Study design
The study design is a conventional two group, parallel RCT with an intervention and control arm (16,17). This unblinded pilot RCT assesses the feasibility of introducing a nurse-led cancer survivorship clinic incorporating symptom management through ePROs and a dietician-led nutrition component in patients with early-stage HR-positive breast and gynaecologic cancer post-primary therapy.
Nurse-led models of care entailing nurses with the appropriate skills and training in survivorship care have been shown to be particularly important with respect to meeting patient’s needs for follow-up care and support, including symptom management (7,18). Moreover, there is clear evidence that diet, nutrition, and physical activity can reduce the risk of certain cancers and more evidence is emerging about the benefits of such for cancer survivors (19,20). Therefore, this study incorporates a dietitian-led component to advise on a healthier diet and lifestyle to reduce the risk of cancer recurrence.
Research ethics
This study will be conducted in accordance with the Declaration of Helsinki, the applicable sections of ICH E6 Good Clinical Practices (21) and the terms of approval of the responsible Clinical Research Ethics Committee of the University’s Teaching Hospital. Full ethical approval for the trial was granted by the Clinical Research Ethics Committee in December 2020 (ECM 4 (y) 20/10/2020). All subsequent amendments to the protocol which impacted or may impact on the conduct of the study have been or will be submitted as amendments for approval to the ethics committee. The most recent protocol amendment was approved in March 2022 (ECM 3 (1) 05/04/2022. The study is registered with ClinicalTrials.gov with a trial registration number of NCT05035173. The manuscript is reported using the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist for a clinical trial protocol (22) (see Additional file 5).
Study participants
Women with early-stage HR-positive breast cancer or gynaecologic cancer within 12 months of completion of primary curative therapy are eligible. Detailed inclusion and exclusion criteria are outlined in Table 1.
Recruitment and screening
Participants will be recruited across a university hospital group comprising of three participating hospitals within a health service region in Southern Ireland. A target sample of 200 participants meeting the predefined inclusion criteria will be recruited. Potential participants will be screened by the research team to determine eligibility and those who meet the inclusion criteria are invited to participate. The study nurse will provide potentially eligible women with oral information about the study and send a follow-up email containing written information in the form of a participant information leaflet and consent form. If potential participants express interest in the study informed consent is sought. All study participants who provide written informed consent either in person, at a clinic visit, or by email or post, are enrolled in the study. The Castor Electronic Data Capture (EDC) platform (https://www.castoredc.com/) will be used to collect and store the study data. Study participants will be facilitated with access to the ePRO measurement system via Castor EDC.
Recruitment will take place over an 18-month period (March 2021 to September 2022). The study duration for each participant is 12 months. Strategies being taken to reach the target sample size of 200 include readily available study brochures and contact details, the use of social media and print media, and education of oncology staff in the participating hospitals about the study.
Randomization
Following consent and enrolment, participants will be randomized, assigned a unique record ID and access to the ePRO measurement system. Randomization of participants will be stratified by cancer diagnosis, with one randomization list for patients with breast cancer and one for patients with cervical and endometrial cancer. Participants will be randomized in a 1:1 ratio to either the intervention group or to the control group, using a computer-generated randomization list using randomly sized blocks of size 4, 6 or 8. Allocation will be done by the study’s principal statistician, via Castor EDC, a secure, computerised database and the study investigators do not have access to the allocation sequence. It is not possible for research team members to be blinded to participants’ group allocation as they will be performing the intervention sessions relevant to each group. However, allocations are only revealed to the research team once a patient has unambiguously consented and enrolled on the trial, and allocations cannot be altered in the database once a patient is enrolled. Furthermore, it is not possible to blind participants to group allocation as they will know which group they are in.
