The PERIOP-OG trial is a prospective and pragmatic randomised controlled multi-centre superiority trial that will compare a programme of peri-operative exercise with standard care in patients with oesophagogastric cancer undergoing NCT followed by surgery. The trial will be conducted in 3 university teaching hospitals in Ireland (Beaumont Hospital, Dublin, The Mercy University Hospital, Cork and Galway University Hospital, Galway) with the exercise training programme delivered in 7 exercise centres nationwide. The exercise training is delivered through ExWell Medical which is a chronic illness exercise and rehabilitation service, and its exercise partners nationwide.
Lead exercise personnel perform assessments after receiving standardised training by lead study coordinators (LL and RT).
An algorithm of the clinical pathway and the timepoints for assessments during the trial is shown in Figure 1. Ethical approval for this study has been received in each participating site prior to study commencement and the trial is registered with clinicaltrials.gov (NCT: NCT0380751).
The primary objective of the PERIOP-OG trial is to demonstrate that a structured community-based exercise programme will result in a clinically significant increase in cardiorespiratory fitness pre-surgery when compared to a standard care control group. Cardiorespiratory fitness will be assessed using a 6-minute walk test (6MWT) at 5 time points in the study – baseline, post NCT, pre-surgery, 4 weeks and 10 weeks after surgery.
Secondary aims of the study include assessing whether exercise training improves other physical health outcomes assessed using upper and lower body strength tests, activity behavior monitoring, body mass index and frailty. Psychological health will be assessed using a series of questionnaires; HRQoL (EQ-5D-5L Health Questionnaire), Functional Assessment of Cancer Therapy (FACT-E), General Self Efficacy (GSE), Mastery (Pearlin Mastery Scale), Surgical Fear Questionnaire (SFQ) and general optimism using the Life Orientation Test-Revised (LOT-R) tool as well as semi structured interviews.
Exploratory end-points include assessment of post-operative morbidity (Clavien-Dindo classification and as agreed by the Esophagectomy Complications Consensus Group (ECCG) (28), the Comprehensive Complication Index, hospital length of stay, nutritional status (serum albumin, sarcopenia score and Foodbook-24), inflammatory markers, cancer staging and response to NCT and a medico-economics analysis of cost effectiveness of the exercise intervention on reducing health care costs and burden. Additionally, rates of NCT toxicity, tolerance and compliance will be measured.
Eligibility criteria include the following: age ≥ 18 years, multidisciplinary team (MDT) referral for neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy prior to oesophagectomy or gastrectomy; confirmed adenocarcinoma or squamous cell cancer of the oesophagus, oesophago-gastric junction or stomach; for oesophageal cancers tumours must be more than 5cm below the crico-pharyngeus muscle.
Exclusion criteria include the following: inability to give informed consent, inability to participate in exercise training (unable to perform 6MWT); patients undergoing primary surgery; distant metastatic disease, previous or concomitant malignancy that would interfere with this treatment protocol and pregnancy.
Recruitment and randomisation
The PERIOP-OG trial is currently recruiting (start date 1st March 2019, proposed end date July 2020). All potentially eligible patients are identified in each centre’s MDT and are approached for inclusion at diagnosis before NCT has started. Eligible patients are given an information leaflet and then 72 hours later are contacted to confirm participation, informed consent is taken and randomisation group revealed. Participants are randomised using central data management to generate a random allocation sequence (1:1). Due to the nature of the study, blinding of patients, data collectors and physiological assessors is not possible but treating surgeons and their teams are blinded to randomisation, as is the primary analyst.
Malnutrition is common in patients diagnosed with oesophagogastric cancers. All participants enrolled in the PERIOP-OG trial follow a standardised nutritional pathway of care. All 3 participating centres have specialist dieticians who are highly trained and dedicated to the care of oesophagogastric cancer patients. All patients have a dietician assessment at the time of diagnosis and an individualised dietary plan with appropriate supplementation structured to ensure sufficient calorie and protein supplementation. Pre- and peri-operative feeding adjuncts (percutaneous enteral feeding or total parenteral nutrition) will be recorded on an individual basis.
Usual care control group
The usual care control group (no formal exercise training) receive routine care throughout their cancer pathway. No specific advice about exercise training is offered. Activity monitors are worn for a period of 7 days by patients in both groups at each time point of assessment and are used to measure the exercise levels of patients within the control group.
