The Wessex Fit-4-Cancer Surgery Trial

Study Overview
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Brief Summary
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Trial Phase: Phase III: A multi-centre efficacy pragmatic factorial design randomised controlled trial with patient informed development and process evaluation Indication: Patients undergoing major electively resectable intra - cavity cancer surgery with or without neoadjuvant cancer treatments (including chemotherapy (NAC), chemoradiotherapy (CRT), or immunotherapy). Objective: To investigate the efficacy of a community based Structured Responsive Exercise-training Programme (SRETP) ± psychological support on surgical outcome by reducing postoperative length of stay (LOS) and complications. Secondary Objective: To investigate the efficacy of a community based Structured Responsive Exercise-training Programme (SRETP) ± psychological support to improve disease-free overall survival. Cardiopulmonary Exercise test (CPET) variables, physical activity, morbidity, radiological markers of sarcopenia, toxicity, tumour down-staging, tumour regression, disability adjusted survival (WHODAS) overall survival and quality of life (QoL).

Detailed Description
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Rationale: Fitter patients have better surgical outcomes. Poor physical fitness measured objectively using cardiopulmonary exercise testing has been associated with increased LOS, increased morbidity and mortality in many patient cohorts undergoing major cancer surgery. Chemotherapy and radiotherapy have detrimental effects on physical fitness, which may in turn have a detrimental effect on the patients' ability to withstand surgery. Research suggests psychological factors including depression and self-efficacy (confidence to manage cancer-related problems) prior to surgery predict recovery trajectories in health-related quality of life up to 2 years after major surgery for colorectal cancer. The aim is to investigate whether SRETP (Prehabilitation) ± psychological support prior to and during cancer treatment before major elective surgery reduces LOS, increases survival and improves their ability to self manage. Additionally, we aim to see if this intervention can bring about long-term behavioural change in relation to physical activity. Trial Design: Phase III: A pragmatic factorial design randomised controlled to assess the effectiveness of a prehabilitation programme delivered prior to cancer treatments and/or major cancer surgery in patients undergoing elective intra-cavity major cancer surgery in Wessex. Sample size: 1560 Intervention: An in-hospital transition to a community based Structured Responsive Exercise-Training Programme (SRETP) ± psychological support (delivered in community/ council gyms or Cancer Support Centers). The intervention/s will be delivered before surgery. Patients receiving neoadjuvant cancer treatments prior to surgery will receive the intervention during and after these treatments. Control: Standard care with extra monitoring

Official Title
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A Pragmatic Factorial Design Randomised Controlled Study to Assess the Efficacy of the Implementation of a Prehabilitation Programme in Patients Undergoing Elective Major Intra - Cavity Cancer Surgery in Wessex

