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Exercise programme

Malcolm A West, MD MRCS

Neoadjuvant chemoradiotherapy (NACRT) prior to surgery for lower gastrointestinal (colon and rectal) cancer is associated with improved survival, but also adversely affects physical fitness, potentially rendering patients unfit for major surgery or increasing the risk of adverse outcome (death and serious complications) after major surgery. The investigators have pilot data using an upper gastrointestinal cancer patient cohort showing that neoadjuvant chemotherapy (NAC)reduces objectively measured exercise capacity (fitness). The investigators therefore propose a blinded, single centre, prospective interventional trial of patients undergoing NACRT prior to elective colorectal cancer resection in an NHS teaching hospital.

The investigators wish to explore various hypotheses:

1. Is exercise intervention feasible and tolerable in this cohort of patients?
2. Can fitness be improved using a structured, responsive exercise training programme (SRETP)?
3. Can SRETP improve quality of life?
4. Can SRETP improve physical activity?
5. Can SRETP improve surgical outcome?
6. Can physiological fitness and oncological outcome be matched to identify an optimal time for physiological recovery following NACRT prior to major surgery.

The investigators aim to recruit 5 patients for a feasibility and tolerably study and 30 patients for an interventional study over 24 months from Aintree University Teaching Hospitals NHS Foundation Trust. Consenting patients will undergo a series of tests designed to evaluate the ability of the muscle to take up and utilise oxygen, namely a cardiopulmonary exercise test (CPET) and VO2 Kinetics tests, all done pre-CRT and at 3,6,9 and 14 weeks post-CRT (pre-surgery). All patients will have their CPET, as well as standard restaging scans at 9 and 14 weeks post NACRT. Outcome, activity and quality of life data will also be collected.

Exercise Training in Colorectal Cancer Patients

Does Short-term Exercise Intervention Improve Pre-operative Physical Fitness Following Neoadjuvant Chemoradiotherapy in Colorectal Cancer Patients?

University Hospital Southampton NHS Foundation Trust

Michelle Mossa

Research and Development Director

Carcinoma

Central Nervous System Depressants

All Drugs and Chemicals

Anesthetics

Anesthetics, Local

The exercise regime consists of 10 sessions of exercise against a constant load, each lasting 60 seconds, separated by 60 seconds of recovery eliciting 90% maximal heart rate. The 6 sessions are held over a 2 week period.

muscle biopsy under local anaesthetic taken from the thigh, again for analysis and storage 3 times: before, during and after the exercise programme

Muscle biopsy

Tamas Hickish, FRCP

This pilot study looks to explore the biological effects of exercise on cancer and muscle cells using a two week exercise program (HIThigh intensity training) on 20 patients with newly diagnosed and operable colorectal cancer following diagnosis and prior to surgery. Maximal oxygen uptake will also be measured. The aim of this pilot is to assess the feasibility of recruiting participants to and carrying out a two week preoperative exercise program in patients with colorectal cancer.

Patients undergoing investigation for symptoms of colorectal cancer presenting to the hospital will undergo standard diagnostic procedures. Once resectable nonmetastatic cancer has been diagnosed (i.e. cancer that has not spread beyond the bowel), is amenable to surgical resection as decided by the colorectal multidisciplinary and if the patient fulfills the selection criteria, they will be asked if they wish to participate in the study. They will be given information regarding the study at the time of diagnosis. If they give their consent then a formal consenting process will take place at the next routine appointment.

During this appointment the patient will have the opportunity to ask questions. A member of the study team will explain the study in detail, answer any questions potential participants (and their partners/ carers) have. The patient is free to refuse participation or withdraw from the study at any time without this affecting their care, this is explained in the information and will be discussed further at the time of informed consent. If the patient agrees to participate in the trial, following the provision of informed consent and before embarking on the exercise programme they will need to fill in two questionnaires, the International Physical Activity Questionnaire (Long) and Dietary Intervention in Primary Care Questionnaire (DINE). They will be counseled to try and maintain their normal exercise level and their calorie intake. Blood samples will also be taken, analyzed and stored for further analysis including possible genetic analysis at a later stage before starting the exercise regime. They will have a muscle biopsy under local anaesthetic taken from the thigh, again for analysis and storage.

Participants will undergo an initial assessment of their baseline exercise ability and oxygen absorption using an upright exercise bike with concurrent ECG readings and breath analysis. The two week preoperative exercise regime will be planned depending on the patient's operation date. The exercise regime consists of 10 sessions of exercise against a constant load, each lasting 60s, separated by 60s of recovery eliciting 90% maximal heart rate.

The 6 sessions are held over a 2 week period. Each patients exercise ability and oxygen absorption will be remeasured at the end of the 2 week period and a second sample of blood taken for comparison. During the operation a sample of adipose tissue near the tumour site will be taken separately to the main sample. A muscle biopsy from the thigh will also be taken at the same time. As a standard of clinical care all patients are reviewed in the outpatient setting 6 weeks postoperatively. When patients attend this follow up appointment a final blood test and muscle biopsy (under local anaesthetic) will be taken to assess the longer term effects of the exercise program. Patient consent will be sought for this separately although it will be discussed at the initial introduction to the study.