Exercise intervention group
The exercise-training programme is started before and continues during NCT. It is continued between NCT and surgery and then resumed for 6 weeks after surgery once patients are deemed clinically fit. The exercise-training programme is based on experience gained from a previous feasibility study performed by our own team.
Participants in the exercise group will be offered an option to participate in either a centre-based exercise programme (CBEP) or a home-based exercise programme (HBEP). This is to cater for all patients as the time-dense schedules of NCT regimens and the long distances some patients have to travel to their treating hospitals often pose a challenge in exercise prescribing. All participants in the exercise group are provided with a fitbit and a step count log.
The HBEP is offered for patients where access to an exercise centre is difficult due to remote or rural living. HBEP involves undertaking exercise independently and is prescribed at the baseline assessment (Figure 1). Patients are given a home programme pack, which includes a manual exercise handbook, an exercise prescription, a rate of perceived exertion (RPE) scale and a log diary. They are also given a link to an online motivational video developed specifically for the PERIOP-OG Home Programme. Participants are educated in aerobic and resistance exercises and the RPE scale and they complete a 10-minute exercise session on the cycle ergometer under the supervision of their personal trainer. This provides an understanding of what exercise intensity level they should aim to achieve during aerobic exercise at home. Additionally, participants are instructed on resistance exercises (i.e. weight selection, technique, breathing, rest periods). HBEP participants receive a weekly telephone call, using a structured proforma, to assess adherence to the programme and to amend the programme if necessary. Participants feedback their daily step count each week. All conversations and the duration of each phone call are documented in participant case report forms. HBEP compliance is also self-reported by the participant using a log diary.
The CBEP takes place in 7 exercises centers nationwide. Participants are prescribed exercise on an individual basis following the principles below. Compliance with the CBEP is recorded by number of sessions attended.
Exercise training protocol
The delivery of the CBEP and HBEP is described using the FITT principle (frequency, intensity, time and type of exercise training) (29).
Frequency - Participants are asked to undertake 2-3 structured exercise training sessions per week during NCT and 3 thereafter.
Intensity - Exercise sessions may be interval based or continuous. Interval training involves a series of exercises repeated at moderate and higher intensities and continuous exercise sessions involve moderate intensity continuous exercise for the entire duration of the exercise period.
Participants in either programme with access to gym equipment engage in interval training of moderate and high intensity (13: somewhat hard to 15: hard on the RPE scale). For those unable to undertake interval training or with no access to gym equipment, a continuous exercise training programme is prescribed based on the RPE scale (13: somewhat hard).
Time –The first interval (moderate to high intensity) exercise session is 30 minutes: 5-minute warm-up followed by 4 repeated bouts of moderate intensity (3 min) to high intensity (2 min) intervals and 5-minute cool down. The first continuous exercise session is also 30 minutes duration: 5 minutes warm-up, 20 minutes of continuous moderate intensity exercise and 5 minutes cool down.
The second and subsequent sessions are 40 minutes long: 5 minutes warm-up followed by 6 repeated bouts of moderate intensity (3 minutes) to high intensity (2 minutes) intervals and a 5 minute cool down. The second continuous exercise session is made up of a 5-minute warm-up, 30 minutes of continuous moderate intensity and a 5-minute cool down. Post-operatively, participants resume exercising initially for 20-minute sessions and increase the duration of exercise by 10 minutes per week until the pre-operative timings are achieved.
Type - CBEP or HBEP participants with access to gym equipment may include the use of any of the following equipment: upright cycle ergometer; recumbent cycle ergometer; treadmill; elliptical ergometer; and rowing ergometer, depending on patient preference. HBEP participants without gym access, may use a combination of walking, jogging or cycling.
Resistance training involves a circuit of 6-10 stations alternating upper and lower body exercises using dumb-bells as outlined in the home-based exercise manual handbook.
Progression - During NCT, there is no progression in exercise intensity. In the time window between completing NCT and surgery, exercise intensity is progressed every 5 sessions. Post-operatively, exercise is progressed by time (as previously outlined) and also by intensity 8 weeks following surgery.
The primary outcome is measurement of cardiorespiratory fitness using the 6MWT measured at baseline assessment and prior to surgery. The 6MWT is performed with participants walking up and down a 20 meter course marked by cones for 6 minutes under instruction to cover as much ground as possible. The number of laps completed is recorded. A standard set of instructions is used as per the European Respiratory Society guidelines. The 6MWT is a validated assessment of cardiorespiratory function in clinical populations (30, 31). A systematic review in 2016 demonstrated that field tests may be able to predict post operative outcome however further validation work is merited (32).
