Chemo Brain Prehab Project: Improving Brain Health After Chemotherapy Through Prehabilitation
Phase: NA
Conditions: Colorectal Cancer, Older Adults (60 - 85 Years Old), Physically Inactive, Chemotherapy
Sponsor: Dr. Chris Gaffney

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Title: Improving Brain Health After Chemotherapy 
Through Prehabilitation 
 
Short Title: ChemoBrain Prehab Project 
 
 
 
RESEARCH REFERENCE NUMBER: 25/EM/0250 
 
STUDY REGISTRY NUMBER AND DATE:  
 
PROTOCOL VERSION NUMBER AND DATE: Version 1.0 (04/12/2025) 
 
SPONSOR NUMBER: 
FUNDER NUMBER: AR2024.07 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Chief Investigator agrees to conduct the study in compliance with the approved protocol 
and will adhere to the national guidelines for the conduct of clinical research. 
I agree to ensure that the confidential information contained in this document will not be used 
for any other purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of the Sponsor 
I also confirm that I will make the findings of the study publicly available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the study will be given; and that any discrepancies and serious 
breaches of Good Clinical Practice (GCP) from the study as planned in this protocol will be 
explained. 
 
 
For and on behalf of the Study Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
 
Chief Investigator: 
Signature:  
 
...................................................................................................... 
 
Date: 23/06/25 
Name: (please print): Dr Christopher Gaffney 
......................................................................................................
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Contents 
TITLE: ............................................................................................................................................................... 1 
SHORT TITLE ................................................................................................................................................... 1 
SIGNATURE PAGE ....................................................................................................................................... 2 
I. KEY STUDY CONTACTS ............................................................................................................................ 5 
II. LIST OF ABBREVIATIONS ......................................................................................................................... 7 
III. STUDY SUMMARY .................................................................................................................................... 8 
IV. FUNDING ................................................................................................................................................ 10 
V. ROLE OF STUDY SPONSOR AND FUNDER ........................................................................................... 10 
VI. ROLES AND RESPONSIBILITIES OF STUDY MANAGEMENT COMMITEES/GROUPS & INDIVIDUALS 10 
VII. PROTOCOL CONTRIBUTORS ............................................................................................................... 11 
VIII. KEY WORDS: ........................................................................................................................................ 12 
IX. STUDY FLOW CHART ............................................................................................................................ 13 
1. BACKGROUND & RATIONALE ................................................................................................................ 14 
2. ASSESSMENT AND MANAGEMENT OF RISK ........................................................................................ 14 
3. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ....................................................................... 16 
3.1. Primary objective ............................................................................................................................... 16 
3.2. Secondary objectives ........................................................................................................................ 16 
3.3. Outcome measures/endpoints ........................................................................................................... 16 
3.4. Primary endpoint/outcome ................................................................................................................. 17 
3.5. Secondary endpoint/outcome ............................................................................................................ 17 
3.6. Table of endpoints/outcomes ............................................................................................................. 17 
4. STUDY DESIGN ...................................................................................................................................... 18 
5. STUDY SETTING ..................................................................................................................................... 18 
6. PARTICIPANT ELIGIBILITY CRITERIA .................................................................................................... 19 
6.1. 
Inclusion criteria ............................................................................................................................ 19 
6.2. 
Exclusion criteria .......................................................................................................................... 19 
7. STUDY PROCEDURES ........................................................................................................................... 20 
7.1. Recruitment ....................................................................................................................................... 20 
7.2. Consent ............................................................................................................................................ 21 
7.3. The randomisation scheme ............................................................................................................... 22 
7.4. Baseline data .................................................................................................................................... 22 
7.5. Study Intervention and Assessments ................................................................................................. 22 
7.6. Withdrawal criteria ............................................................................................................................. 29 
7.7. Storage and analysis of clinical samples ............................................................................................ 29 
7.8. Definition of the end of Study ............................................................................................................. 30 
8. SAFETY REPORTING ............................................................................................................................. 31 
8.1. Definitions ......................................................................................................................................... 31 
8.2. Workflow of reporting concerns to the direct care team and documentation........................................ 32 
9. STATISTICS AND DATA ANALYSIS ........................................................................................................ 33 
9.1. Sample size calculation ..................................................................................................................... 33 
9.2. Planned recruitment rate ................................................................................................................... 33 
9.3. Statistical analysis plan ..................................................................................................................... 33 
9.4. Procedure(s) to account for missing or spurious data ......................................................................... 34 

 
 
 
 
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10. DATA MANAGEMENT ........................................................................................................................... 34 
10.1. Data collection tools and source document identification .................................................................. 34 
10.2. Data handling and record keeping ................................................................................................... 35 
10.3. Access to Data ................................................................................................................................ 35 
11. ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 35 
11.1. Research Ethics Committee (REC) review & reports ........................................................................ 35 
11.2. Public and Patient Involvement (PPI) ............................................................................................... 36 
11.3. Regulatory Compliance ................................................................................................................... 36 
11.4. Protocol compliance ........................................................................................................................ 37 
11.5. Data protection and patient confidentiality ........................................................................................ 37 
11.6. Financial and other competing interests for the Chief investigator, Principal Investigators at each site 
and committee members for the overall study management ..................................................................... 38 
11.7. Amendments ................................................................................................................................... 38 
11.8. Post Study Care .............................................................................................................................. 38 
11.9. Access To The Final Study Dataset ................................................................................................. 38 
12. DISSEMINIATION POLICY..................................................................................................................... 38 
12.1. Dissemination policy ........................................................................................................................ 38 
12.2. Authorship eligibility guidelines and any intended use of professional writers ................................... 39 
13. REFERENCES ....................................................................................................................................... 40 
14. APPENDICES ........................................................................................................................................ 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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i. KEY STUDY CONTACTS 
Lead Investigator 
Ms. Katie Hoad 
Lancaster Medical School 
Faculty of Health & Medicine 
Lancaster University 
Lancaster, LA1 4YG 
+44 (0) 7832158964 
k.hoad@lancaster.ac.uk 
Chief Investigator 
Dr Christopher Gaffney  
Lancaster Medical School 
Faculty of Health & Medicine 
Lancaster University 
Lancaster, LA1 4YG 
+44 (0) 1524 593 602 
c.gaffney@lancaster.ac.uk 
Co-Investigator 
Dr. Helen Nuttall  
Fylde College, 
Lancaster University 
Lancaster, LA1 4YG 
+44 (0) 1524 592 842 
h.nuttall1@lancaster.ac.uk 
Principal Investigators For Each 
Participating Site 
Mr. Daren Subar  
Department of General Surgery  
East Lancashire Teaching Hospitals NHS Trust 
Blackburn, BB2 3HH 
+44 (0) 1524 735 604 
daren.subar@elht.nhs.uk 

 
 
 
 
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Dr. Deborah Williamson  
Department of Oncology 
Lancashire Teaching Hospitals NHS Trust 
Preston, PR2 9HT 
+44 (0) 1772 522 984 
deborah.williamson@lthtr.nhs.uk 
Dr. Chan Ton  
Department of Oncology 
University Hospitals of Morecambe Bay NHS 
Foundation Trust 
Royal Lancaster Infirmary 
Lancaster, LA1 1BF 
+44 (0) 1539 732 288 
chan.ton@mbht.nhs.uk 
Sponsor 
Lancaster University, 
Bailrigg, LA1 4YW 
+44(0) 1524 593 017 
sponsorship@lancaster.ac.uk 
Funder(s) 
North West Cancer Research  
Mr Alastair Richards 
131 Mount Pleasant,   
Liverpool, L3 5TF 
alastair@nwcr.org 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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ii. LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AR 
Adverse Reaction 
BDNF  
 
 
 
    Brain-Derived Neurotrophic Factor 
 
 
 
CPET 
Cardiopulmonary Exercise Test 
ECG 
electrocardiogram 
EEG 
Electroencephalogram 
ERP 
Event Related Potentials 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
IPAQ 
International Physical Activity Questionnaire  
 
ISRCTN 
International Standard Randomised Controlled Study’s 
 
Number 
NHS 
National Health Service 
PAR-Q+ 
Physical Activity Readiness Questionnaire 
PIS 
Participant Information Sheet 
PPI 
Public and Patient Involvement 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SSC 
Study Steering Committee 
VEGF 
Vascular Endothelial Growth Factor 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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iii. STUDY SUMMARY 
Study Title 
Improving Brain Health After Chemotherapy Through 
Prehabilitation 
Short Title 
ChemoBrain Prehab Project 
Study Design 
Multi-Centre Randomised Control Trial 
Intervention: Prehabilitation Group 
Control Group: Standard Care Group 
Study Participants 
Stage II and III colorectal cancer patients who are 
undergoing chemotherapy 
Planned Sample Size 
86 patients with colorectal cancer were divided into 
Group 1: Intervention (Prehabilitation; n = 43), and 
Group 2: Control (Standard Care With No 
Prehabilitation; n = 43).  
Randomisation 
Block randomisation will be performed at an 
independent site (Lancaster University), and the 
sequence will be shared with the recruitment team via 
sealed envelopes. 
Allocation Concealment 
The study arm allocation will be provided in sealed 
envelopes. 
Counties of Recruitment 
Lancashire 
Intervention 
Supervised moderate-intensity exercise programme for 
participants to attend twice per week [online] and two 
unsupervised, self-paced exercise sessions. Totally to 4 
exercise sessions per week at home. This will include 
warm-up and cool-down sessions. Strength training will 
focus on muscle groups and avoiding core exercise, 
which can increase the risk of excessive abdominal 
pressure. Grades of resistance band (or equivalent) will 
be provided, and regression and progression to exercise 
will be offered to individualise exercise programmes 
according to participants’ mobility and capabilities. 
Participants will be provided with four-week supply of 
multivitamins (Forceval) before chemotherapy, and then 
X amount as part of standard of care (dependent on the 
number of rounds of chemotherapy (4-24 weeks 
supply)). The multivitamins will be taken in addition to 
the exercise programme.  