Conditions
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Cancer

Intervention / Treatment
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* Behavioral: SRETP
* Behavioral: Psychological support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged over 18 years old scheduled to have major intra-cavity cancer surgery with a curative intent, defined as thoracic, colorectal, oesophagogastric, urological and hepatobiliary (inc. pancreatic). surgery alone (unimodal) surgery combined (multimodal) with cancer treatments (neoadjuvant chemotherapy, chemoradiotherapy or immunotherapies). All patients deemed by the MDT as potentially curable or undergoing neoadjuvant cancer treatments prior to restaging and surgery. Exclusion Criteria: Patients will be excluded if under the age of 18 years, if their tumour is considered surgically non- resectable, having absolute or relative contraindications to completing a CPET, patients are unable to perform CPET due to other coexisting acute illness or conditions (e.g. lower limb dysfunction), patients decline surgery, if their weight exceeds 145kg patients unable to give informed consent. Patients having >2 mm ST depression if symptomatic or 4 mm if asymptomatic or >1 mm ST elevation during any CPET will need to be withdrawn from study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2x2 factorial design randomised controlled interventional trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>Usual care plus additional monitoring | |
| Experimental: SRETP<br>Structured Responsive Exercise Training Programme (SRETP) prior to surgery | Behavioral: SRETP<br>* SRETP will involve short periods of exercise at a high intensity interspersed with short periods of exercise at a moderate intensity (aerobic interval training). We will also include resistance training in each session. Exercise intensities during the interval exercise-training program are specific to each patient and derived from CPET. Moderate intensity exercise is below the anaerobic threshold (AT). Patients will exercise at 80% of oxygen uptake (VO2) obtained at the anaerobic threshold (80%AT) for moderate intensity exercise - 3 minutes. Severe exercise intensity is recognised as 50% of the difference between the VO2 AT and VO2 Peak (50%∆) - 2 minutes.<br>|
| Experimental: Psychological support<br>Psychological support prior to surgery | Behavioral: Psychological support<br>* Support sessions will be patient-centred, giving the patient an opportunity to raise any issues/concerns they are having, this may include (but will not be limited to) ways of coping with their reactions to cancer, family and relationship issues, exploring personal issues and dealing with practical issues. Patients will have access to other resources available at the cancer centres including but not restricted to further information about their condition and how to access financial support. These processes reflect the best practice currently being delivered by cancer support centre staff in the Wessex region. Any patient deemed at risk (i.e. from suicidal ideation or self harm) will be reported to their GP, followed up by a letter.<br>|
| Experimental: SRETP and psychological support<br>Structured Responsive Exercise Training Programme (SRETP) and psychological support prior to surgery | Behavioral: SRETP<br>* SRETP will involve short periods of exercise at a high intensity interspersed with short periods of exercise at a moderate intensity (aerobic interval training). We will also include resistance training in each session. Exercise intensities during the interval exercise-training program are specific to each patient and derived from CPET. Moderate intensity exercise is below the anaerobic threshold (AT). Patients will exercise at 80% of oxygen uptake (VO2) obtained at the anaerobic threshold (80%AT) for moderate intensity exercise - 3 minutes. Severe exercise intensity is recognised as 50% of the difference between the VO2 AT and VO2 Peak (50%∆) - 2 minutes.<br>Behavioral: Psychological support<br>* Support sessions will be patient-centred, giving the patient an opportunity to raise any issues/concerns they are having, this may include (but will not be limited to) ways of coping with their reactions to cancer, family and relationship issues, exploring personal issues and dealing with practical issues. Patients will have access to other resources available at the cancer centres including but not restricted to further information about their condition and how to access financial support. These processes reflect the best practice currently being delivered by cancer support centre staff in the Wessex region. Any patient deemed at risk (i.e. from suicidal ideation or self harm) will be reported to their GP, followed up by a letter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-operative length of hospital stay | Date of hospital admission minus date of discharge would equal length of post-operative stay (LOS). | up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in objectively measured cardiopulmonary exercise testing variables - Oxygen uptake at anaerobic threshold (ml/kg/min) and oxygen uptake at peak exercise (ml/kg/min) | Change in cardiopulmonary exercise variables i.e. oxygen uptake (VO2) at anaerobic threshold (AT) and at peak exercise. A clinically significant difference in physical fitness is defined as ≥ 2ml/min/kg VO2 at AT. | up to 15 weeks | 
| Overall survival - 1 | Overall survival at 1 year post surgery | 1 year post-operatively | 
| Overall survival -2 | Overall survival at 5 year post surgery | 5 years post-operatively | 
| Disease free survival | Clinical or radiologically measured disease free survival | 1 year post-operatively | 
| Post-operative morbidity -1 | Patients post-operative morbidity survey (POMS) will be characterised on day 3, 5, 7 and 15. The POMS 18-item survey will be used to address nine domains of postoperative morbidity (pulmonary, infectious, renal, gastrointestinal, cardiovascular, neurological, wound complication, haematological and pain). | POMS at day 3,5,7 and 15. | 
| Post-operative morbidity -2 | On day of discharge, patient's surgical complications (if any) will be graded using the Clavien-Dindo classification of surgical complications This classification is used to assess overall hospital morbidity following surgical procedures. Patients are graded as 0 (no complications) or Grade I-V based on the level of complication, including the number of organ system involvement. Grade V is defined as death of a patient. A record of the Comprehensive Complication Index (CCI) - an update of the Clavien-Dindo classification will also be collected | up to 1 year | 
| Physical activity -1 | Number of steps while active using a triaxial accelerometer eg. Senseware | Baseline up to 1 year post-operatively | 
| Physical activity -2 | sleep efficiency using a triaxial accelerometer eg. Senseware | Baseline up to 1 year post-operatively | 
| Physical activity -3 | metabolic equivalents using a triaxial accelerometer eg. Senseware | Baseline up to 1 year post-operatively | 
| Physical activity -4 | Godin Leisure Time and Exercise questionnaire - A self-reported measure of physical activity | Baseline up to 1 year post-operatively | 
