The Wessex Fit-4-Cancer Surgery Trial (WesFit): a protocol for a factorial-design, pragmatic randomised-controlled trial investigating the effects of a multi-modal prehabilitation programme in patients undergoing elective major intra–cavity cancer surgery

Introduction

The number of new cancer cases per year is expected to rise to 23.6 million by 2030. Depending on the cancer cohort, major curative cancer surgery is associated with post-operative morbidity in up to 50% of gastrointestinal cancer patients and up to 60% in pancreatic cancer patients especially after neoadjuvant cancer treatments.^1–3 Improved surgical, oncological and anaesthetic techniques, enhanced recovery pathways and perioperative care have delivered consistent improvements in length of hospital stay, in-hospital morbidity and readmission rates after major surgery. However, over half of patients over the age of 60 years after major abdominal surgery live with reduced functional capacity, physical fitness and quality of life (QoL), with a significant proportion never regaining pre-operative fitness or independent living.^4,5 Our group and others have described the association between reduced pre-operative physical fitness^6–11 (and its decline with neoadjuvant cancer treatments) and poor post-operative outcomes in upper and lower gastrointestinal cancer patients. Furthermore, we have reported on the associations between reduced physical fitness and reduced mitochondrial function,¹² QoL^13,14 and physical activity¹⁵ after cancer treatments before surgery.

Cancer prehabilitation is a novel process that occurs between the time of cancer diagnosis and continues throughout the cancer treatment pathway. The time before cancer diagnosis and surgery is an emotionally salient time where patients are receptive to changes in behaviour regarding their nutrition, fitness and psychological coping. Physical fitness, nutritional and psychological multimodal prehabilitation are targeted, tailored interventions with the aim to prevent, minimise and/or rescue the severity of anticipated treatment-related impairments that may cause significant disability when recovering from major cancer surgery.¹⁶ Given the multi-system impact of cancer and its treatment(s), prehabilitation interventions have adopted a ‘multimodal approach’, that may be defined as the incorporation of two or more intervention components specifically selected for their potential cumulative or synergistic effects on health outcomes. Reviews of prehabilitation in surgical oncology identify many limitations in the current evidence, yet acknowledge encouraging findings including improved fitness, endurance time, length of hospital stay, surgical complication rates, and health-related QoL with prehabilitation interventions.^17–26 Recently, multinational consensus statements jointly from Macmillan Cancer Support, the Royal College of Anaesthetists and the National Institute for Health Research in the United Kingdom,²⁷ Exercise and Sports Science Australia^28,29 and the Academy of Medical Royal Colleges in the United Kingdom³⁰ aim to advance the care provision, inform a change in policy, inform service provision, and implement a practice to benefit people living with cancer. Specifically, effective prehabilitation using multimodal physical activity, exercise, nutrition and psychological support, underpinned by behaviour change support, to improve cancer outcomes is advocated. Thus far the evidence is mostly based on uni-modal interventions, for example exercise interventions to improve physical fitness and post-operative complications^{20,22,31–34} and respiratory interventions to improve pulmonary specific morbidity,²⁶ however literature utilising multimodal interventions (mostly exercise and nutrition) to improve outcomes is now emerging.^18,19,35,36

To date exercise prehabilitation trials have focused on in-hospital training with little consideration for sustainable models of delivery. There has also been a lack of inclusion of behavioural science to facilitate engagement and longer-term behaviour change post-surgery. Furthermore, increasingly, evidence suggests that psychological factors impact physiological and psychological outcomes in both the short and long term, with implications for recovery from surgery, QoL and re-attainment of independent living.³⁷ A systematic review of psychological prehabilitation before cancer surgery suggests such interventions can positively impact QoL and psychological outcomes (such as distress and anxiety). However prehabilitation studies including a psychological component have tended to be small, therefore, an evaluation of a psychological intervention together with an exercise intervention as part of a multimodal prehabilitation programme in cancer patients is urgently needed.²³

Protocol

Study design and setting

The Wessex Fit-4 Cancer Surgery trial (WesFit) is a multi-centre, 2 × 2 factorial design, randomised-controlled, single blind, phase III clinical trial designed to compare the effect of structured prehabilitation programmes, against standard pre-operative care on patient outcome following major intra-cavity surgery for cancer (Figure 1). Participant recruitment, assessment and intervention are organised by NHS Hospital trusts who oversee referral to our community partners in local gymnasiums (exercise and behaviour change intervention) and Cancer Support centres (psychological intervention). The trial was registered with clinicaltrials.gov (NCT03509428) on April 26th, 2018. This protocol follows the SPIRIT guidelines – see Reporting guidelines.⁵⁶

Figure 1. Trial summary diagram.

