Effect of perceived injustice-targeted pain neuroscience education compared with biomedically focused education in breast cancer survivors: a study protocol for a multicentre randomised controlled trial (BCS-PI trial)

This protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials recommendations32 and was registered prior to recruitment on ClinicalTrials.gov: NCT04730154. All items from the WHO Trial Registration Data Set can be found in online supplemental appendix 1 and all protocol versions in online supplemental appendix 2.

Study design and study setting

This is a multicentred randomised controlled trial with two balanced treatment arms and with blinding of assessors and investigators. The trial is spread over five different hospitals in Flanders, Belgium (online supplemental appendix 3).

Eligibility criteria

To be eligible, participants must fulfil the definition of survivorship introduced by the European Organisation for Research and Treatment of Cancer (EORTC) Survivorship Task Force, in which a cancer survivor is as follows: ‘any person who has been diagnosed with cancer, has completed his or her primary treatment (with the exception of maintenance therapy) and has no evidence of active disease’.33 Additionally, participants need to:

  1. be women aged ≥18 years;

  2. be in complete remission and should have finished their primary breast cancer treatment with curative intent ≥3 months (adjuvant hormonal therapy and immunotherapy are tolerated);

  3. report a pain severity of ≥3/10 on the Brief Pain Inventory (BPI);

  4. be able to speak and read Dutch;

  5. show a level of perceived injustice of ≥17/48 on the Injustice Experience Questionnaire (IEQ).

Participants will be excluded if they:

  1. are diagnosed with new neoplasms or metastases;

  2. have a chronic disease which is not well controlled and/or is causing pain (eg, fibromyalgia and rheumatoid arthritis);

  3. are suffering from a severe psychological/psychiatric disease;

  4. are suffering from dementia or cognitive impairment (unable to understand instructions and/or ≤11/28 on the Six-item Cognitive Impairment Test (6-item CIT));34 35

  5. recently started a new treatment/training which is not yet at a stable level.

To facilitate participant recruitment and optimise the external validity of the study findings, assessments will take place at five different hospitals in Belgium (online supplemental appendix 3). Additionally, pharmacies, patient support groups, occupational health services, social media and advertisements in local newspapers will be used as recruitment strategies. The initial screening of interested participants will be executed by independent investigators at the hospitals or by phone. After this short screening, an online questionnaire (±5 min) will be sent to the participant to define the BPI pain severity score and the total IEQ score. Eligible patients will be asked to provide written informed consent (online supplemental appendix 4). With this consent, participants agree to keep appointments for treatment sessions, not to initiate any new treatment/medication from the moment they are contacted by phone for study inclusion until 3 months after the intervention or to participate in any other medical-scientific study during participation.

Interventions

To balance non-specific treatment effects, the duration, format, number of sessions and didactical approach will be identical in both treatment groups (see structured description of treatments in table 1). All participants will receive an online session (±1 hour) followed by three individual one-to-one sessions (±45 min), allowing them to individually tailor the sessions. After each session, all participants will be asked to report the content of the session in a personal logbook and to report co-interventions, medical consumption (eg, the type, dose, method of administration and frequency of medication) and any other healthcare visits and interventions. The one-to-one sessions are provided by trained physiotherapists at the study site of the participant’s preference and will be spread over a 4-week period.

Table 1

Overview of the content of the sessions in both intervention groups

Treatment development and training

The treatment manuals, including the pre-recorded sessions, were developed before study initiation. The perceived injustice-targeted PNE and motivational interviewing manual were developed by combining research and the input of clinical experts in the field of PNE, perceived injustice and motivational interviewing. The biomedically focused pain education was developed by research experts in the field of breast cancer.

The training of the physiotherapist will be done by one of the developers of the manuals. Both trainings consist of a minimum of two contact moments of ±2 hours spread over ±3 weeks. The physiotherapists will be selected based on their experience and/or interest in working with cancer survivors. Moreover, experience with one of the two types of education provided in the trial was screened in advance in order to control for contamination (eg, a therapist with experience providing PNE cannot provide biomedically focused pain education).

