to engage with eReCog will be measured using the Intrinsic Motivation Inventory (IMI)45 by intervention participants only at follow-up (table 2). Four subscales of the IMI will assess interest/enjoyment, perceived competence, effort/importance and value/usefulness of the intervention. Respondents use a 7-point Likert-type scale ranging from ‘1’ (not at all true) to ‘7’ (very true) to rate each item. The tool has demonstrated reliability and validity.46 Responses to items comprising each subscale are summed to create subscale scores; higher scores reflect higher levels of the targeted construct.

Statistical considerationsSample size

The target sample for this pilot randomised controlled trial (RCT) is 38 patients. The sample size is largely pragmatic, based on available funds, study timeframes (ie, a 12-month recruitment period) and anticipated dropout of 20% by the follow-up assessment. Stepped rules of thumb for pilot sample sizes were also considered. Assuming a medium-sized effect on study measures (0.3 ≤ d <0.7), a sample of 15 per arm is needed for a 90% powered main trial.47

If 38 patients are accrued in 12 months, the expected monthly accrual rate is three patients per month with an exact 95% CI of 2.2–4.3 patients per month; the corresponding CI for the accrual rate over 12 months is 26.9–51.2 patients (estimates calculated in R V.4.2.1 using the ‘epitools’ package).32 48 Assuming a base proportion of 0.5, a sample of 38 patients will provide a 95% CI for retention that is no wider 0.3 (±margin of error = 0.15) (estimate calculated in R V.4.2.1 using the ‘binom’ package). If the target of 38 patients is reached in less than 12 months, recruitment will cease. Power will be insufficient to detect minimum clinically important differences between trial arms on study measures; however, if the CIs for trial arm comparisons contain important differences at follow-up, the intervention will be viewed as promising.32

Statistical analysis

The analysis will include all available data and be performed in R (reference index V.4.3.1 or higher).49 The study statistician (KG) will be not blinded to group allocation, as it is very likely that allocation may be deduced based on the number of participants who complete the motivation and usability questionnaires. Neuropsychological tests and patient-reported outcome measures will be scored according to the author guidelines. Values for missing tests and measures will not be imputed.

Counts and percentages will be used to summarise missing data, including missing items and forms on neuropsychological tests and patient-reported outcome measures, at baseline and follow-up. Descriptive statistics (counts and percentages, means and SD, or medians and interquartile ranges, as appropriate) will be used to summarise demographic and clinical characteristics by study arm. Recruitment data will be summarised using a rate and 95% CI using the Poisson distribution. Adherence, retention, usability, intrinsic motivation and compliance with study measures data will be summarised using a proportion and 95% CI using the Wilson method.50

Descriptive statistics (means, SD and ranges) will be used to summarise test/(sub)scale scores at each assessment by study arm. Differences in test/(sub)scale scores at follow-up will be summarised using a mean and 95% CI, as well as 75% and 85% confidence intervals; these will be compared with estimates of minimum clinically important differences,32 where available. If appropriate, analysis of covariance will be used to estimate differences between study arms adjusting for participants’ baseline scores.

Patient and public involvement

No patients or members of the public were included in the design of the study. The results will be disseminated to participants after the study on request, which will be completed by the study team.

Discussion

This novel pilot study will assess the feasibility and acceptability of methods and procedures for a future RCT of a web-based cognitive rehabilitation programme (eReCog) in people who have received chemotherapy for aggressive lymphoma. This is the first time that eReCog has been undertaken by this patient population, in the post-treatment phase, when cognitive impairment and physical side effects are debilitating.9

This study will address a significant gap in evidence regarding interventions to improve the survivorship experience for people reporting CRCI. The selection of a web-based intervention has the potential to provide better support for cancer patients with cognitive difficulties by helping them return more smoothly to daily living activities, social interactions and work, thus improving their quality of life during and after cancer treatments.51 A mobile web-based intervention will increase equity of access to people with lymphoma, regardless of geographical location, who are normally isolated and cannot benefit from these interventions.52 It has the advantage of allowing individuals to manage their own care, while being remotely supervised, and has the potential to provide a new therapeutic option for people with cancer experiencing cognitive symptoms.

Potential limitations of the study include the recruitment of people who do not have reliable internet connection or less computer literate, restricting their ability to engage with the web-based intervention. Also, as participants will not be routinely monitored if they access cognitive rehabilitation programmes independently of the study, there will be no regulation of ‘drift’ from the control arm to the intervention arm, and finally, the study statistician will not be blinded to group allocation is also a potential study limitation.

Web-based cognitive rehabilitation programmes have shown improvements in quality of life and cognitive symptoms in cancer patients.17 18 21 Nevertheless, there is little known about methods and procedures for a future study of a web-based cognitive rehabilitation programme (eReCog) in people who have received chemotherapy for aggressive lymphoma. For the first time, we will investigate the usability and motivation to engage with the eReCog intervention among people with lymphoma. Findings from this study will inform a future, large multi-site RCT to test the effectiveness of a novel intervention to improve cognitive outcomes and quality of life.

Ethics and dissemination

Ethical approval was granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee approval number HREC/97384/PMCC. The study is registered at the Australian and New Zealand Clinical Trials Registry ACTRN12623000705684. The trial is open to patient recruitment. Participants will not be exposed to any undue risks or harm by participation. This trial will be conducted in compliance with the principles of the Declaration of Helsinki (2013) and the principles of Good Clinical Practice and the Australian National Statement on Ethical Conduct in Human Research.53 We anticipate the study will be completed in September 2024 and report results in 2024–2025. Future publications and presentations will explore feasibility outcomes and patterns of cognitive function over time in this cohort of patients, and relationships between outcomes.

Ethics statementsPatient consent for publication

Not applicable.