Intervention group
There are two distinct disciplinary components of the complex survivorship intervention, one is the nurse-led clinic targeting improved symptom management, and the other is a dietitian-led component focused on enhancing diet and nutrition (Table 2). The intervention group will have access to the services offered by the WHI cancer survivorship clinic at the start and end of the study period and when needed during the 12-month study period. Participants in the intervention group will receive a link to a survey via email and undertake ePROs at baseline, and at 12 months (end of study). The survey includes a series of assessments concerning symptoms, quality of life, nutrition, and body composition.
Once the ePRO baseline assessment survey is completed, participants in the intervention arm will be invited to attend an initial clinic visit entailing consultations with the study nurse and study dietitian. Participants will receive a study resource folder containing routine standard information and resources about survivorship. They will also receive a “Survivorship Personal Treatment Care Plan” depending on their type of cancer and an “Education and Symptom Management Pathway” which is tailored according to the results of the baseline ePROs. There will be ongoing monitoring of intervention group participants’ symptoms during the study period (months 2, 4, 6, 8, 10) and a trigger system will notify the nurse and/or dietitian of worsening or severe ePRO scores. This trigger system or clinical judgement will prompt symptom evaluation and management in-between routine clinic visits by the study nurse for the intervention arm. The type of symptom support available to intervention group participants will range from supported self-management (i.e., targeted information and advice, telephone support) to onsite clinic-based specialist advice and support, or referrals as specified within a symptom management pathway. Symptom pathways in this study will be available for common symptoms assessed in the ePRO measures such as joint pain, depression, anxiety, vaginal dryness, dyspareunia, hot flashes, cognitive impairment, and fatigue. In the event of no trigger alerts, the study nurse will follow-up with intervention participants via a phone call at 6-months.
The dietitian consultation at baseline provides intervention participants with “Personalized Nutrition Care Plans” involving diet education and nutrition counselling, based on their dietary intake and diet quality assessment ePRO scores. History of alcohol intake and physical activity levels will also be discussed at the initial visit. There will be ongoing self-reported monitoring of intervention participants’ weight and nutritional status during the 12-month intervention period. Participants in the intervention group will be given personal nutrition care plans and nutritional counselling if they trigger on the ePRO system or based on clinical judgement.
Control group
The control group is an active comparator receiving the current standard of care. Control group participants will also attend the WHI cancer survivorship clinic to have consultations with the nurse and dietitian at the start and end of the study periods. At the initial clinic visit, they will receive a “Survivorship Personal Treatment Care Plan” depending on their type of cancer and survivorship resource information. Baseline and end of study assessments of dietary intake and body composition measurements will be recorded during these two clinic visits. The control arm participants will not complete ePROs or attend the clinic in-between baseline and end of study time points. During this period their care will involve routine surveillance via their usual care pathway as per international guidelines comprising of multidisciplinary oncology teams and/or other specialists or services as required.
Participant flow through the study
Figure 1 depicts an overview of study participation using the Consolidated Standards of Reporting Trials CONSORT flow diagram (23).
To promote participant retention and completion of follow-up surveys, an automatic reminder will be emailed if a completed ePRO survey is not returned within 24 hours. There will be a second reminder via telephone call within 72-hours, and after seven days the ePRO symptom survey will be locked. The reasons for discontinuation of participation (Table 3) in the trial will be recorded in the Case Report Form.
Measures
Table 4 (see Additional file 3) provides an overview of the study outcomes and data collection time points. The pilot trial will evaluate the feasibility of introducing a cancer survivorship clinic. The study will also survey the effect of the intervention on key ePROs, i.e., HRQOL and symptoms experienced. The five targeted issues that the trial is focusing on are: fatigue, hot flashes, fear of cancer recurrence, vaginal discomfort, and diet and weight gain/loss concerns. The European Organization for Research and Treatment of Cancer Quality of Life (EORTC QOL) patient reported core and disease specific measures will be used pre- and post the intervention (i.e. at baseline and end of study) to assess HRQOL. Other pre- and post-data being collected includes self-care agency and quality of life.