Experimental treatment: perceived injustice-targeted PNE + motivational interviewing

The first online pre-recorded PNE session focuses on a better understanding of post-cancer pain prior to the first one-to-one session. The primary focus of the treatment plan is to shift maladaptive pain behaviour to beneficial pain behaviour. Therefore, the mechanisms underlying pain will be explained to clarify the rationale for changing. Perceived injustice will be introduced as a contributing factor for pain and central nervous system sensitisation. This can serve as a first step in accepting their condition and the associated suffering and should ease talking about perceived injustice during the next session. The content will be based on the books ‘Explain Pain’ and ‘Pijneducatie, een praktische handleiding voor paramedici’ as previously used in other chronic pain populations36 37 but adapted to BCSs.38 The information will be presented in different ways by using pictures, examples and metaphors.22 At the end of the first session, participants will have to read the perceived injustice-targeted PNE information leaflet summarising the information of the online session. Since an important portion of BCSs reports impairments in attention due to the so-called ‘chemo brain’,39 40 it will be valuable to have additional written information as well as the recorded session at the participant’s disposal to minimise the impact of loss of concentration.

Therapists will start the first one-to-one PNE session by discussing the participant’s responses to the online questionnaires, as well as their experience and questions regarding the online PNE session and the information leaflet. This information will be used to situate the participant within the phases of behavioural change, as well as to define perpetuating factors (eg, acceptance and opioid use) to start an individually tailored treatment. The practical guideline accounting for perceived injustice in cancer survivors will be used.31 Both valued life goals and treatment goals will be set within a shared decision-making process.

The second and third one-to-one PNE sessions will consist of individually tailored PNE based on the participant’s stage of change. The (perceived injustice-targeted PNE and) motivational interviewing will aim at encouraging participants in pursuing life goals again and restart valued occupations while experiencing pain by eliminating the feeling of wanting to control or avoid pain.15 41 In addition, pain acceptance will be addressed by broadening their understanding of their pain problem, including discussing the possible pain-aggravating role of anger and frustration. During the communication, following motivational interviewing principles, the therapist is supportive, empathetic, positive and hopeful and relies on the therapeutic alliance to assist in changing certain health behaviours based on the person’s internal thoughts such as perceived injustice, decisions and motivation. Motivational interviewing also aims to strengthen personal commitment by respecting the individual’s autonomy and assists in reaching a specific goal by exploring personal intentions or reasons for change.29 30

Active comparator: biomedically focused pain education

The first online pre-recorded biomedically focused pain education session will contain information about the different types of pain (nociceptive pain, neuropathic pain and nociplastic pain) and how oncological treatment methods, such as surgery, chemotherapy, radiotherapy and hormone therapy, are able to provoke pain with a primary focus on structural tissue damage. The role of different structures and injured versus healthy tissue in acute and persistent pain will be discussed. Pain will be explained from a biomedical perspective (eg, injured tissues causing pain) and a biomechanical point of view (eg, pain is explained as deviance from, eg, normal expected movement patterns and postures). At the end of the first session, participants will have to read the information leaflet from Stand Up to Cancer regarding ‘Pain in and after treatment’ summarising the information provided during the online session. The use of the leaflet within the study has been approved by Stand Up to Cancer.

During the first one-to-one session, participants’ responses to the online questionnaires and the participant’s experience with and questions regarding the online education module and the information leaflet will be discussed at the beginning of this session. After this, participants will receive accurate information about pain medication (eg, indication of use and adverse effects), if relevant, based on the cancer pain management proposed by WHO (World Health Organization).42

During the second one-to-one session, additional questions that arose after reading the information leaflet will be addressed. Second, additional pain treatment methods are explained, such as specialised techniques for nerve pain (eg, transcutaneous electrical nerve stimulation) and others (eg, physical activity). Therefore, participants will receive advice, including concluding treatment options, on how to deal with their pain. Goals will be set from a biomedical point of view.

The third one-to-one session will be used to support self-management. The latter will adhere to current best-evidence practice guidelines43–45 including advice on activity self-management (eg, to stretch muscles, increase their physical activity level gradually and tips regarding nutrition).