MDT: multidisciplinary team, CPET: cardiopulmonary exercise test, SREPT: structured responsive exercise training programme, WHODAS: World Health Organisation Disability Adjusted Survival.

Outcome measures

Baseline assessment will occur as close as possible to the MDT treatment decision. All patients repeat assessments immediately prior to surgery. Patients undergoing neoadjuvant cancer treatment (e.g. chemoradiotherapy for locally advanced rectal cancer patients) will undergo repeat CPET every 4-weeks (depending on site availability), in order to assess continued eligibility and to moderate training intensities according to physiological adaptation. Post-operative assessment occurs during hospital admission, at 30 days post-surgery, at 6- and 12- weeks post-surgery and 12-months post-surgery. The schedule of observations and procedures can be found in the Extended data.⁵⁶

Primary outcome

Length of stay is defined as the number of days a patient stays in hospital following surgery. It is calculated by subtracting the date of surgery from the date of discharge. The date of surgery is defined as day 0 of a patient’s post-operative hospital stay.

Secondary outcomes

Exploratory outcomes

Process evaluation

Qualitative in-depth semi-structured interviews will be conducted with patients enrolled in the trial and professionals involved in the delivery of the trial at two time points. Interviews of up to 1 hour will be conducted either face to face at a location convenient to the participant or by telephone depending on preference. A researcher with experience in qualitative interviewing and who is not part of intervention delivery will conduct the interviews. Firstly, patients from all arms of the study (N = 12) and key stakeholders; personal trainers, research nurses and counsellors (N = 5) will be interviewed regarding their experiences of the trial once the first 30 patients have reached 12 weeks post-surgery. The sample size is pragmatic based on the time and resource available early in the trial and will provide an opportunity for the research team to reflect on the experiences of patients and professionals involved in the trial, identifying barriers and facilitators to trial processes and implementation (professionals) and trial experiences (patients). If any amendments to the trial are deemed necessary, a substantial amendment will be submitted to the ethics committee and Health Research Authority (HRA) for approval.

Following completion of the trial structured interviews will be conducted with 25 patients (with representation from all 4 study arms) to understand patient experience of the trial and subsequent behaviour change. The sample size is will allow for purposive sampling with sampling characteristics including a range of age, sex, disease type, and whether or not they received neoadjuvant treatments. Interviews will also be conducted with stakeholders involved in the delivery of the trial, to include personal trainers, counsellors, research nurses (including other research team members) and members of clinical care teams, commissioners and cancer centre staff (N = 15). These interviews will seek to understand the barriers and facilitators to the implementation of the trial into clinical practice and within the community setting. All interviews will be audio-recorded, transcribed verbatim managed through NVIVO software (v12) and analysed using thematic analysis with an inductive approach. Normalisation process theory will inform data collection and analysis.⁵⁵

Estimation of sample size

From previous studies, the median length of stay in the control group is estimated to be 7 days. To detect a clinically meaningful difference of a (significance level to detect a hazard ratio of 1.17 when the control group median in-patient time is 7 days) 1 day reduction in LOS with 85% power, alpha = 0.05, a sample size of 1560 participants will need to be recruited over 3 years, with a one year follow-up period. The sample size allows for a 20% drop-out.

Sample size calculations for 2×2 designs are based on the two main comparisons (i.e. exercise vs. no exercise and psychological support vs. no support). The trial sample size is the larger of these 2 comparisons, so in this case, the sample size calculation is powered on the psychological support comparison. The sample size calculation assumes that there is no interaction between the interventions.

Statistical analysis plan

Descriptive statistics will be used to summarise the baseline demographic and clinical variables. For continuous variables, if the data are normally distributed, the mean and standard deviation will be calculated. If the data are not normally distributed, the median and interquartile range will be calculated. For categorical or binary variables, these will be summarised as frequency and percentage of total. There will be a variety of data consistency and quality checks performed at various stages of the data capture process, e.g. regular calibration and monitoring of measuring instruments, use of control standards in assays. All extreme values (mean +/- 3* standard deviation) and improbable values, as defined by clinical opinion will be investigated. In depth descriptions of these procedures exist in the trials data management plan, data management procedure and the data validation plan (code book) held by the sponsor. Outcomes assessors and statisticians will be blinded to trial arm until completion of analysis.