The Symptom Survey ePRO package includes items from both The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) (8) and The Patient-Reported Outcomes Measurement Information System (PROMIS) (24,25). Participants in both study arms will complete ePRO symptom questionnaires at baseline and end of study timepoints. The ongoing monitoring of symptoms is for the intervention arm only occurring at 2, 4, 6, 8, and 10 months. In addition to the PRO-CTCAE and PROMIS items, the following data will also be collected on an ongoing basis: fear of cancer recurrence, self-reported adjuvant endocrine therapy medication adherence, weight and direct health care resource use.
Both arms of the study will partake in nutritional and physical assessments at baseline and end of study timepoints conducted by a dietitian. Dietary intake assessments include two 24 Hour Dietary Recalls (24HDR) (26–28) and a Food Frequency Questionnaire (FFQ) (29). The first 24HDR assessment will be done face to face in the clinic by the study dietitian to capture a week day dietary intake. The second 24HDR will also be done by study the dietitian, using T-Pro, a telehealth platform, to capture a weekend day dietary intake alongside the self-reported FFQ. Portion sizes will be validated through the use of a food atlas. Dietary quality will be measured using the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) (30) standardized scoring system. Physical assessments of body weight, height, body mass index (BMI), body composition, waist circumference and muscle strength will be recorded. Participants nutritional status will be monitored over the 12-month period via the ePRO symptom surveys where data relating to changes in body weight, concerns about weight gain, nutritional risk and physical activity will be collected at baseline and 12-month timelines for the control group, and at baseline, months 2, 4, 6, 8, 10 and 12 for the intervention group. The Malnutrition Screening Tool (MST) (31) will be used to identify participants at risk of malnutrition. The Nordic Physical Activity Questionnaire NPAQ-short (32) will be used to measure participants physical activity levels.
For the process evaluation, information will be sought on the user experience of the clinic and the computer-based ePROs. This will be done through the administration of a short post-intervention survey to participants from both groups, containing questions on usability and satisfaction. Other quantitative descriptive data will be compiled from the study’s records in order to describe what was delivered in terms of the intervention, and to whom, focusing in particular on the questions of fidelity, dose and reach. In addition, qualitative data will be gathered at the end of the study from a subset of participants from both study arms who will be invited to take part in semi-structured interviews or focus groups to give their opinions of involvement in the WHI cancer survivorship clinic. Interviews or focus groups with implementers of the intervention, namely health care professionals, and key stakeholders, will also be conducted to discuss perceived facilitators and barriers to the roll-out of the pilot clinic.
The economic evaluation will consider the implementation costs of the intervention, estimated using trial information and health care resource utilization collected via a researcher designed tool. Descriptive data regarding the number of resources used by each participant will also be presented, based on analysing data from patient hospital record forms, Case Report Forms, use of resources forms, and patient diaries. Effectiveness will be measured in terms of quality-adjusted life-years (QALYs).
Insert Table 4 here (Additional file 3).
Adverse Events
Study related adverse events are not envisaged. There are no anticipated excess risks to participants receiving the intervention, and all participants are guaranteed access to the current standard of care. If study participation results in any event that has negative consequences for the participant, this information will be recorded by the Principal Investigator of the study in the Castor EDC platform and will be reported to the sponsor of the study i.e., the University, and the University’s Teaching Hospital Research Ethics Committee.
Data management and analysis
The study’s protocol is accompanied by a Data Management Plan. For confidentiality purposes, a study-specific ID code will serve as a unique identifier on the Case Report Forms for all study participants. The codes will be stored separately from the main study database and other study documentation. This unique ID subject code will be linked to the participant’s identifying information by a participant identity list maintained by the study’s Principal Investigator in a secure location at the clinical site of the study. The list of ID codes will not be forwarded to any third party. The purpose of the ID code is to facilitate subsequent follow-up of participants in the event of requiring symptom management intervention.