Outcome measures

The primary outcome is pain severity. The secondary outcomes are health-related quality of life, perceived injustice and outcomes for a cost-utility analysis. Sleep, fatigue, pain cognitions, depression, anger, acceptance, treatment adherence and compliance, and co-interventions will be added as explanatory outcomes. The outcomes are all self-reported questionnaires and based on the Dutch Oncoline recommendations and on previous studies performed in cancer46–54 and non-cancer pain populations.55–61 An overview of the assessments is presented in table 2. Assessments will be performed online at the following timepoints:

  • T0: within the week before the randomisation and the intervention (baseline)

  • T1: immediately after intervention

  • T2: 6 months after intervention

  • T3: 12 months after intervention (primary endpoint)

  • T4: 24 months after interventions (extended endpoint)

Table 2

Study outcome measures by assessment time point

Personal characteristics

Personal characteristics including date of birth, nationality, race/ethnicity, level of education, professional situation, family income, relationship status, physical activity, smoking status, alcohol consumption, body mass index, comorbidities, lymphoedema, type of breast cancer treatments received, time since onset of complaints, time since complement of breast cancer treatment and treatment expectations will be collected at baseline.

Primary outcome: pain

BPI is developed by the Pain Research Group of the WHO Collaborating Centre for Symptom Evaluation in Cancer Care.62 It is a 14-item self-reported questionnaire assessing worst pain, pain severity and pain interference in patients over the past week on a scale of 0 to 10.62 Pain interference is measured as the average of the seven interference items. BPI is the most common, reliable and valid outcome measure to assess pain in cancer survivors (Cronbach’s alpha and test-retest reliability score >0.80).62

Secondary outcome measure: quality of life

Health-related quality of life is an established prognostic indicator of breast cancer.63 The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30) is a 30-item cancer-specific questionnaire developed for the assessment of the quality of life in patients with cancer.64 65 The EORTC QLQ-C30 is widely used in cancer studies, has been translated and validated in Dutch and shows acceptable psychometric properties.64 The internal consistency measured by Cronbach’s alpha resulted in 0.94.48

Secondary outcome measure: perceived injustice

The 12-item IEQ will be used to assess perceived injustice.66 Participants must rate the frequency of 12 different pain-related statements on a 5-point Likert scale ranging from 0 (not at all) to 4 (all the time). The sum of all items gives the total score which ranges from 0 to 48. The higher the score on the IEQ, the higher the level of perceived injustice. A cut-off value of 17 was calculated by taking the 75th percentile,66 which suggests a clinically relevant degree of perceived injustice in BCS. The IEQ has good (test-retest) reliability (ICC=0.86–0.87) in its Dutch version.67 The scores derived from the IEQ are found to be valid60 68 with an excellent internal consistency in advanced cancer.69

Secondary outcome measures for cost-effectiveness analysis

A cost-effectiveness analysis will be conducted following the manual by Hakkaart-Van Roijen et al.70

Healthcare use (including co-interventions) will be assessed using the Medical Consumption Questionnaire (MCQ).71 This is a well-established, generic, instrument-to-measure total (in-)direct medical consumption.71 Indirect costs will include costs related to productivity loss. These will be assessed using the Productivity Cost Questionnaire (PCQ).72 Both questionnaires are easy to use and able to generate valid data.73 74 In accordance with their user manuals, the questionnaires will be modified to match the respective setting.

Health-state utilities will be obtained from the EuroQol EQ-5D-5L and will be used to calculate quality-adjusted life years (QALY).75 76 The EQ-5D-5L items are scored on a 5-point Likert scale for five different dimensions.75 The EQ-5D-5L is a reliable and valid measurement tool for the evaluation of overall health in breast cancer.50 77 Moreover, Belgian population norms are available for the EQ-5D-5L.78 The use of the latter three tools is recommended by the Institute for Medical Technology Assessment, Erasmus University Rotterdam.79

Explanatory outcomes

A detailed overview of several explanatory outcomes which all have been proven to be related to the development of chronic pain80 can be found in table 3.

Table 3

The explanatory outcomes with their measurement tool(s)

Treatment fidelity

Fidelity criteria will be developed before the start of the interventions. Independent investigators, experienced with the treatment, will evaluate a random selection of the tapes of each therapist using the fidelity criteria to score the audiotapes of the treatment sessions provided.81

Patient and public involvement

One of the biggest Belgian Cancer charities, Kom op tegen Kanker, reviewed all parts of the trial, including the design, management and conduct of the trial. We received input from their experience with patients who survived breast cancer. We carefully assessed the burden of the trial interventions on patients. We intend to disseminate the main results to trial participants and will seek patient and public involvement in the development of an appropriate method of dissemination.