 
 
 
 
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Control 
Standard care group.  
Intervention duration 
The maximum duration of prehabilitation participation 
will last a maximum of 28 weeks, however, there may be 
delays to treatment due to chemotherapy-related side 
effects (e.g., low white blood cell count).  
Follow up duration 
3 months 
Planned Study Period 
5th January 2026 to 16th September 2027 
 
Objectives 
Outcome Measures 
Primary 
 
Use physiological blood-
based markers to establish 
if prehabilitation promotes 
an improvement in brain 
health in colorectal cancer 
patients prior to starting 
chemotherapy. 
Brain-Derived 
Neurotrophic Factor 
(BDNF) and Vascular 
Endothelial Growth Factor  
(VEGF). 
 
We will use neuroscientific 
measures of brain function 
(electroencephalography 
(EEG)) and cognitive 
function at baseline and 
post-chemotherapy to 
determine if prehabilitation 
neuroplasticity reduces the 
negative effects of 
chemotherapy on the 
brain. 
EEG spectral ratios and 
oscillation analysis that 
focuses on brain activity 
during a battery of 
cognitive function tests.  
Cognitive outcomes 
(executive function, 
memory, attention, and 
processing speed; with 
audition) 
Secondary 
 
We will measure changes 
in cognitive-related quality 
of life in colorectal cancer 
patients at Study Visit 1 
and at 3 months after 
chemotherapy cessation to 
determine whether 
prehabilitation had an 
impact. 
Quality-of-life 
questionnaire 
 
 
 

 
 
 
 
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iv. FUNDING  
FUNDER(S) 
(Names and contact details of ALL organisations providing funding and/or support in 
kind for this study) 
FINANCIAL AND NON 
FINANCIAL SUPPORT 
GIVEN 
North West Cancer Research:  
Mr Alastair Richards, CEO, alastair@nwcr.org.  
Funding for the research study was also provided.  
£237,181.19 
 
v. ROLE OF STUDY SPONSOR AND FUNDER 
Lancaster University, as the Sponsor, assumes overall responsibility for the initiation and 
governance of the study. This includes ensuring that the research complies with relevant 
ethical, legal, and regulatory standards, and that appropriate risk management, insurance, and 
oversight mechanisms are in place. The Sponsor, in its supervisory role, will monitor and 
support the project through established protocols delivered by the university’s Clinical Research 
Governance Team, ensuring that the study is conducted to high scientific and ethical standards, 
and that outcomes are appropriately reported and disseminated. 
North West Cancer Research, as the Funder, is a registered charity, whose role is to provide 
financial support to enable the research to be conducted. While the Funder may outline 
strategic priorities and conditions for the use of funds, it does not assume legal or regulatory 
responsibility in this study. The Funder is not the Sponsor and is therefore not involved in the 
management, oversight, or conduct of the research. The sponsor and the research team are 
responsible for ensuring that the study meets ethical, legal, and governance requirements. The 
Funder may require progress updates, a final report, and evidence of dissemination in line with 
its commitment to transparency and impact.  
 
vi. ROLES AND RESPONSIBILITIES OF STUDY MANAGEMENT COMMITEES/GROUPS & 
INDIVIDUALS  
The public and patient involvement (PPI) steering committee will consist of individuals with lived 
experience of colorectal cancer, including experience of chemotherapy-related cognitive 
impairments (‘brain fog,’ ‘chemo-brain’), and carers of people who have undergone 
chemotherapy treatment. The group will be facilitated and chaired by the lead investigator, who 
will ensure inclusive, well-managed discussions and support the contribution of all members in 
informing the design, management, and dissemination of the research.  
The Study Steering Committee (SSC) will provide overall oversight of the study and ensure that 
it is conducted according to the highest standards of scientific and ethical integrity. The 
committee will include the Lead Investigator (Hoad), Chief Investigator (Gaffney), Co-
Investigator (Nuttall), Clinical Lead (Subar), and three academic members with expertise in 
clinical trial management and oversight. In alignment with the best practice in PPI, a 
representative from the study’s PPI advisory group will also participate in quarterly SSC 

 
 
 
 
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meetings to ensure that the perspectives of those with lived experience inform study 
governance. Management challenges may arise in the timing of recruitment and enrolment into 
the exercise prehabilitation, especially across multiple hospital sites. Recruitment and retention 
issues will be addressed in our steering group meetings and monitoring of the testing protocol. 
 
vii. PROTOCOL CONTRIBUTORS & ROLES AND RESPONSIBILITIES 
Hoad is a research associate currently based at Lancaster Medical School with a background 
in exercise physiology. She was involved in cerebrovascular and cardiovascular health in 
patients with stroke and during cardiac rehabilitation. Hoad is employed for 2.5 years to conduct 
this 
project. 
Hoad 
will 
recruit 
all 
participants, 
conduct 
all 
data 
collection 
(CPET/Bloods/EEG/Cognitive Battery) during hospital visits, run the intervention (exercise 
sessions), manage data, and analyse all data with guidance from Gaffney and Nuttall.  
 
Gaffney (Lecturer in Sports Science, Lancaster University, UK) is a physiologist based in 
Lancaster Medical School with expertise in skeletal muscle metabolism. His experience covers 
research involving patients, elite athletes, and his industrial partners including work with NASA 
and SpaceX. Gaffney will provide oversight of the project, support the lead investigator (Hoad) 
in CPET and blood panels data and prepare data for publication.  
 
Nuttall (Lecturer in Cognitive Neuroscience, Lancaster University, UK) is a neuroscientist with 
expertise in cognitive neuroscience and sensorimotor function, using auditory brainstem 
responses (ABRs), frequency following responses (FFRs), electroencephalography (EEG), 
transcranial magnetic stimulation (TMS), and motor evoked potentials (MEPs). Nuttall will 
support the lead investigator (Hoad), assist with all EEG and cognitive-related data, and 
prepare data for publication.  
 
Subar is a consultant laparoscopic and Hepato-Pancreato-Biliary surgeon with an interest in 
minimal access surgery. He is the lead for robotic HPB in the department, which will soon be 
launched. He is also the lead in research and development in the Department of General 
Surgery. Subar will be the clinical co-investigator/lead clinician of the project and principal 
investigator at East Lancashire NHS Teaching Hospitals and will review lists of patients weekly 
throughout the recruitment window.  
 
Williamson is a consultant clinical oncologist based at the Lancashire Teaching Hospital NHS 
Trust. Her research has focused on cancer, specifically the optimisation of chemoradiotherapy 
and standardisation of clinical trial outcomes. Williamson will be the clinical co-investigator of 
the work, principal investigator at Lancashire Teaching Hospital NHS Trust and will review lists 
of patients weekly throughout the recruitment window. 
 
Ton is a consultant medical oncologist at the Royal Lancaster Infirmary, University Hospitals 
Morecambe Bay Trust. Ton will be the clinical co-investigator of the work, principal investigator 

 
 
 
 
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at University Hospitals Morecambe Bay Trust, and will review lists of patients weekly throughout 
the recruitment window. 
 
viii. KEY WORDS: 
Prehabilitation, Colorectal Cancer, Chemo-Brain, Chemotherapy-
Induced Cognitive Impairment, Exercise, Quality of Life. 
 

 
 
 
 
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ix. STUDY FLOW CHART 
 

 
 
 
 
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1. BACKGROUND & RATIONALE 
Colorectal cancer is 37% higher in the North-West than the national average, and recent 
analysis suggests that overall survival in the North-West is the worst in England at 58.1% (95% 
CI: 57.3%, 58.9%)1,2. Colorectal cancer is treated with chemotherapy, including fluorouracil, 
capecitabine, and oxaliplatin. These drugs do not just kill the tumour, they also damage cells 
across the body, which can lead to common side effects, such as hair loss. A further common 
side effect is “chemo-brain,” which describes a range of symptoms, including problems with 
memory and thinking speed. Such symptoms reduce the quality of life and increase stress in 
patients.  
One of the most promising new avenues for optimising patient treatment in cancer is 
“prehabilitation” 3,4 a term used to capture exercise and nutrition interventions to prepare 
patients before treatment. Prehabilitation has excellent surgical benefits. It can improve 
cardiorespiratory fitness before cancer treatment, improves functional capacity, reduces post-
operative complications, and reduces hospital length of stay3-5, thus offering patient-centred 
and economic benefits. The benefits before chemotherapy are less well defined, but the 
mechanisms that improve outcomes for surgery remain intact in patients who undergo 
chemotherapy. 
Exercise improves both the body and brain. For the body, it improves cardiovascular function 
and promotes muscle protein synthesis and skeletal muscle accretion5. In the brain, exercise 
increases growth factors in the blood, which collectively improves brain health and cognitive 
reserve. These include Brain-Derived Neurotrophic Factor (BDNF) and Vascular Endothelial 
Growth Factor (VEGF)6. Exercise-induced increases in new cells in the nervous system result 
in increased white matter volume, gray matter volume, and neural activity in the brain7. Exercise 
also promotes greater connectivity within the nervous system and the formation of new blood 
vessels, which increases cerebral blood flow7. Therefore, exercise can improve brain health 
and function. Exercise can help build the body up before chemotherapy breaks the body down, 
alleviating some side effects associated with chemotherapy. We will use an existing 
prehabilitation intervention we have developed, which increases fitness and reduces hospital 
length of stay in colorectal cancer patients undergoing surgery, to try and improve the 
symptoms of chemo-brain of those undergoing chemotherapy and improve quality of life. Given 
the known link between cardiorespiratory fitness and markers of brain health7, we hypothesise 
that prehabilitation will also improve chemo-brain symptoms resulting from chemotherapy. 
 