Patients are free to withdraw from the study at any time and if there are any adverse events or concerns regarding the continuation of the study for a patient then they will be withdrawn.

EDICT - Exercise inDuced Changes In Colorectal Cancer Tissues

Clinical and Biological Effects of a Preoperative Exercise Programme in Colorectal Tumour and Skeletal Muscle Tissues (Exercise inDuced Changes In Colorectal Cancer Tissues)

To assess the feasibility of carrying out a two week preoperative exercise program in patients with colorectal cancer and to assess the effects of preoperative exercise on the proliferation of colorectal cancer cells by measuring the change in the percentage of cells staining positive for Ki67 (a measure of cell proliferation).

Measuring changes in molecular markers for the effects of exercise and/or diet on AMPK/mTOR signalling pathway (phosphorylated 4EBP1 (P4EBP1), phosphorylated protein kinase B (PPKB/AKT), and phosphorylated AMPK (PAMPK).

Measuring changes in AKT expression normal colonic tissue - Intensity of AKT1/AKT2 staining, or AKT phosphorylation, a marker of insulin receptor signalling in cells.

Assessing Apoptosis index - Percentage of tumour cells staining positive for DNA fragmentation, a marker of cells undergoing apoptosis and therefore cell death.

Measuring changes in molecular markers that may mediate or modify exercise/dietary effects in tumour tissues (IR, IGF1R, p53 and its transcriptional target p21, ER, progesterone receptor, tumor necrosis factor-alpha converting enzyme and TIMP3).

Assessing gene expression profiles focusing on gene associated with insulin resistance.

Assessing the 11 gene signature that help to predict maximal oxygen uptake gain in patients before and after exercise

Cortisol levels to evaluate levels of biological stress.

Postoperative complications up to 30 days postoperatively

Moderator variables including state of motivational readiness for exercise, weight change, depression and anxiety

The Royal Bournemouth Hospital

This will consist of an 8-week exercise programme, performed twice per week.

Standard practice including opportunistic exercise advice and patients' self-directed physical activity

Dearbhaile O' Donnell, MD

Juliette Hussey, PhD

Julie M Walsh, MSc

Many cancer survivors suffer symptoms such as fatigue and dyspnea which may persist for years or months after their chemotherapy has finished. Despite the known benefits of exercise and its potential to address many of the symptoms after cancer, the type of practical exercise programme which best suits this population is not known.

Many exercise programmes performed in cancer survivors take place over many weeks or months and include people with specific types of cancer. Such programmes may therefore not be suitable for the majority of cancer survivors and would pose serious practical difficulties with high drop-out rates and expensive resource consumption if they were extended into clinical practice.

We propose to run an 8-week exercise intervention in a mixed cancer population.

Hypothesis: A brief, individually tailored 8-week intervention will increase fitness and improve other physical symptoms in a mixed cancer survivor population after chemotherapy.

Background: Many cancer survivors suffer a range of physical and psychological symptoms with may persist for years or months after treatment finishes. Despite the known benefits of exercise and its potential to address many of these adverse effects of treatment, the role of exercise as well as its optimum duration, frequency, and intensity in this population has yet to be fully elucidated. Many cancer rehabilitation programmes presented in the literature are very long, have tight eligibility criteria and are not likely to be practical in the majority of cancer survivors. We plan to investigate a novel brief 8-week intervention which aims to increase physical fitness, and address other physical symptoms in a heterogeneous cancer survivor population.

Methods/design: Approximately 60 cancer survivors 2-6 months after completion of chemotherapy, usually adjuvant, with curative intent will be recruited through oncology clinics in a single institution and randomised to usual care or an exercise intervention. The exercise intervention consists of two specifically tailored, supervised, moderate intensity aerobic exercise sessions per week for 8 weeks. All participants will be assessed at baseline (0 weeks), post intervention (8 weeks), and at 3-month follow-up. The primary outcome measure is fitness, and secondary patient-related outcome measures include fatigue, quality of life, and morphological outcomes. A further secondary outcome is process evaluation including adherence to and compliance with the exercise program.

Discussion: This study will provide valuable information about the physical outcomes of this 8-week supervised aerobic programme. Additional process information and economic evaluation will inform the feasibility of implementing this program in a heterogeneous population after chemotherapy treatment with curative intent.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Exercise Training in Colorectal Cancer Patients	NCT01325909	Rectal Cancer	Exercise progra...	18 Years -	Liverpool University Hospitals NHS Foundation Trust
EDICT - Exercise inDuced Changes In Colorectal Cancer Tissues	NCT02056691	Colorectal Canc...	Exercise progra... Muscle biopsy	18 Years -	The Royal Bournemouth Hospital
PEACH Trial: Prescribed Exercise After Chemotherapy	NCT01030887	Cancer	Exercise progra...	21 Years - 70 Years	University of Dublin, Trinity College

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