| Health related quality of life -1 | Changes in health related quality of life measurements using validated questionnaires; including: EQ-5D-5L 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. Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health care as well as in population health surveys | Baseline up to 1 year post-operatively | 
| Health related quality of life -2 | Changes in health related quality of life measurements using validated questionnaires; including: Cancer specific quality of life will be measured using the EORTC-QLQ-C30. | Baseline up to 1 year post-operatively | 
| Health related quality of life -3 | Changes in health related quality of life measurements using validated semi-structured interview techniques | Baseline up to 1 year post-operatively | 
| Mental well being -1 | Self-efficacy (confidence) to self-manage chronic disease (SEMCD), measured using the Lorig SEMCD scale A confidence scale that represents the patients confidence that a regular task can be achieved. 1 = Not confident at all and 10= totally confident. | Baseline up to 1 year post-operatively | 
| Mental well being -2 | Patients knowledge skills and confidence to manage their own health and care will be measured using the Patient Activation Measure (PAM) Agreement or disagreement with statements. Choice between disagree strongly, disagree, agree, agree strongly and not applicable | Baseline up to 1 year post-operatively | 
| Mental well being -3 | Anxiety and depression will be measured using the Hospital Anxiety and Depression Scale (HADS) A tick box questionnaire relating to anxieties and depression that a patient might have felt over the past week. Choices are most of the time, a lot fo the time, from time to time, and not at all for most questions. | Baseline up to 1 year post-operatively | 
| Mental well being -4 | Resilience, measured using the Connor-Davidson Resilience Scale (CD-RISC2) Patients are asked to choose x in a box that best indicates how much they agree with the following statements resilience over the past month. Options are not at all true; rarely true; sometimes true; often true; true nearly all of the time | Baseline up to 1 year post-operatively | 
| Mental well being -5 | Brief illness perception questionnaire (B-IPQ) - A self- reported nine-item scale designed to rapidly assess the cognitive and emotional representations of illness by a questionnaire. Various illness questions are asked and the patient picks a number from 0 to 10; 0= no affect at all and 10= severely affects my life. | Baseline up to 1 year post-operatively | 
| Complex health interventions evaluation | Medical research council (MRC) RE-AIM reporting | Baseline up to 1 year post-operatively | 
| Radiological markers of sarco-cachexia measured from routine CT scans | CT, MRI, PET CT full report from radiologist including TNM stage, venous invasion, resection margin involvement, tumour metabolic activity, RECIST staging and any other cancer pathway specific staging/restaging test. Raw DICOM files from radiological softwares or via the PACS team will be downloaded securely to measure radiological markers of sarco-cachexia. | Baseline up to 1 year post-operatively | 
| Toxicity and adverse events | Neoadjuvant cancer therapy induced toxicity measured using the CTC AE v4 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -1 | Radiology - CT, MRI, PET CT - Tumour Node Metastasis (TNM v7) stage | Baseline up to 1 year post-operatively | 
| Tumour outcomes -2 | Radiology - CT, MRI, PET CT full report from radiologist mainly including venous invasion | Baseline up to 1 year post-operatively | 
| Tumour outcomes -3 | Radiology - CT, MRI, PET CT full report from radiologist mainly including resection margin involvement | Baseline up to 1 year post-operatively | 
| Tumour outcomes -4 | Radiology - CT, MRI, PET CT full report from radiologist mainly including tumour metabolic activity | Baseline up to 1 year post-operatively | 
| Tumour outcomes -5 | Radiology - CT, MRI, PET CT full report from radiologist mainly including RECIST staging | Baseline up to 1 year post-operatively | 
| Tumour outcomes -6 | Radiology - CT, MRI, PET CT full report from radiologist mainly including tumour regression score | Baseline up to 1 year post-operatively | 
| Tumour outcomes -7 | Histopathology - TNM score version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -8 | Histopathology - differentiation grading using TNM version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -9 | Histopathology - extramural tumour extension using TNM version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -10 | Histopathology - lymphovascular invasion using TNM version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -11 | Histopathology - perineural invasion using TNM version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -12 | Histopathology - venous invasion using TNM version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -13 | Histopathology -resection margin status using TNM version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -14 | Histopathology - tumour regression grading (TRG/ Mandard Score) | Baseline up to 1 year post-operatively | 
| Tumour outcomes -15 | Histopathology -lymph node status using TNM version 7 | Baseline up to 1 year post-operatively | 
| Tumour outcomes -16 | Histopathology - number of lymph nodes involved using TNM version 7 | Baseline up to 1 year post-operatively | 
| Disability adjusted survival | WHODAS v2.0 will ask patients to rate whether their health condition has had impact upon them in regards to 7 disability and functionality domains (understanding and communicating, getting around, self-care, getting along with others, life activities: household, life activities: work/school, and participation in society). This includes a measure of cost effectiveness. | Baseline up to 1 year post-operatively | 
| Tumour microenvironment | Endoscopic and surgical paired tumour biopsies will be taken as part of the oesophageal cancer clinical and molecular stratification study (OCCAMS) if the patient has been consented to the bio-banking study. Endoscopic and surgical paired tumour biopsies will be taken as part of TARGET LUNG study if the patient has been consented to the bio-banking study. Other tumor types will be banked in centers taking part in the International Cancer Genome Consortium. Clinical cancer pathway pathological samples embedded in paraffin and used in routine clinical practice may also be requested at a later stage for tumour analyses. Tumour biopsy +/- at endoscopic ultrasound (pre Cancer treatments and upon diagnosis) and at surgery (where possible depending on availability at site and cancer cohort) | Baseline up to 1 year post-operatively | 
| Nutrition -1 | Height (cms) and weight (kg) will be combined to report BMI in kg/m^2 | Baseline up to 1 year post-operatively | 
| Nutrition -2 | Patient Reported Experience Measures (PREMS) including symptom and appetite questionnaires (Council of Nutrition Appetite Questionnaire- CNAQ) (in My Medical Record as part of standard clinical care) | Baseline up to 1 year post-operatively | 
| Nutrition -3 | Patient self-completing online assessment (myFood24 incorporated in My Medical Record) | Baseline up to 1 year post-operatively | 
| Nutrition -4 | Malnutrition Universal Screening Tool as part of standard clinical care | Baseline up to 1 year post-operatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, mortality, morbidity, surgery, colorectal, upper gastrointestinal, hepatobiliary, urology, lung, nutrition, psychology