2. ASSESSMENT AND MANAGEMENT OF RISK 
Potential Risks 
Cardiopulmonary exercise testing (CPET) carries a small but important risk of adverse events. 
To minimise the risk of exertional arrhythmias, cardiac events, or syncope, participants will be 
pre-screened using the Physical Activity Readiness questionnaire (PAR-Q+), with medical 
clearance obtained if needed before the first visit to the hospital for testing. Resting 
electrocardiography (ECG) may be performed as part of the test prior to cycling. All tests will 
be supervised by the lead investigator who has appropriate first aid training, with access to 
medical personnel readily available at each participating hospital site. To reduce the risk of 
musculoskeletal injury from sudden or excessive exertion, functional movement screening will 

 
 
 
 
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be conducted prior to testing, and a gradual ramping protocol will be used. Each test will include 
an appropriate warm-up and cool-down period.  
There are no potential risks associated with EEG recordings; however sanitiser/disinfectant for 
cleaning skin where the cap is to be placed. Participant could potentially experience an allergic 
reaction, or sensitive skin following chemotherapy compared to normal. EEG hydro-links will be 
a fitted into the cap, therefore also maintaining a sterile field. Although the EEG system is not 
diagnostic, any incidental EEG findings which warrants further investigation will be reported to 
the direct care team. These would include any EEG findings that also suggest underlying 
symptoms. The EEG data would not be analysed in real time and does not have any direct 
diagnostic value, but as part of good clinical practice, as outlined above, will be discussed with 
them if any incidental findings are noted. Additionally, the cognitive function test battery and 
physical evaluation can potentially lead to fatigue, frustration, or emotional disturbance. The 
study will be conducted with close attention to patient safety and will not interfere with or alter 
the standard of care that patients would normally receive. If they do suffer any other symptoms 
or they become concerned in any way prior to their next study visit or after the study has 
finished, they should contact the lead investigator or any investigators named on this sheet  
(chief or principal investigators) prior to their next visit.  
Home-based exercises carry potential risks in both supervised and unsupervised sessions. 
Such risks include adverse events: cardiovascular events, neurological complications such as 
neuropathy-related balance issues, as well as general safety such as falls and musculoskeletal 
injuries. All exercises (aerobic and resistance/strength) will include adaptations to suit the 
participants’ individual circumstances. For example, providing a chair to perform resistance 
band exercises. Family, friends, or caregivers must be present in the household for both 
supervised and unsupervised sessions. If the participant is unable to contact the emergency 
services, someone will be present to assist. Support will also be provided during supervised 
exercise sessions. The participant will be provided with an emergency contact list. Calls 
between the lead investigator (or member of the research team) will provide an opportunity to 
screen for any injuries and side effects of treatment (e.g. neuropathy) which will inform any 
appropriate adaptations to exercise sessions. 
Regarding the use of multivitamins (Forceval), the principal investigator during the screening 
process will exclude participants with any contraindications to taking these multivitamins (e.g. 
impaired kidney and liver function, listed in Section 6.2) which can be indicated through markers 
and medical history on patient medical records. Routine blood count checks conducted as part 
of the standard of cancer care will provide additional monitoring for potential adverse changes. 
The multivitamin used will be dispensed and recorded by the participating hospital, ensuring 
that the direct care team (oncologists, oncology nurses, and PIs) is aware of supplementation 
but remains blinded to group assignment. Awareness of multivitamin use alongside blood count 
results may help the direct care team identify potential concerns and, in collaboration with the 
research team, determine whether further steps are needed. Participation may be terminated if 
clinically indicated to safeguard patient wellbeing. 
Venepuncture for the collection of blood samples for neuroplasticity assessment carries minor 
risks, including bruising, haematoma, infection, and vasovagal syncope. To minimise these 
risks, all procedures will be carried out by a trained healthcare clinician or nurse using an 

 
 
 
 
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aseptic technique. Pressure will be applied to the puncture site following sample collection to 
reduce the likelihood of bruising and haematoma. Participants will be observed post-procedure 
to monitor for any adverse reactions, including signs of fainting or discomfort, ensuring a proper 
and appropriate response if required. The blood samples for the brain markers are not for 
clinical use and will be analysed at the end of the testing period, i.e., when the last participant 
is tested at Visit 3. Thus, the findings of these samples will not be communicated to a clinician 
(member of the direct care team or general practitioner (GP)) as it will be weeks/months from 
when they were collected. 
Before the first visit to the hospital for testing, the Informant Questionnaire On Cognitive Decline 
In The Elderly (IQCODE, self-report form) (via Qualtrics, https://lancasteruni.eu.qualtrics.com) 
and the Mini-Cog (WebCog, https://rishik4.github.io/webcog/#/) will be used to assess cognitive 
function, and physical activity engagement via the Physical Activity Readiness Questionnaire 
for Everyone (PAR-Q+) and International Physical Activity Questionnaire (IPAQ) can be found 
in the appendices. All questionnaires will be completed to check eligibility to take part, and if 
the participant is eligible, they will be scheduled into a testing slot at their participating hospital 
site (visit 1). It is important to highlight that these questionnaires cannot be used as clinical 
assessment tools in this setting and that the lead researcher is not qualified to provide a 
diagnosis of cognitive impairment. If the patient is concerned by the results of the 
questionnaires or would like further information, they will be advised to contact their direct care 
team or GP. A GP letter can be provided by the research team to the patient to give details 
about the screening questionnaires used and evidence about potential cognitive decline if they 
seek to speak to their GP for advice. 
 
3. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
3.1. Primary objective 
1. We will use physiological blood-based markers of (VEGF and BDNF) to establish if 
prehabilitation promotes an improvement in brain health in colorectal cancer patients 
prior to starting chemotherapy. 
2. We will use neuroscientific measures of brain function (EEG) and cognitive outcomes at 
baseline and post-chemotherapy to determine if prehabilitation neuroplasticity reduces 
the negative effects of chemotherapy on the brain. 
 
3.2. Secondary objectives 
1. We will measure changes in the FACT-COG questionnaire in colorectal cancer patients 
at Study Visit 1 and at 3 months after chemotherapy cessation to determine if 
prehabilitation improves quality of life. 
 
3.3. Outcome measures/endpoints 
We will use a range of physiological (CPET, blood panels), neuroscientific (EEG) and 
psychological (cognitive function test battery, quality of life questionnaire) to determine if our 

 
 
 
 
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prehabilitation intervention improves chemo-brain and quality of life in patients with colorectal 
cancer. Our intervention will be delivered across Lancashire, with the aim of reducing health 
inequalities and negative health outcomes associated with cancer treatment in the region. 
 
3.4. Primary endpoint/outcome 
We will measure brain function at three-time points; baseline (after diagnosis/before 
prehabilitation, visit 1), after 3-4 weeks prehabilitation (before chemotherapy, visit 2) and after 
the final round of chemotherapy (3-4 days after infusion of the final round, visit 3). Outline in 
Figure 1. Chemotherapy typically range from to 2-8 rounds of infusion, with each round being 
spaced out by 2-3 weeks. The maximum duration of prehabilitation participation is approx. 28 
weeks; however, the intervention may be extended (endpoint to visit 3) due to delays to 
treatment from chemotherapy-related side effects (e.g., low blood cell counts). Thus, time is 
needed to be given to participants in order to recover, reduce the risk of infection and worsened 
side effects. Participation in the prehabilitation programme will not influence or delay the timing 
of any scheduled chemotherapy treatment. 
 
3.5. Secondary endpoint/outcome 
There will be a 3 month follow up following chemotherapy to assess changes in quality of life. 
This data collection is feasible to complete within a 2 year period.  
 
3.6. Table of endpoints/outcomes 
Objectives 
Outcome Measures  
Timepoint(s) of evaluation 
of this outcome measure (if 
applicable) 
Primary Objective 
 
We will use physiological 
blood-based markers of 
(VEGF and BDNF) to 
establish if prehabilitation 
promotes an improvement in 
brain health in colorectal 
cancer patients prior to 
starting chemotherapy. 
Visit 1 (day 0), Visit 2 (3-4 
weeks), Visit 3 (8-24 weeks) 
 
We will use neuroscientific 
measures of brain function 
(electroencephalography 
(EEG)) and cognitive 
outcomes at baseline and 
post-chemotherapy to 
determine if prehabilitation 
neuroplasticity reduces the 
Visit 1 (day 0), Visit 2 (> 3 
days before first 
chemotherapy), Visit 3 (3-4 
days after final 
chemotherapy) 

 
 
 
 
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negative effects of 
chemotherapy on the brain. 
Secondary Objectives 
 
We will measure changes in 
the FACT-COG questionnaire 
in colorectal cancer patients 
at Study Visit 1 and at 3 
months after chemotherapy 
cessation to determine if 
prehabilitation improves 
cognitive-related quality of 
life. 
Visit 1 (day 0) and Follow Up 
(3 months following 
chemotherapy) 
 
4. STUDY DESIGN 
A multi-centre randomised control trial (RCT) using a prehabilitation group (exercise and 
nutrition programme) and a control group (standard care). 
 
5. STUDY SETTING 
Participants will be recruited via weekly clinician reviews by the principal investigators at the 
East Lancashire Teaching Hospitals Trust (Subar), Lancashire Teaching Hospitals NHS Trust 
(Williamson), and University Hospitals Morecambe Bay NHS Trust (Ton). Recruitment and 
testing will be conducted at each participating site. These Trusts are affiliated with Lancaster 
University.  
 
East Lancashire Teaching Hospitals Trust (ELTH): The research environment at the East 
Lancashire Hospitals NHS Trust is dynamic and rapidly advancing, reflecting its commitment 
to delivering high-quality, patient-centred research. The East Lancashire Hospitals NHS Trust 
has expanded its research portfolio over the past decade, actively participating in national and 
international studies across specialities, including oncology. In collaboration with the NIHR 
Clinical Research Network Greater Manchester, East Lancashire Hospitals NHS Trust has 
enhanced its research infrastructure, providing patients with greater access to innovative 
clinical trials.  
 
Lancashire Teaching Hospital NHS Trust (LTHTR): The research environment at Lancashire 
Teaching Hospital NHS Trust is nationally recognised, underpinned by its designation as an 
NIHR Clinical Research Facility in partnership with the Lancashire Care NHS Foundation Trust 
and Lancaster University. The Trust activity supports over 150 research projects across a broad 
spectrum of clinical areas, including oncology, consistently surpassing NIHR recruitment 
targets. The Lancashire Teaching Hospital NHS Trust is committed to research excellence is 
further demonstrated by its strategic partnership with Lancaster University, fostering a robust 
clinical academic faculty and supporting the development of early phase clinical trials.  
 