An on-site Trial Master Folder (TMF) containing confidential data in the form of hard copies of regulatory documents and participant related information will be kept in a locked cabinet in a locked room, accessible only by the study’s research team members. An electronic TMF containing confidential regulatory documents, participant related information, and patient public interactions will be maintained in a dedicated database in a secure location. This confidential electronic data will be stored and backed-up monthly in encrypted folders on a health service laptop, and in the validated web-based nutritional analysis software tool, Nutritics (https://www.nutrics.com/app/#). Access to the database will be controlled at the level of the individual with specific roles assigned, with concomitant access right (e.g., data manager, data entry, auditor etc.). At the end of the study, all anonymized data will be available to the study’s principal statistician, while researchers nominated by the Principal Investigator will also be able to access the final trial dataset.
The study’s primary data catalogue, encompassing primary participant data (Case Report Forms) and participant responses to electronic surveys will be collected and managed using the Castor EDC platform. This platform meets national and international guidelines with respect to data privacy and data protection standards. Once data entry is finalized, study data will be assessed for incompatible, discrepant, or clinically implausible values. Outlying values for all distributions, in isolation and over time, will be identified. Any concerning data will be reconciled against original source data. Following completion of cleaning the database will be locked.
Sample size
Given that the main objective of this study is to evaluate the feasibility of introducing a survivorship clinic, a pragmatic approach was taken in determining the sample size for this pilot trial, considering the numbers of potentially eligible patients attending the institution, and funding availability. Sample size rationale is therefore based on recruitment of the largest possible sample which will maximize the ability to identify barriers to implementation of the clinic, and collect information in parallel arms that will be required to properly design a next step efficacy study (45,46) (e.g., robust estimation of estimator variability, even for binary outcomes) (47). It is thus anticipated that a sample of approximately 200 participants will enable the achievement of the study objectives i.e., 140 participants with early-stage breast cancer and 60 participants with cervical or endometrial cancer, and guide next step study design.
Statistical analyses
The primary objective of the study, namely an evaluation of the feasibility of the clinic, will be assessed according to several outcomes, including the number of enrolled participants who complete the baseline and follow-up ePRO surveys, and the number of participants who partake in healthcare professional consultations following ePRO data triggers; the number of participants that require medical review and the timeframe involved; the average consultation time; the number of participants enrolled in the clinic; extra health care professional time and resources needed to run the intervention.
While this is a feasibility study, we will also take advantage of the collection of ePROs (described above) to estimate the efficacy of the intervention using generalized linear models with adjustment for baseline outcome and key prognostic covariates in the intention to treat sample. Higher PRO-CTCAE responses represent worse functioning, indicated by higher frequency, greater severity, and/or more interference. Higher PROMIS T-scores indicate more symptoms, indicated by more of the domain being measured. Health-related quality of life (QLQ) scores assessed by the EORTC core, and breast cancer, cervical cancer and endometrial cancer modules will be analysed by linearly transforming scores to a 0-100 scale, with a high or healthy level of functioning representing a high functional score. EQ-5D-5L-QALY scores will be reported, with a high score representing high functionality problems. Appraisal Self-Care Agency R-scores will be reported, with a higher score representing better self-care agency. Adjuvant endocrine therapy medication adherence will be assessed by analysing participants’ self-reporting data.
All estimates will be reported with 95% confidence intervals and exact p-values. Data analyses will be conducted and/or supervised by the study’s principal statistician, under established quality systems and standard operating procedures, and in accordance with ICH E9 Statistical Principles for Clinical Trials (48) and ICH E6 Good Clinical Practices (21), and following a detailed statsitical analsysis plan that will be pre-registred prior to database lock. Analyses will be conducted using the R Project for Statistical Computing and the RStudio integrated development environment (IDE) statistical software packages. The trial reporting will be done following Consolidated Standards of Reporting Trials CONSORT and the CONSORT addendum for pilot and feasibility trials (49). Missing data will be evaluated, and based on what is observed, and dealt with in whatever manner deemed most appropriate based on current best practices.