Patient and public involvement

Patient and public involvement has been included throughout. As part of the development of WesFit 2 focus groups and 1 interview were conducted with patients who had been encouraged to exercise prior to cancer treatment including: an individual who had undergone exercise in a community setting following general practitioner (GP) referral, a focus group (N = 12) of patients and carers who had taken part in clinical trials conducted by University Hospital Southampton (UHS) NHS Foundation Trust where they had performed in-hospital exercise training and a focus group (N = 2) of patients and cares who had attended the ‘Fit 4 surgery’ school at UHS. This informed the design of the trial such as the inclusion of support from personal trainers after surgery and the most appropriate language used to communicate the psychological element of the trial. These discussions also informed the managed process of community referral with links to the clinical teams clearly visible to patients to ensure they felt safe. Three patient representatives are included in the trial management group. They review and revise all patient facing documentation and trialled completion of all patient reported outcome measures. They were also consulted regarding the burden of the trial on participants. They will also help inform and facilitate future dissemination plans.

Ethics and dissemination

The trial was initially authorised by London – Westminster Research Ethics Committee (REC reference 18/LO/0129) on 06/03/2018. Before a patient is randomised to the WesFit Trial, written informed consent will be obtained. When obtaining consent from a patient, the trial and the patient information sheet will be introduced in full. Written confirmation that the patient has given their consent to participate in the trial will be recorded by member of the research team according to local practice.

The chief investigator and trial sponsor will have access to the full dataset. Generalisable results will be published in scientific journals, incorporated into multi-disciplinary society guidelines and presented at cross-disciplinary international scientific conferences, patient groups, cancer charities and NIHR strategic partners.

Monitoring and trial management

University Hospital Southampton NHS Foundation Trust is acting as sponsor for this trial. The sponsor will ensure that all regulatory policies adhered to in line with GCP and phamacovigilance policies. Day to day trial management, including site set-up, training and urgent consideration of safety concerns, will be the responsibility of the chief investigator. The trial management group will meet monthly and oversee the day to day running of the WesFit trial.

A project board will be responsible for all governance and finance frameworks and have oversight of the study conduct and management. The board will have an independent chair and consist of representatives from the sponsor, patient groups and study partners.

Data collection, quality and storage

Data will be collected and stored on password protected databases by trial personnel, who are trained in good clinical practice (GCP) and the General Data Protection Regulation (GDPR). Local Principle Investigators will be responsible for ensuring data accuracy and will complete a signed delegation log. Patient reported outcome measures will be completed on paper or using the electronic case report form (ALEA^TM) depending on patient preference. All patient reported outcome data will be entered into the electronic case report form (ALEA^TM) and data validation will take place according to the procedures set out in the data management plan and data validation plan. Clinical data will be collected from patients’ medical records and entered directly into the electronic case report form (ALEA™) with data validation taking place as per the above statement. Prior to any statistical analysis, all variables will be checked for the number of missing values, impossible values and improbable values. Impossible and improbable values will be defined by clinical opinion. Improbable values will also include values that are outside three standard deviations of the mean value. Any questions regarding the data will go back to the data manager. Descriptive statistics will be calculated for all variables, and distributional assumptions will be checked.

Data collected prior to participant withdrawal or deviation from the protocol will be included, unless participant withdraws consent for its use. Electronic copies of the case report form will be transferred using secure nhs.net email accounts, with data encrypted to ensure anonymity. All procedures for handling, storing, destroying and processing data will be compliant with the Data Protection Act 2018.

All trial documentation and data will be archived centrally by the sponsor at the end of trial in a purpose designed facility for ten years in accordance with regulatory requirements. Access to these archives will be restricted to authorised personnel. Electronic data sets will be stored indefinitely.

Data monitoring committee

An external, independent Data Monitoring Committee (DMC) will be convened on instruction of the CI and co-investigators on behalf of the project board. It will be made up of experts in the field who are not engaged in any trial activity. The DMC will be responsible for safeguarding the interests of the study participants and assuring the integrity and credibility of the clinical trial.

Safety reporting

All adverse events are to be recorded in the relevant case report form. Adverse events during CPET are reported to the chief investigator, and adverse events during exercise training (pain and muscle soreness) or psychological support sessions (mental health concerns) are reported to the trial coordinator by the instructor/counsellor and recorded in the relevant case report form by the research physiologist/nurse. Fatal or life-threatening serious adverse events (SAEs) are reported within 24 hours of the local site becoming aware of the event. The SAE form documents the nature of the event, date of onset, severity, corrective therapies given, outcome and causality (that is, unrelated, unlikely, possibly, probably, or definitely). Questions concerning adverse event reporting are directed to the chief investigator in the first instance.

Conclusion

The Wessex Fit-4-Cancer Surgery trial will be the first pragmatic, robustly conducted randomised controlled study investigating whether a structured and responsive multi-modal exercise training programme +/- psychological intervention will result in a reduced hospital length of stay, improved disability-free survival, reduced in-hospital complications and improved health-related QoL for patients undergoing major inter-cavity resection of cancer.

Data availability