 
 
 
 
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University Hospitals Morecambe Bay NHS Trust (UHMBT): The research environment at 
University Hospitals Morecambe Bay NHS Trust is collaborative, reinforced by strong 
partnerships with Lancaster University and the University of Cumbria across its three main 
hospital sites: Furness General Hospital, Royal Lancaster Infirmary, and Westmorland General 
Hospital. These formalised agreements focus on joint initiatives in research, innovation, 
education, and workforce development; aiming to enhance health outcomes across the region. 
The University Hospitals Morecambe Bay NHS Trust actively participates in clinical research 
areas of oncology. The Trust research and development department comprises a 
multidisciplinary team that supports the governance, performance, and quality of research 
studies. 
 
6. PARTICIPANT ELIGIBILITY CRITERIA 
All eligible participants will be given a patient information sheet at the first meeting with their 
direct care team. This will be determined before the randomisation process. The eligibility 
criteria were carefully decided to ensure that participants were medically appropriate for 
selection. Participants will be considered for participation once they meet the inclusion criteria 
and none of the exclusion criteria, as detailed below.  
 
6.1. 
Inclusion criteria 
The inclusion criteria: participants aged 60-85 years and diagnosis of stage II or III 
colorectal cancer undergoing chemotherapy, including fluorouracil, capecitabine, or 
oxaliplatin. Confirmation of patient medical records of participants being scheduled to 
receive either neoadjuvant or adjuvant chemotherapy, with suitability and tolerability to 
receive chemotherapy confirmed by their direct care team via patient medical records 
(e.g., dependent how the patient’s health and recovery following surgery). The duration 
between surgery and the start of chemotherapy is typically 6+ weeks, dependent on the 
patients’ recovery. Participant is fluent in English. Prehabilitation benefits those most 
who are not habitually active; therefore, exclusion criteria include structured exercise in 
the 6 months prior to the point of consent. Equal numbers of males and females will be 
included.  
 
6.2. 
Exclusion criteria 
The exclusion criteria: participants with co-morbidities which impact the metabolic 
response to exercise, for example diabetes, current musculoskeletal injury/physically 
rendering them unable to undergo CPET, atrial fibrillation, palliative disease, 
haematological malignancy, synchronous cancer disease, and lack the capacity to 
consent. Evidence of pre-existing cognitive impairment, including diagnosis of dementia, 
other neurodegenerative disorders, or clinically indicated mild cognitive impairment. 
Participant has no diagnosis of profound hearing loss. Participants without access to the 
internet within their home will not be able to take part due to the online element of the 
exercise programme. 

 
 
 
 
V1.0 04.12.25                                  ChemoBrain Prehab Protocol                                      IRAS ID: 356825  
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Further exclusion criteria related to multivitamins (Forceval): Participants will be 
excluded if they have hypercalcaemia, haemochromatosis, or allergic to peanut or soya. 
Concomitant use of medications that interact with Forceval, such as phenytoin or 
tetracycline antibiotics will also lead to exclusion. Individuals with impaired kidney or liver 
function (e.g., chronic kidney disease) will not be eligible.  
 
7. STUDY PROCEDURES  
7.1. Recruitment 
The principal investigator or suitably trained member of the direct care team with delegated 
duties to do so, at each participating hospital site will review lists of colorectal cancer patients 
weekly throughout the recruitment window. Potential participants meeting the inclusion criteria 
will be passed to the lead investigator who will select patients while consulting with the lead 
clinician of the project (Subar). Recruitment will continue for a period of 8-12 months. At three 
monthly periods the recruitment rate will be assessed to gauge progress and address 
recruitment issues. 
 
7.1.1. Screening 
Initial eligibility will first be assessed by the principal investigator or a suitably trained and 
delegated direct care team member at each participating hospital site, who will screen for 
potential participants meeting the eligibility criteria through patient medical records through on-
site system(s) (Section 6.1 and 6.2). Eligible patients must receive adjuvant chemotherapy 
(after surgery or radiotherapy) confirmed within their treatment plans to be suitable for study 
participation. This usually refers to the period of six or more weeks from the point at which the 
patient begins chemotherapy after surgery. If a suitable patient is identified, the principal 
investigator/member of the direct care team will liaise with the lead investigator to arrange a 
date and time for screening, coordinated around the patient’s oncology appointment. No 
identifiable patient information will be disclosed at this stage. The direct care team member will 
briefly introduce the study to the participant in the clinical consultation and obtain verbal consent 
from the lead investigator to approach them or join the consultation to discuss the study further. 
The lead investigator will enter the consultation and discuss the study. Patients who expresses 
interest will be given a study participant information sheet and provide verbal consent to be 
contacted in a one-week follow-up call. Those who confirm interest within this time period will 
provide verbal consent to proceed and will begin the formal screening process during the 
telephone call. Screening questionnaires will include the International Physical Activity 
Questionnaire (IPAQ) to confirm the absence of structured exercise participation within the 
previous six months, a key exclusion criterion. The  physical activity readiness questionnaire 
(PAR-Q+) will be used to assess whether participants are safe to exercise with medical 
clearance, if needed. These questionnaires were completed during telephone calls. The 
IQCODE and Mini-Cog will be administered to screen for cognitive impairment. The IQCODE 
assesses self-reported cognitive changes in older adults, and the Mini-Cog self-reported 
cognitive function. These questionnaires will be sent to the potential participant via an online 

 
 
 
 
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link following the telephone call which needs to be returned as soon as possible, before a testing 
visit can be scheduled (if eligible). Screening questionnaires (IPAQ, PAR-Q+, IQCODE, and 
Mini-Cog) will be completed before the baseline visit (visit 1) to confirm eligibility. Eligible 
participants will also be re-contacted, verbal consent to take part will be obtained, and the first 
research visit will be arranged.  
After completing the above, if an individual is found to be ineligible during screening with the 
lead investigator, efforts will be made to minimise disappointment and reduce distress. They 
will be encouraged to seek advice about exercise chemotherapy from their direct care team. 
Additionally, the patient will be directed to the Macmillan Cancer Support to access the Physical 
Activity and Cancer booklet (https://www.macmillan.org.uk) as well as the exercise guidelines 
provided by Cancer Research UK (https://www.cancerresearchuk.org). If there are any 
concerns that the individual expresses from the cognitive function questionnaires (IQCODE or 
Mini-Cog) then the researcher will advise for them to speak to their direct care team or GP. The 
researcher can provide details of the questionnaires in a GP letter to provide support. The 
questionnaires are not diagnostic tools.  
 
7.1.2. Payment  
Participants will be reimbursed for travel costs to and from each study visit. Car travel will be 
reimbursed at a rate of 45p per mile, which reflects with standard mileage reimbursement within 
the UK. Participants will complete the claims forms to receive payment through the project’s 
funding. Public transport costs will be reimbursed at the exact price paid for tickets or fares. 
Participants must provide proof of purchase such as a ticket or receipt to ensure transparency 
and accurate reimbursement across all modes of travel. 
 
7.2. Consent  
Verbal consent for the patient to be approached about this study will first be obtained by the 
principal investigator or direct care team member. The direct care team member will then introduce 
the lead investigator, who will inform the patient about the study. They patient will be provided with 
the participant information sheet and ask for verbal consent to follow-up one week later via 
telephone. At the follow-up telephone call, if the potential participant expresses interest in the 
study, they will undergo the screening for cognitive function and physical activity. The participant 
will then receive another call with the outcome of these assessments and, if eligible, arrangements 
will be made for the first study visit. At Visit 1 (baseline assessment), written informed consent will 
be obtained, signed, and dated only after the participant has received full information about the 
study and confirmed their decision. Participants remain free to withdraw from the study at any 
point without giving a reason and without prejudice.  
 

 
 
 
 
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7.3. The randomisation scheme  
Using a permuted block randomiser, we will randomise 86 patients with colorectal cancer into 
Group 1: Intervention (Prehabilitation; n = 43) and Group 2: Control (Standard Care With No 
Prehabilitation; n = 43).  
 
7.3.1. Method of implementing the randomisation/allocation sequence 
A computer-generated randomised sequence will be performed at the Lancaster University Health 
Statistics Department. Randomisation will be stratified by sex, staging, and rounds of 
chemotherapy required. This sequence will be delivered to the investigating team via sealed 
envelopes. Eligible participants will be randomised on a 1:1 basis to standard care: exercise and 
nutrition. To ensure 1:1 randomisation allocation, the lead investigator will review allocation at the 
end of the recruitment period. Allocation details will be contained in sealed envelopes. Eligible 
patients who have consented will be given a unique participant number. The participants will be 
randomised after the baseline CPET. 
 
7.4. Baseline data 
All participants recruited in both the intervention and control group will undergo a baseline 
measurement on cardiopulmonary fitness (CPET), blood samples (BDNF and VEGF), brain 
activity (EEG), cognitive function, and cognitive-related quality of life at visit 1. This baseline 
data will be collected before group assignment (assigned following CPET). 
 