Nutritics will be utilized to capture dietary intake information, and data from the multiple 24HDR assessments will be analysed using the United Kingdom’s composition of foods data from McCance and Widdowson’s integrated dataset (26), the United States Department of Agriculture (USDA) Food Composition Database (27), and the Irish food composition database (28). Data concerning changes in nutritional status will be complemented by nutrient data from the European Prospective Investigation into Cancer Study EPIC-Norfolk Food Frequency Questionnaire (FFQ) (29) based on version 6 (CAMB/PQ/6/1205). Data gathered via the FFQ will be entered into a validated processing tool, FETA (Φετα) FFQ EPIC Tool for Analysis, based on the Compositional Analyses from Frequency Estimates CAFE system (29). Changes in diet quality scores will be based on the WCRF/AICR standardised scoring system (30), with higher scores representing a better diet quality. BMI scores will be calculated based on combined weight and height scores and is part of the WCRF/AICR scoring system. Changes in waist circumference will be calculated based on physical assessments performed by the study dietitian. Segmental Body Composition scores will be measured by the Body Composition Monitor bioimpedance spectroscopy. Muscle strength scores will be measured in terms of handgrip strength measurements based on the Jamar Dynamometer (Model 091011725), with the handle in the second position as recommended by the American Society of Hand Therapists (50). Nutritional risk scores will be assessed by the MST (31) with a higher score representing a higher risk of malnutrition.
For the process evaluation, the results of the usability and satisfaction survey will be summarized visually in a Table and presented as response distributions (number, percentage). Analysis of the usability and satisfaction survey questions will involve the summation of usability and satisfaction scale scores and examination of these across respondents, with 0.80 the proposed threshold for defining usability and acceptability, counting only positive endorsements (4=agree, 5=strongly agree) (10,51). Qualitative data will be analysed thematically.
The economic evaluation will consider the potential cost effectiveness of the intervention by comparing incremental costs and effects of the intervention with the control incremental cost effectiveness ratio (ICER), in accordance with national guidelines (52). Effectiveness will be measured in terms of QALYs. This will be informed by applying the Irish EQ-5D-5L Value Set (53) to the EQ-5D-5L data collected in the trial. A probabilistic sensitivity analysis will be conducted to investigate uncertainty around parameter inputs and results.
Data Monitoring
The University as the study sponsor is the Data Controller responsible for the study. Castor EDC provides for a full audit trail of user actions to be recorded and data check procedures for Castor EDC will be conducted every three months from the start of the recruitment process by the study team. Biannual monitoring reports will be provided to the study’s Sponsor Office, and a Clinical Trial Audit will be provided by the study’s Clinical Research Facility as required from the Sponsor Office. The study team will provide annual reports to the study’s funders as expressed in the funding agreements. Based on the non-medical intervention and low risk nature of participation in the study, a Data Monitoring Committee was deemed to be unnecessary.
Dissemination
In consultation with the study funders, it is planned to disseminate the key findings of the pilot trial after the end of the study whereby anonymized individual participant data sets will be shared in the form of results within peer-reviewed publications, academic conferences, workshops, and seminars. Planned public and patient dissemination outputs include public blogs, media, and outreach engagement events, including press articles and seminars. The protocol is published on the ClinicalTrials.gov website, trial registration number NCT05035173. Post-study shared outputs including the study protocol, data dictionary and analysis scripts will be available via the Open Science Framework.
Patient involvement
The study team members are collaborating with a public and patient involvement (PPI) panel in the design, development, implementation, analysis, and dissemination of the study. The PPI panel includes patient advocates who have had breast or gynaecological cancers, and stakeholders including clinical and academic experts, wider members of the multidisciplinary team, community support groups, as well as the trail’s funders.