- The sit to stand test. Participants sit on a chair (height 43-45 cm) with arms crossed across their chest, feet flat on the floor, parallel to each other, and approximately shoulder width apart. Participants then stand up and sit down 10 times as quickly as possible and must fully extend their legs on each stand. The time taken to perform 10 repetitions will be timed. Participants will perform two trials and the best trial will be recorded as their score (33).
- The handgrip test. This is measured using a hand dynamometer (Takei 5401 Hand Grip Dynamometer (Digital)). The test is conducted in a standing position with the upper arm tight against the participant’s trunk and the forearm at a right angle to the upper arm. The gripping handle is set to a comfortable width to ensure the participant can rest the fat pads of the phalanx of the four fingers on the handle. The participant is instructed to squeeze the handle with maximum force for 5 seconds and the value recorded. The participant will complete three trials on each hand. The highest score will be recorded (34).
Physical activity and sedentary behavior is assessed using a 7-day ActivPAL3 triaxial accelerometer. Participants in both groups are instructed to wear this device on the midpoint of the anterior aspect of the right thigh continuously for seven days at the 5 time points of assessment. The accelerometers don’t provide participants with any feedback: data can only be analysed centrally by the lead researchers. Total activity counts per day as well as time in sedentary behavior are recorded for both groups.
BMI is calculated in the standard manner.
Fraility is assessed by the Risk Analysis Index. It has been reported as a valid tool for measuring frailty in surgical populations (35). It provides a prospective, pre-operative assessment of frailty in clinical practice. It provides a score between 0 and 81 taking into account demographic, clinical and independence information.
This is assessed using a number of validated questionnaires and semi-structured interviews. The questionnaires are as follows;
- Life Orientation Test-Revised (LOT-R) – Assesses optimism and consists of ten items assessing expectancy of positive versus negative outcomes. Higher scores represent higher levels of optimism (36).
- EQ-5D-5L health questionnaire is a standardised measure of health status developed by the EuroQoL Group in order to provide a simple, generic measure of health for clinical and economic appraisal (37).
- Functional Assessment of Cancer Therapy-Esophageal (FACT-E) questionnaire. This is a health-related quality of life instrument validated in patients with esophageal cancer. It is composed of a general component (FACT-G) and an esophageal cancer subscale (ECS) (38).
- The Surgical Fear Questionnaire (SFQ) will assess participants fear of surgery and is a validated and reliable eight-item index of surgical fear consisting of 2 subscales: fear of the short-term consequences of surgery and fear of the long-term consequences of surgery (39).
- General Self Efficacy (GSE) and Mastery (Pearlin Mastery Scale). A highly reliable and validated measurement of self-efficacy. This questionnaire consists of seven items designed to assess psychological coping resources (Mastery) (40).
- Semi-structured interviews will explore patients’ perceptions of the surgical pathway.
Exploratory outcomes will include:
Nutritional Status is assessed using the following tools:
- Glasgow Prognostic Score provides cancer prognosis based on serum biomarkers CRP and Albumin (41).
- Foodbook-24, a web-based, dietary tool consisting of a 24 hour dietary recall and food frequency questionnaire (42).
- Sarcopenia – Standard care for all patients is to undergo a staging CT scan at the time of diagnosis and then a restaging CT scan after NCT. Sarcopenia will be measured at these 2 time points using SliceOmatic software (Tomovision, Magog, Canada). At the L3 level total skeletal muscle, subcutaneous fat and visceral fat will be measured. Skeletal muscle mass will be calculated as skeletal muscle / height (m)2 and will be recorded by two individuals, both of whom will be external to the trial group.
Post-operative Morbidity Outcomes
- Post-operative Morbidity Score (POMS) is an 18-item tool that addresses morbidity relevant to the post-surgical patient (43).
- The Clavien-Dindo classification of surgical complications consists of 7 grades that rank post-operative complication severity (44).
- The Comprehensive Complication Index (45) integrates all post-operative complications with their respective severities, on a scale ranging from 0 (no burden from complications) to 100 (death).
- Patients undergoing oesophagectomy will have post-operative morbidity recorded as per the Esophagectomy Complications Consensus Group (28) mortality will be assessed at 30 days and 90 days.