7.5. Study Intervention and Assessments 
7.5.1. Intervention (Prehabilitation) 
Exercise Programme 
Participants will be taught how to perform exercises safely at home. For the intervention group, 
the CPET-derived parameters at baseline such as VO2 peak will be used to prescribe an 
individualised exercise programme at the precise target moderate intensity for the aerobic 
components of the intervention (60% of VO2 peak). This will consider the participants’ 
capabilities to perform the exercises along with functional fitness assessments performed at 
the baseline visit. The exercise programme will be designed, delivered, and overseen by the 
lead investigator, who will hold a valid exercise-instructor level 4 qualification in cancer care. 
The supervised exercise programmes can be delivered by a suitably qualified exercise 
instructor in the lead investigator’s absence. The intervention is underpinned by the Theory of 
Planned Behaviour, which suggests that intention to exercise is shaped by attitudes, social 
norms, and perceived controls. To encourage adherence, the approach aims to promote 
positive beliefs about exercise, provide support from family/friends/peers to reinforce social 
norms, and enhance perceived control by helping participants integrate physical activity into 
their routine and environments, especially before starting chemotherapy.  
The exercise programme will be performed four times per week before and during 
chemotherapy. There will be 2 supervision sessions and 2 unsupervised sessions, self-paced 
sessions that will be performed remotely from the participant’s home. An online supervised 

 
 
 
 
V1.0 04.12.25                                  ChemoBrain Prehab Protocol                                      IRAS ID: 356825  
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exercise sessions will be delivered by the lead investigator. The online sessions will be held on 
Microsoft Teams call, in which participants will be provided with links to join the call. The 
exercise programme will involve 40-minute sessions of aerobic and strengthening exercise: to 
include 5-minute warm up, 20-minute aerobic exercises at moderate intensity (60% V̇ O2 peak 
determined by the CPET), 10-15 minutes of strength/resistance training, followed by a 5-minute 
cool down. The strengthening exercises will focus on upper and lower muscle groups. Different 
grades of resistance bands and dumbbells will be provided and used. Alternative and equivalent 
exercises, through regressions and progressions, will be employed by the lead investigator 
based on the participants mobility capabilities. For unsupervised sessions, participants will be 
provided with an exercise booklet, along with exercise videos created for the study, to be 
performed independently. Participants will be educated in the primary exercises of this 
programme with progression and regression versions of each exercise. The exercise 
programme will be updated on a frequent basis but will continuously include the primary 
exercises with slight variations or the inclusion of similar exercises to prevent participants losing 
interest in the exercise programme. The participants involvement in the exercise programme 
and any changes to their individual exercise prescription will be managed by the lead 
investigator in liaison with the clinical team, if required. For all supervised and unsupervised 
exercise sessions, participants in the prehabilitation group will be required to have a family 
member, carer, or friend present to provide immediate assistance in the event of an emergency 
incident. Participant will provide the contact details of their next of kin to the lead investigator 
prior to the supervised exercise sessions. A sample of the exercise programme can be found 
in the appendix.  
 
Psychological Support 
In addition to the supervised and unsupervised exercise sessions, participants will receive 
weekly telephone calls from a member of the research team. These calls will provide 
behavioural support to help participants achieve their weekly exercise targets and will be 
structured using the Theory of Planned Behaviour. Discussions will focus on identifying 
individual motivators and barriers to exercise, with this information used to adapt both the 
exercise sessions (through progressions and regressions) and the overall approach to 
supporting each participant’s engagement in the intervention. The lead investigator is  not a 
healthcare professional. If any medical concerns are raised during the call, participants will be 
advised to contact their direct care team or the oncology helpline. If urgent situations they will 
be instructed to call 999 or 111.  
 
Nutrition 
At the first visit (baseline), participants will have a nutritional blood test using the Abridged 
Scored Patient-Generated Subjective Global Assessment (abPG-SGA)5 that will collect several 
markers: full blood count, urea and electrolytes, glucose, liver function tests, magnesium & 
phosphate, calcium & albumin, clotting function, copper, zinc, selenium, iron, ferritin, B12, 
folate, manganese, C-reactive protein and vitamin D). The lead investigator will be present at 
all initial visits and with the research team’s support will collect the blood samples. Samples will 
be labelled before being sent to the pathology laboratory at each participating site. Any queries 

 
 
 
 
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regarding results from the nutritional blood tests will be assessed by the dietitian as part of 
standard of care. 
Prehabilitation participants will be given a multivitamin (Forceval Capsules, United Kingdom), 
to be taken orally once per day throughout the duration of the intervention (before and during 
chemotherapy). The multivitamins will be taken in addition to the exercise programme. 
Compliance will be checked by asking participants to bring in used capsule trays at visits 2 and 
3.  
Forceval capsules are a multivitamin supplement that contains a combination of 24 essential 
vitamins (Vitamin A, D2, B1,2,6,12, C, E, Biotin, Nicotinamide, Pantothenic Acid and Folic Acid), 
minerals and trace elements (Calcium, Iron, Copper, Phosphorus, Magnesium, Potassium, 
Zinc, Iodine, Manganese, Selenium, Chromium, Molybdenum). Each vitamin and mineral plays 
a vital role in the efficient daily maintenance of the body. Multivitamin administration will be 
managed and dispensed as part of the standard of care and will be monitored by the 
participating hospital, with appropriate documentation and oversight. Patients with 
contraindications to multivitamin use will be excluded prior to enrolment (Section 6.2). Blood 
samples will be collected in this study and provided to the hospital for routine analysis of 
nutritional tests (abPG-SGA), in which the research team will collect nutritional marker data 
relevant to this study following analysis. As part of standard care, the direct care team will have 
access to the test results and will be able to take action, if required. Notably, only participants 
within the prehabilitation arm will receive multivitamin supplementation as an adjunct to 
standard care. Beyond the prescriber, the other members of the direct care team will remain 
blinded to group allocation to minimise bias. If the research team needs to report any concerns 
during the collection of blood samples, they will follow the notification cascade steps from the 
reporting workflow in Section 8.2. 
 
Support During Intervention 
To further support participants’ efforts to increase their activity and engage in exercise sessions, 
they will be provided with online resources, including exercise programmes and videos. 
Participants will also have the option to join a private Microsoft Teams group chat, moderated 
by the lead investigator. In this group chat: 
 
1. Announcements about weekly dates/times of online supervised exercise sessions will 
be posted. 
2. Participants can indicate which sessions they will attend. 
3. All exercise programmes, exercise videos and additional resources will be archived in 
the group chat for easy access. 
4. Links for online supervised exercise sessions will be posted in the chat. 
 
When participants opt in (via the consent form), they are informed that names and email 
addresses may be visible to others during Microsoft Teams exercise sessions. All participants 
will be reminded to keep any visible information strictly confidential and to avoid using it for any 
purpose outside the study, including contacting other participants directly. The use of Microsoft 
Teams is covered by the University’s existing Office 365 data protection documentation, 

 
 
 
 
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ensuring full compliance with institutional and legal requirements. This is further explained in 
the Data Protection Impact Assessment (DPIA). Members of the Microsoft Teams group will 
include the lead investigator and participants in the prehabilitation group. 
If a participant wishes to opt out of the Microsoft Teams group, they will still receive all the same 
resources, updates, and Teams call links (for the supervised exercise sessions) via email. 
 
Habitual Activity 
All participants, including those in the standard care group, will have their habitual physical 
activity measured using the activity device (ActiGraph wGT3X-BT1, Ametris, Florida). This 
device is a triaxial accelerometer that captures bodily acceleration at a sampling rate of 30 Hz. 
Data will be processed using ActiLife software, with step counts derived using the Freedson 
algorithm and extracted in 10-second epochs. Participants will wear the device on the non-
dominant wrist for seven consecutive days during three distinct periods: the first week of 
prehabilitation before chemotherapy, the first week of chemotherapy, and the week before the 
final chemotherapy cycle. The device will provide measures of total movement, moderate to 
vigorous physical activity (minutes), non-sedentary time (minutes), and step count (steps per 
day) over each 7-day period. Data from these measures will be transferred directly from the 
device when participants return to their participating hospital site. Habitual physical activity 
measures obtained from this device will be used to compare the prehabilitation and standard 
care groups. 
The prehabilitation group will use the Xiaomi Smart Band 9 (Xiaomi, China) to motivate and 
monitor activity during the exercise programme (both supervised and unsupervised) and daily 
living activities. This wrist-worn device includes an accelerometer, gyroscope, six-axis motion 
sensor, heart rate sensor (photoplethysmography, PPG), and blood oxygen sensor. 
Participants will wear the device on their dominant hand throughout the intervention. It provides 
objective quantification of total daily activity through step count (steps per day), distance 
(metres), standing time (minutes), and time spent in moderate to high-intensity activity 
(minutes). Moderate intensity reflects activity that elevates heart rate to 50–75% of the 
individual’s estimated maximum, while high intensity exceeds 70% of maximum, making 
conversation difficult. Based on established thresholds for step count, fewer than 3,000 steps 
indicates low activity, and 3,000–10,000 steps indicates moderate activity. 
Data collection will be synchronised with the fitness application, which can remotely export 
measures every two weeks as CSV files accessible only to the research team. The lead 
investigator will provide prompts during supervised sessions and check-in calls to encourage 
device use. If participants experience skin irritation from the silicone straps, these can be 
replaced with nylon straps. Any day containing null values will be treated as non-wear or device 
failure. The device will be collected at the final visit (visit 3). If a participant withdraws from the 
study, they will be asked to return the device to their participating hospital or, alternatively, will 
be provided with a pre-paid postage envelope. 
 
Adherence To The Intervention 
Adherence to the intervention will be assessed in four ways: (1) marking attendance at 
supervised sessions, (2) weekly check-ins during telephone calls, (3) null data values from the 

 
 
 
 
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Xiaomi device, and (4) data from the activity device (ActiGraph) measuring minutes of moderate 
intensity or greater activity, excluding habitual activity outside prescribed sessions. 
 
Ongoing care 
Both groups will be seen in the outpatient setting at time intervals predetermined by their direct 
care team. Each participant’s cancer care plan will not be affected by study visits or the 
prehabilitation programme (intervention group). Visits will be arranged, where possible, to 
coincide with appointments with the direct care team to minimise the burden of travel. 
 
7.5.2. Assessments 
In summary, cardiopulmonary fitness (CPET), blood sampling, brain activity, cognitive function, 
and cognitive-related quality of life will be assessed at visit 1 (baseline). Visits 2 and 3 will 
include repeated assessments of cardiorespiratory fitness, blood sampling, brain activity, and 
cognitive function. At the three-month follow-up after the final chemotherapy session, cognitive-
related quality of life will be reassessed via telephone or post. Visit 1 (baseline) takes place 3–
4 weeks before chemotherapy (time-to-treatment). Visit 2 occurs within 72 hours of starting 
chemotherapy and visit 3 will take place 3–4 days after the last chemotherapy session. See 
Figure 1. 
 
Figure 1. Illustration of the timeline of the study visits, assessments, and intervention. 
 