Sample size calculation

Sample size calculations were performed with G*Power 3.1.3 for between-group differences (t test) at 12 months of follow-up. The sample size calculation was based on an earlier trial regarding a conservative intervention for treating pain in BCS that had the same primary outcome (eg, BPI) and identical 12-month follow-up.46 Based on that earlier trial46 and calculation methods described by Lakens,82 the effect size was set to 0.44, based on an observed difference of 1.8 on BPI and a CI between 0.9 and 2.6 for 83 participants. The type I error was set to 0.05 and the type II error to 0.2. The resulting sample size for a one-sided test was 65 per treatment arm. Accounting for a risk of loss to follow-up of 20%, a total sample size of 156 participants is needed.

Treatment allocation

Randomisation (figure 1) will be done separately for each treatment centre by an independent researcher. Randomisation occurs using a computer-generated random number sequence (developed by Gerard E Dallal, PhD—http://www.randomization.com). A list with participant numbers and the group allocation that results from this randomisation procedure will be stored on a private SharePoint which is only accessible by the independent researcher. Participants will be scheduled by the therapists to receive their first assessment within 1 week of randomisation.

Figure 1
Figure 1

Flowchart of the BCS-PI trial (breast cancer survivor-perceived injustice trial).

Blinding

Due to the nature of the intervention, blinding participants to the content of the intervention is impossible. However, participants will not be informed about whether they received the experimental or control intervention. The statistician will be blinded to group allocation. All outcome measures are self-reported and eventual queries concerning the questionnaires will be addressed by a blinded independent assessor. The interventions will take place at different times during the day so that participants of different intervention groups do not meet and between-group contamination is avoided.

Data collection, data management and confidentiality

All questionnaires will be processed in an online software program REDCap.83 REDCap is General Data Protection Regulation compliant. Data, both numeric and textual, filled in by the participants online will be saved automatically. Encrypted identifiers (ie, a unique pseudonymised participant ID) will be used to separate the personally identifiable information from the clinical data. This link will be stored securely in REDcap. Clinical data will be saved under the pseudonymised participant ID. REDCap will be used for data storage, management and processing. Additionally, data will be stored on an encryption and password-secured Institutional SharePoint with sufficient storage space and limited access to the research team trained in human subject protection. Confidential individually identifiable data, including the pseudonymisation key, will be stored in a separate folder. Long-term data preservation will be done in the Vrije Universiteit Brussel University Archive.

To avoid loss to follow-up, REDCap automatically sends follow-up assessments and a reminder in case of no response for each endpoint. In addition, participants will be contacted by telephone and/or get reminders by email to complete all assessments.

Statistical analysis

A linear mixed model for repeated measures will be used to evaluate treatment effects over time in terms of pain, health-related quality of life, perceived injustice and opioid use. Such analysis allows more precise parameter estimates and can handle missing data. The baseline value of the outcome, explanatory outcomes (table 3), medication use and demographics will be considered covariates. Statistical and clinically significant differences will be defined, and the effect size will be determined. In addition, the numbers needed to treat will be calculated.

QALY’s (health effect) for the cost-effectiveness analysis will be calculated from utility scores derived from the EQ-5D-5L using Belgian population norms.78 Both direct healthcare costs (calculated based on the information gained from the MCQ) and indirect costs (productivity loss costs calculated based on the information gained from the PCQ)84 will be determined. Healthcare use will be valued using unit reference prices published by RIZIV-INAMI85 86 and BCFI-CBIP.87 All costs will be expressed in euros; indexed using the Health Index for Belgium, if necessary84; and reported in detail in a non-aggregated form. The incremental cost-effectiveness ratio will be calculated, and probabilistic sensitivity analysis will be performed. The impact of methodological choices will be evaluated by scenario analyses. Dissemination of the cost-utility analyses will follow the Consolidated Health Economic Evaluation Reporting Standards.88

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