Blood Markers of Inflammation
C- reactive protein and white cell count will be measured.
Health Economic Outcomes
An exploratory analysis will be made of the cost of the exercise intervention and the net monetary benefit on health care costs and health care interactions arising during the time period of the study will be calculated.
Rates of NCT toxicity, tolerance and compliance will be collected.
Patient and Public Involvement (PPI)
Patient and public volunteers are members of the trial steering committee and their experience and input was used to help shape the study design. Volunteers attend quarterly trial steering meetings and receive monthly newsletters and trial management meeting minutes. They will assist with trial delivery and conduct as well as trial reporting. Additionally, they guide our dissemination plan using social media, presentation at conferences, dissemination to patient advocacy groups and journal articles.
Adverse events are recorded in the relevant case report form by the lead site researcher. Fatal or life-threatening serious adverse events are reported within 24 hours of the research team becoming aware of the event. The serious adverse events form documents the nature of the event, date of onset, severity, corrective therapies given, outcome and causality (i.e. unrelated, unlikely, possibly, probably, definitely). Any queries relating to adverse event reporting will be directed to the principal investigator.
Sample size calculation
The sample size calculation was based on results from a recent publication by Minnella et al (46) which identified a pre-operative increase in 6MWT of 60m from a baseline score of 450m - an approximate 13% improvement. Assuming a similar baseline score, a 15% difference can be detected with a p-value of 0.05 and power 80% with a sample of 26 participants with full data in the 2 groups. With an anticipated 20% drop out, recruitment of 62 participants is anticipated.
The analysis will be performed as an intention-to-treat analysis. No interim analysis will be conducted. Data validity will be conducted prior to analysis and corrected as appropriate.
The study population will be described separately for the two randomised groups using variables obtained at baseline. The variables will be described as mean (SD) and numbers (%) as appropriate.
The primary analysis of the primary outcome will be conducted using t-tests of independent group mean differences in 6MWT. The mean difference and 95% confidence interval will be reported and illustrated graphically. Individual change in 6MWT will be calculated from baseline and compared at different time points using t-tests.
The secondary analysis of the primary outcome will use mixed-level analysis with intervention group, time point and interaction of intervention and time points. This analysis will include baseline score for the outcome measure as a covariate. The estimated parameter for the interaction variables will be interpreted as the difference-in-difference between the two groups over time. A separate analysis will explore potential differences in the intervention group between participants who received the intervention at a training centre and those who trained at home. This analysis will be expanded to include descriptive baseline variables such as sex and age. The secondary analysis will use mixed-level analysis and include baseline score and baseline characteristics as covariates.
The cost-effectiveness analysis will be conducted from a societal perspective over the duration of the trail period. No extrapolation of long-term economic outcomes is planned. The EQ-5D-5L data reported at each time point will be used to estimate quality-adjusted life years using time-weighted utility scores. The utility scores will be calculated for each individual at each data point using the Irish scoring algorithm for EQ-5D-5L (47). The area under the curve denotes the QALY and incremental QALY is determined as the mean group difference.
Cost of the intervention and subsequent health care resource use will be calculated for each individual using average cost per participant for the intervention programme and self-reported data on healthcare utilisation. Unit costs will be obtained from national sources and assigned to the resource utilisation and aggregated over the whole trial period for each individual. Net monetary benefit (NMB) will be estimated as the cost minus the QALY gain multiplied by an assumed threshold value per QALY.
Participants with missing data either because of early drop-out, loss to follow-up or missed participation in the data collection can bias the results. By design there will be no missing data at baseline because only participants with complete baseline data will be randomised.
Missing variables in outcome measures will be handled according to instrument developers’ guidelines. As a general rule, if more than 20% of the items of an instrument are missing the summary score will be assigned as missing. Missing data will be reported as part of the summary presentation of the raw data. Logistic regression will be used to explore whether participants with missing data have different characteristics than the completers or whether missing data can be assumed missing by random.
Procedures for data checking and entering
Data will be double data entered, and data validation will take place according to the procedures set out in the data management plan and data validation plan. 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.
The Standard Protocol Items-Recommendations for Interventional Trials (SPIRIT) table provides an overview of the study conduct, review, reporting and interpretation and is presented in Table 2. The final report will follow the Consolidated Standards of Reporting Trials (CONSORT), as well as the Template for Intervention Description and Replication (TIDieR).