Cardiopulmonary Exercise Test (CPET) & Functional Fitness 
Participants will be advised to take their regular medication but to avoid caffeine, alcohol, 
cigarettes, and strenuous exercise on the day of each visit. For two hours prior to testing, 
patients must fast except for water. They should wear comfortable sports clothing and 
appropriate shoes. The CPET will be performed using a cycle ergometer at each participating 
site. Cycle ergometry allows accurate determination of work rate, enabling evaluation of the 

 
 
 
 
V1.0 04.12.25                                  ChemoBrain Prehab Protocol                                      IRAS ID: 356825  
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VO2–work rate relationship. Gaseous analysis will be conducted using a gas analyser, and 
continuous oxygen saturation will be monitored with a pulse oximeter. 
After explaining the test protocol to the participant, a resting data collection period (rest 
phase/baseline) will be followed by resistance-free pedalling (unloaded cycling phase), then a 
continuous, gradual, uniform increase in work rate until the participant reaches their limit of 
tolerance (incremental phase). Pedalling frequency will be maintained between 60 and 80 
rotations per minute. Increments will be adjusted based on the participant’s physical fitness 
level, aiming to reach maximal effort. 
Additionally, overall functional fitness will be assessed prior to CPET to track changes in 
participants’ abilities across testing visits. This will allow personalised adjustments to the 
exercise programme during prehabilitation, based on any functional limitations. Following the 
Senior Fitness Test protocol8, participants will perform sit-to-stand tests, arm curls, grip strength 
using a dynamometer, sit and reach, back scratch, up-and-go test, six-minute walk test, and 
three-minute step test. Their scores will be compared to age- and sex-specific norms (men and 
women aged 60–64, 65–69, 70–74, 75–79, 80–84, and 85–89 years) outlined by Jones and 
Rikli8. Normal score ranges and test descriptions are provided in the appendix. 
 
Brain Activity and Cognitive Function  
The participant will be fitted with an EEG cap using saline-based hydro-links during each testing 
visit at the participating sites. The participant will then complete a resting measure, followed by 
a modified change detection task to assess memory while EEG activity is recorded. 
Electrophysiological measures of brain activity will be used to assess brain function and are 
sensitive to neural changes resulting from chemotherapy-induced cognitive impairment. In 
chemotherapy-induced cognitive impairment, there is an overall slowing of brain activity. Using 
the EEG system, brain activity during the cognitive test battery will be recorded throughout each 
testing session. Subsequent analysis will focus on frequency band oscillations, including theta 
(4–8 Hertz) and alpha (8–13 Hertz) bands. Power spectral density will be calculated to quantify 
the relative contribution of each band, enabling identification of neural activation patterns 
associated with cognitive performance in subdomains such as executive function, attention, 
memory, and processing speed. Specific regions of interest will be defined to examine spatial 
variation in oscillatory activity; however, all hydro-link sites will be assessed. 
The cognitive test battery will be objectively assessed using the National Institutes of Health 
(NIH) Toolbox Cognitive Domain (http://nihtoolbox.org/). This toolbox comprises a series of 
researcher-administered, computer-adaptive tests that take approximately 20 minutes to 
complete. The adaptive feature of the tests is designed to minimise practice effects, as well as 
floor and ceiling effects. We will examine age-standardised scores from four tests to assess all 
subdomains: executive function and attention will be assessed using the Flanker Inhibitory 
Control and Attention Test; memory will be assessed using the List Sorting Working Memory 
Test; and processing speed will be assessed using the Oral Symbol Digit Test. 

 
 
 
 
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To ensure that any deficits in auditory instructions and cues are not due to hearing loss, an 
audition test (Words-In-Noise Test) will be used to differentiate between hearing loss and 
chemotherapy-related cognitive impairment. The tests will be administered by the researcher, 
and participants will use a digital tablet with audio guidance for each test. Each test will take 
between three and seven minutes to complete. 
The EEG and cognitive assessment will last approximately 50 minutes: 15 minutes for setup 
and 35 minutes to complete the resting measure and cognitive test battery, with breaks between 
tests (see Figure 3). Detailed descriptions of these tests have been previously published, and 
the battery has been validated in adults and normed for individuals aged 3 to 85 years9,10. 
 
 
Flanker Inhibitory Control and Attention Test 
The participant is asked to focus on a particular stimulus (centre fish) while inhibiting attention to the stimuli flanking it. 
 
 
List Sorting Working Memory Test 
The participant is asked to recall and sequence different 
stimuli that are presented visually and via audio. 
Oral Symbol Digit Test  
Participants are asked to orally call out the number that 
corresponds to each symbol in a grid. 
Figure 3. Illustration of what participants will see for each cognitive sub-domain being assessed. 
 
 
 

 
 
 
 
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Blood Samples 
Chronic exercise can increase brain-derived neurotrophic factor (BDNF), which in turn has 
neurotrophic and neuroprotective properties that can improve cognitive function. BDNF and 
vascular endothelial growth factor (VEGF) will be measured using an Enzyme-Linked 
Immunosorbent Assay (ELISA) from blood serum. The lead investigator will be present at all 
initial visits, and a research nurse or suitably trained staff member will collect, process, and 
label the samples before storing them at each participating site. All samples will be transported 
via courier from each site to Lancaster University for ELISA analysis following the final 
participant test visit. 
Blood will be drawn by site staff from a cubital vein into a S-Monovette 7.5 ml Z tube (with 
clotting activator; Sarstedt), left to coagulate for 30 minutes at room temperature, and 
centrifuged at 2000 g at room temperature for 10 minutes. The serum supernatant will be stored 
at -80°C in 0.5 ml aliquots within one hour of blood sampling. Blood samples will be used to 
determine BDNF and VEGF levels. The timing of blood samples will be consistent across 
testing visits at each site (± 2 hours). 
 
Cognitive-Related Quality of Life 
To evaluate cognitive-related quality of life, we will use the FACT-Cog questionnaire. This 
validated tool is currently used to measure cognitive-related quality of life in cancer patients 
and its impact on daily activities. The questionnaire includes several subscales: perceived 
cognitive impairment, perceived cognitive abilities, impact on quality of life, and comments from 
others. Each item is scored from 0 (not at all) to 4 (very much), with some items reverse scored. 
We will measure changes in cognitive-related quality of life using the FACT-Cog questionnaire 
in colorectal cancer patients at Study Visit 1 and again at three months after chemotherapy 
cessation to determine whether prehabilitation improves quality of life post-treatment. 
 
7.6. Withdrawal criteria  
Any study participant can withdraw from the study at any time by contacting the lead investigator 
or any member of the research team, without providing a reason and without affecting their 
legal rights. If they withdraw, the information collected up to that point cannot be erased and 
may still be used in the project analysis. 
 
7.7. Storage and analysis of clinical samples  
Lancaster University does not hold a Human Tissue License. However, according to the 
Human Tissue Authority, blood serum is not classified as relevant material when extracted 
using standardised methods that guarantee the sample is completely acellular. This study will 
use a method that renders the material acellular. Therefore, there are no external storage 
regulations for serum. Nonetheless, Lancaster University maintains its own sample tracking 
database, and samples will be analysed and stored under the NHS Research Ethics 

 
 
 
 
V1.0 04.12.25                                  ChemoBrain Prehab Protocol                                      IRAS ID: 356825  
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Committee’s Favourable Opinion. The serum supernatant will be stored at -80°C in 0.5 ml 
aliquots within one hour of centrifugation following blood sampling. All samples will be 
transported by a licensed biological samples courier from each participating site to Lancaster 
University for analysis using an Enzyme-Linked Immunosorbent Assay (ELISA) on blood 
serum. No samples will be stored outside the listed institutions (Lancaster University and 
participating hospitals involved in this study). Samples will not be shared with other 
institutions, either within or outside the UK. 
Following Lancaster University’s disposal procedures, blood samples will be handled as 
hazardous clinical waste, disposed of via clinical waste bins, and destroyed by incineration. 
All blood samples will be destroyed once analyses of blood-based markers of brain health via 
ELISAs are complete at the end of the study. All procedures will comply with the seventh 
revision of the Declaration of Helsinki and Good Clinical Practice guidelines. Blood samples 
will be stored in accordance with Human Tissue Authority Codes of Practice. The study 
protocol will be preregistered on the ISRCTN registry, and findings will be published within 12 
months of trial completion. The ISRCTN registry will be updated throughout the study and 
with any outputs generated. 
 
7.8. Definition of the end of Study 
The final follow-up at three months, using the quality of life questionnaire (FACT-Cog) 
completed by the last participant, will signal the end of the study. However, not all participants 
will have identical cancer treatment plans, as the number of chemotherapies rounds and their 
duration may vary. 
 

 
 
 
 
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8. SAFETY REPORTING 
8.1. Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom an 
intervention has been administered, including occurrences 
which are not necessarily caused by or related to that 
intervention. 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to the 
intervention  
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence 
that: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
 results in persistent or significant disability/incapacity 
 consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered 
serious if they jeopardise the participant or require an 
intervention to prevent one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" 
refers to an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event which might 
have caused death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting investigator, believed with reasonable probability to be 
due to one of the Study treatments, based on the information 
provided. 
 

 
 
 
 
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8.2. Workflow of reporting concerns to the direct care team and documentation 

 
 
 
 
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9. STATISTICS AND DATA ANALYSIS 
9.1. Sample size calculation 
Sample sizes were calculated in G*Power based on repeated measures mixed models to detect 
medium effect sizes (f = 0.25), with a power of 0.8 and an alpha of 0.01. A sample size of 34 
participants per group meets the power criteria. To allow for 20% attrition, 43 participants per 
group will be recruited. While the power calculation is based on the primary outcome, the study is 
sufficiently powered for each of the secondary outcomes. 
 
9.2. Planned recruitment rate 
Total recruitment rate will be 86: 43 participants in the interventional group and 43 participants in 
the control group. 
 
9.3. Statistical analysis plan 
9.3.1. Summary of baseline data and flow of patients 
Baseline comparability between the randomised groups will be assessed descriptively, without 
statistical testing, in accordance with CONSORT guidelines for randomised trials. Variables 
used to assess baseline characteristics will include: 
 Age (continuous) 
 Sex (categorical: male/female) 
 Cancer Stage (categorical: stage II and III) 
 Chemotherapy regimen (categorical) 
 Anthropometrics (continuous: e.g., height and weight) 
 Comorbidity status (categorical)  
 Education (categorical) 
 IPAQ physical activity level and PAR-Q (categorical) 
 Mini-Cog score (ordinal) 
These variables will be summarised using appropriate descriptive statistics: means and 
standard deviations for continuous normally distributed data, medians, and interquartile ranges 
for non-normally distributed data, and counts and percentages for categorical variables. No 
inferential statistical comparisons will be conducted on baseline data, in line with best practice 
in RCT reporting. 
The flow of participants through each stage of the trial (enrolment, allocation, follow-up, 
analysis) will be presented in a CONSORT flow diagram. This will include the number of 
participants assessed for eligibility, excluded (with reasons), randomised, receiving the 
allocated intervention, lost to follow-up, and included in the final analyses. Reasons for 
exclusion or withdrawal will be recorded and reported where available. 

 
 
 
 
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9.3.2. Primary outcome analysis 
Anonymised data spreadsheets will be password protected and transferred on encrypted 
storage devices to Lancaster University for analysis. All data will be analysed on Lancaster 
University computers and backed up to the Lancaster University servers. 
We will employ mixed ANCOVAs with Group (control vs prehabilitation) as the between-subjects 
factor and Time (Study Visit 1, Study Visit 2) as the within-subjects factor, with physiological 
outcomes as the dependent variables. Staging will be included as a covariate. Significance 
level will be corrected to account for multiple testing. Additionally, we will employ mixed 
ANCOVAs with Group (control vs prehabilitation) as the between-subjects factor and Time 
(Study Visit 1, Study Visit 3) as the within-subjects factor. Cancer staging and rounds of 
chemotherapy will be used as covariates, with EEG spectral ratios/cognitive outcomes as the 
dependent variables. The threshold of significance will be corrected to account for multiple 
testing. 
 
9.3.3. Secondary outcome analysis 
We will employ mixed ANCOVAs with Group (control vs prehabilitation) as the between-subjects 
factor and Time (Study Visit 1, 3-month follow-up after chemotherapy cessation) as the within-
subjects factor, with quality-of-life score on the FACT-Cog as the dependent variable. Staging 
and rounds of chemotherapy will be included as covariates. 
 
9.4. Procedure(s) to account for missing or spurious data  
Efforts will be made throughout the study to minimise missing data. Strategies include flexible 
scheduling of study visits, where possible, and prompt data entry with certification against 
source documents. The reasons for any missing data will be systematically recorded, including 
participant withdrawal, clinical contraindications loss to follow-up, or technical issues.  
 
10. DATA MANAGEMENT  
10.1. Data collection tools and source document identification 
Participants will be issued a unique participant identification number. All study encounters, 
including consent, will be recorded in the participants’ native hospital notes. Data will be entered 
into a purpose-built master database held on a secure NHS server. Members of the immediate 
research team (lead investigator and co-investigators) will be responsible for entering this data. 
Physical paper copies will also be filed in a Trial Master File and stored in a designated locked 
cabinet in the principal lead’s office at each participating site. 
Some electronic data will be automatically generated and transcribed into the master 
spreadsheet. Laboratory analysis data will be stored on secure Lancaster University computer 
servers. 
Questionnaires will be issued to participants at their baseline visit and requested to be 
completed. If participants are unable to complete them on the day, pre-paid envelopes will be 
provided for return. The second round of questionnaires will be issued at the three-month 

 
 
 
 
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follow-up assessment (FACT-Cog) and participants will be asked to return them via pre-paid 
envelopes if they are unable to complete them over the telephone. A letter will accompany the 
questionnaires, indicating that completion is voluntary and there is no obligation should the 
questionnaire cause anxiety or distress. Contact details of the lead investigator will be provided 
for participants wishing to discuss any aspect of the questionnaire. 
 
10.2. Data handling and record keeping  
The research team will preserve the confidentiality of participants in accordance with the Data 
Protection Act. All data collected will be accurately recorded and securely stored by the team, 
and no identifiable information will be accessible to individuals outside the study team. 
Clinical, demographic, CPET, blood panel, and EEG data will be anonymised at the point of 
collection before being transferred outside the participating hospital’s clinical areas to 
Lancaster University. Data will be identified only by ID numbers, with personal information 
accessible only via a code held by the lead and chief investigators. 
All data transfers will be conducted via the secure, encrypted university cloud (OneDrive) 
managed by Lancaster University and verified by the participating hospital site’s IT team. The 
only non-digital data will be the signed consent forms, which will be securely stored in the 
principal lead’s office at each participating site and transferred to the chief investigator’s office 
at Lancaster University once all visit assessments are complete. All collected data will reside 
on Lancaster University’s secure, encrypted network, accessible only through password-
protected computers within the university. After the study concludes, data will be stored for 
the minimum period specified in the protocol and then destroyed accordingly. 
Participants retain the right to withdraw from the study at any time without providing a reason. 
If a reason is given, it will be recorded as well as any ‘loss to follow-up.’ Participants will be 
asked to consent to the retention of any data collected up to the point of withdrawal. 
 
10.3. Access to Data 
There will be no access to identifiable participant data outside the research team at any stage 
of the project. Trust guidelines on data protection and General Data Protection Regulations 
(GDPR) guidance will be adhered. 
 
11. ETHICAL AND REGULATORY CONSIDERATIONS 
11.1. Research Ethics Committee (REC) review & reports 
Before the initiation of the trial, all trial-related materials—including consent forms, the 
participant information sheet (PIS), protocol, and other relevant documentation—will be 
submitted to the relevant Research Ethics Committee (REC) for approval, as well as to the 
Health Research Authority via the Integrated Research Application System (IRAS). 
Any subsequent amendments to these documents will be submitted for further approval. 
Participants’ rights to refuse participation in the trial without providing a reason must be 

 
 
 
 
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respected. After a participant has entered the trial, the clinician remains free to provide 
alternative treatment to that specified in the protocol at any stage if they consider it to be in 
the participant’s best interest. The reasons for doing so must be documented. 
Following randomisation, participants cannot change their allocated group (i.e., prehabilitation 
or standard care), and data will be analysed according to this allocation. However, 
participants remain free to withdraw from testing, the intervention (prehabilitation group), or 
follow-up at any time without giving a reason and without prejudice to their treatment. 
 
11.2. Public and Patient Involvement (PPI) 
The PPI steering committee includes four individuals with lived experience of colorectal cancer 
(including chemotherapy and “brain fog”-type symptoms) and two carers of people undergoing 
chemotherapy. Initial meetings have helped shape the study design, including the delivery of 
the intervention and testing visits. For example, the committee reviewed the frequency and 
duration of the proposed testing sessions to ensure they are realistic alongside treatment 
schedules and minimise participant burden. Reflections from these early discussions have 
directly informed considerations of participant burden, such as scheduling tests flexibly around 
hospital appointments (where possible), providing comprehensive instructions for home-based 
exercises (e.g., offering different formats such as programme booklets and videos), 
recommending multivitamin capsules once a day rather than a drink version, and addressing 
barriers and facilitators to exercising at home. 
The PPI steering committee has reviewed participant-related documents (e.g., participant 
information sheet and consent form) to ensure they are accessible, sensitive, and avoid 
overwhelming language. The committee will continue to meet throughout the study and advise 
on strategies to support participants who may experience chemotherapy-related symptoms. 
Current recommendations include offering rest breaks, splitting sessions into shorter segments 
(e.g., aerobic and resistance exercises separated during the day instead of back-to-back), and 
providing prompts for study activities. 
All meetings will be chaired by the lead investigator to ensure effective time management and 
that every voice is heard. Members will receive INVOLVE rates of payment, and travel 
expenses will be reimbursed. A support plan will be implemented to encourage engagement 
and minimise burden for steering group members. At the end of the study, members will receive 
the final report and will be invited to contribute to dissemination plans and outputs to ensure 
findings are communicated in a way that is meaningful to patients and carers. All patient-facing 
documents will be reviewed by the steering group for any submissions or amendments to NHS 
ethics. 
 
11.3. Regulatory Compliance  
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki 
(2013), the principals of Good Clinical Practice (2016), the UK Data Protection Act, and the UK 
Policy Framework for Health and Social Care Research. 
 

 
 
 
 
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11.4. Protocol compliance  
The trial steering committee (TSC) will be established by and operate under the authority of 
Lancaster University [Sponsor]. Membership will comprise the lead investigator, chief 
investigator, co-investigators, three independent academics external to the study team, and a 
PPI Advisor drawn from the PPI Steering Committee. Mrs Becky Gordon, as the Sponsor’s 
representative, will also attend TSC meetings to maintain direct oversight. 
The TSC is authorised to provide independent oversight of the study’s conduct, progress, and 
compliance with protocol, ethics, and regulatory requirements. It will advise the lead investigator 
and research team on operational issues and emerging challenges, such as risks to participant 
safety, data integrity, and overall study delivery, and recommend mitigation actions as needed. 
The TSC will report concerns or escalate decisions to the Sponsor or Funder [North West 
Cancer Research] when necessary to ensure proper governance is maintained. 
An authorised individual, external to the project and not employed by Lancaster University, will 
be responsible for data monitoring. This includes overseeing data quality, participant safety, 
and overall trial integrity by reviewing data for accuracy, completeness, and compliance with 
protocols. In the event of concerns, this individual will conduct unbiased interim analyses, 
review safety data, identify potential risks or benefits, and make recommendations for protocol 
modifications or, if necessary, trial termination to ensure participant safety and the scientific 
validity of the study. The lead and chief investigators, along with the lead clinician, will support 
this authorised individual in monitoring activities as required. 
 
11.5. Data protection and patient confidentiality  
The study will be conducted in compliance with the approved protocol, the Declaration of 
Helsinki (2013), and the UK Data Protection Act. The principal investigator, or a suitably trained 
member of the direct care team with delegated duties, will review lists of colorectal cancer 
patients (via medical records) weekly throughout the recruitment period. Patients will be given 
the PIS at their initial outpatient clinic appointment. Verbal consent will be obtained to contact 
potential participants by phone. The lead investigator of the research team will follow up via 
telephone and, if the prospective participant agrees to take part, obtain informed consent at the 
participant’s baseline assessment visit. The lead investigator will code the samples; no 
identifying information will be available to anyone outside the research team. All documentation 
will be accurately recorded and secured on password-protected databases and in a physically 
held site file. 
Participants retain the right to withdraw from the study at any time without providing a reason. 
If a reason is given, it will be recorded along with any ‘loss to follow-up.’ Participants will be 
asked to consent to the retention of any data collected up to the point of withdrawal. 
Blood samples will be transported to Lancaster University for data analysis and will not be 
shared externally outside the research team for additional research. All data will be stored only 
on Lancaster University computers, and loaned laptops will be used to access data, with access 
restricted to authorised research members involved in this study. 

 
 
 
 
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11.6. Financial and other competing interests for the Chief investigator, Principal 
Investigators at each site and committee members for the overall study management  
On behalf of all investigators, we declare that we have developed the research questions and 
authored the research proposal herein. We further have no conflicts of interest to declare 
relating to this work. 
 
11.7. Amendments  
If an amendment is needed during a study, the Amendment Tool must be completed to 
determine its category (A, B or C), which reflects its impact on participating sites; separate from 
whether the amendment is substantial or non-substantial. The Sponsor, Lancaster University, 
is responsible for authorising the amendment and completing the declaration section of the 
Amendment Tool; no amendment should be submitted without prior sponsor authorisation.  
Once submitted, the amendment and relevant documents must be shared with affected 
participating sites. Category A and B amendments require to be reviewed within 35 days, 
assess whether they can support and implement the changes. Category C amendments still 
need to be shared to take appropriate administrative action, but they do not require a capacity 
and capability review.  
Communication to affected participating sites is important to agree implementations plans, 
discuss any impact on activities or costs, and address concerns. If a site cannot support the 
amendment, options such as site closure should be discussed. Investigators and participating 
sites should work to the most recent approved documents relevant to their role in the study. 
 
11.8. Post Study Care 
The chief investigator will have control of the data and act as the custodian for all data generated 
by the study and will be responsible for ensuring the secure storage of this data for a period of 12-
36 months following the end of the study; this includes data from CPET, EEG, cognitive 
assessments, and quality of life measures.  
 
11.9. Access To The Final Study Dataset 
Only the lead and chief investigators and the research team will have access to the code which 
will be linked to patient identifiable details kept in the Trial Master File. 
 
12. DISSEMINIATION POLICY 
12.1. Dissemination policy 
This work is expected to yield several publications in reputable international journals, and the 
findings will be presented at regional and international conferences. Following study completion, 
we will host a Results Open Evening for participants, GPs, scientists, and the general public. If the 
intervention is successful, we will have identified a potential target group of patients likely to benefit 
from prehabilitation and will seek to implement our intervention at scale. 

 
 
 
 
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12.2. Authorship eligibility guidelines and any intended use of professional writers 
Authorship on the overall study report will be granted to the Lead Investigator (first author), Chief 
Investigator (senior/final author), and Co-Investigators (co-authors) based on substantial 
contributions to the study’s design, data acquisition, analysis or interpretation, and manuscript 
preparation. No professional medical writers will be involved, or if they are, they will be 
appropriately acknowledged for their contributions. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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13. REFERENCES 
1. El-Sayes, J., Harasym, D., Turco, C. V, Locke, M. B. & Nelson, A. J. Exercise-Induced 
Neuroplasticity: A Mechanistic Model and Prospects for Promoting Plasticity. The 
Neuroscientist 25, 65–85 (2018). 
2. Franklyn, J. et al. Geographical variations in long term colorectal cancer outcomes in England: 
a contemporary population analysis revealing the north–south divide in colorectal cancer 
survival. Surg Endosc 37, 5340–5350 (2023). 
3. Huang, G. H., Ismail, H., Murnane, A., Kim, P. & Riedel, B. Structured exercise program prior to 
major cancer surgery improves cardiopulmonary fitness: a retrospective cohort study. 
Supportive Care in Cancer 24, 2277–2285 (2016).  
4. Lambert, J. E., Hayes, L. D., Keegan, T. J., Subar, D. A. & Gaffney, C. J. The Impact of 
Prehabilitation on Patient Outcomes in Hepatobiliary, Colorectal, and Upper Gastrointestinal 
Cancer Surgery: A PRISMA-Accordant Meta-analysis. Ann Surg 274, 70–77 (2021). 
5. Lambert, J., Subar, D. & Gaffney, C. Prehabilitation for gastrointestinal cancer surgery. in 
Recent strategies in high risk surgery (ed. Faintuch, J.) vol. In Press (Springer Nature, 2024) 
6. North West Cancer Research. North West Regional Report. (2021).  
7. Rich, B., Scadeng, M., Yamaguchi, M., Wagner, P. D. & Breen, E. C. Skeletal myofiber vascular 
endothelial growth factor is required for the exercise training-induced increase in dentate gyrus 
neuronal precursor cells. J Physiol 595, 5931– 5943 (2017). 
8. Jones, C.J. and Rikli, R.E., 2002. Measuring functional. The Journal on active aging, 1, pp. 24-
30. 
9. Weintraub, S., Dikmen, S.S., Heaton, R.K., Tulsky, D.S., Zelazo, P.D., Bauer, P.J., Carlozzi, 
N.E., Slotkin, J., Blitz, D., Wallner-Allen, K., and Fox, N.A., 2013. Cognition assessment using 
the NIH Toolbox. Neurology, 80(11_supplement_3), pp.S54-S64.  
10. Weintraub, S., Dikmen, S.S., Heaton, R.K., Tulsky, D.S., Zelazo, P.D., Slotkin, J., Carlozzi, 
N.E., Bauer, P.J., Wallner-Allen, K., Fox, N. and Havlik, R., 2014. The cognition battery of the 
NIH toolbox for assessment of neurological and behavioral function: validation in an adult 
sample. Journal of the International Neuropsychological Society, 20(6), pp.567-578. 
 
 
 
 
 
 
 
 
 
 

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14. APPENDICES 
Appendix –Schedule of Assessment 
Procedures 
Visits (3 visits & follow up) 
Screening 
Baseline 
Assessments 
Follow Up 
 
 
Visit 1 
Visit 2 
Visit 3 
 
Eligibility Assessment 
/ 
 
 
 
 
Informed Consent 
/ 
/ 
 
 
 
Screening Questionnaires 
/ 
 
 
 
 
Demographics 
/ 
/ 
 
 
 
Medical History 
/ 
 
 
 
 
Physical Examination 
 
/ 
 
 
 
Randomisation 
 
/ 
 
 
 
Functional Fitness 
 
/ 
/ 
/ 
 
Cardiopulmonary Exercise 
Test 
 
/ 
/ 
/ 
 
Randomisation 
 
/ 
 
 
 
Electroencephalogram 
 
/ 
/ 
/ 
 
Cognitive Test Battery 
 
/ 
/ 
/ 
 
Blood Samples 
 
/ 
/ 
/ 
 
Quality Of Life Questionnaire 
 
/ 
 
 
/ 
Nutrition Assessment 
 
/ 
/ 
/ 
 
Physical Activity Monitor 
 
/ 
/ 
/ 
 
 
Appendix  – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
 
 
 
 
 
 
 
 
 

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Questionnaire on Cognitive Decline in the Elderly (Short IQCODE, Self Report) 
 You will be asked 16 questions about everyday situations relating to memory and the management 
of daily tasks. You will be asked if there have been any changes in the way you respond/manage in 
these contexts compared to ten years ago (2016). Each question is scored from 1 (much improved) 
to 5 (much worse). 
 
Compared with 10 years ago (201_), how are you at... 
 
Remembering things about family and friends - eg, occupations, birthdays, addresses? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Remembering things that have happened recently? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
 
Appendix - Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Self-
Report Version (Patient) 

 
 
 
 
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Recalling conversations a few days later? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Remembering your address and telephone number? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Remembering what day and month it is? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 

 
 
 
 
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Remembering where things are usually kept? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Remembering where to find things which have been put in a different place from usual? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Knowing how to work familiar machines around the house? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 

 
 
 
 
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Learning to use a new gadget or machine around the house? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Learning new things in general? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
Following a story in a book or on TV? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 

 
 
 
 
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Making decisions on everyday matters? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Handling money for shopping? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Handling financial matters - eg, the pension, dealing with the bank? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 

 
 
 
 
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Handling other everyday arithmetic problems -  eg, knowing how much food to buy, knowing how 
long between visits from family or friends? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 
 
 
Using your intelligence to understand what is going on and to reason things through? 
o Much Improved 
o A bit improved 
o Not much change 
o A bit worse 
o Much worse 

 
 
 
 
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Appendix – Mini-Cog 
 

 
 
 
 
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Appendix – International Physical Activity Questionnaire (IPAQ) 
 

 
 
 
 
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Appendix – The Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) 
 

 
 
 
 
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Appendix – FACT-Cog (version 3) 
 
 

 
 
 
 
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Appendix –Sample Exercise Programme 
Warm Up 
Time (seconds) 
Notes (All body weight) 
Shoulder Rolls 
30 
Regression: Seated / Progression: Lightly March 
Shoulder Shrugs 
30 
Regression: Seated / Progression: Lightly March 
Hip Rotation 
30 
Regression: Seated / Progression: Larger Rotations 
High Knees 
30 
Regression: Chair Or Wall Support Or Seated / Progression: Lightly March 
Squat 
30 
Regression: Seated Squat / Progression: Add Weight 
 
Aerobic Exercise 
Time (seconds) 
Reps 
Sets 
Note 
Arm Circles 
20-30 
10 
2-3 
Body Weight 
Regression: Seated / Progression: Lightly March 
Side Moving Jacks 
20-30 
10 
2-3 
Body Weight 
Regression: No Arm Movement / Progression: Jumping Jacks 
Marching (Front) 
20-30 
10 
2-3 
Body Weight 
Regression: Seated / Progression: Weights 
Shadow Boxing 
20-30 
10 
2-3 
Body Weight / Weights 
Regression: Forward Pointing / Progression: Weights (Increase) 
V Steps 
20-30 
10 
2-3 
Body Weight  
Regression: Step Straight Forward / Progression: Punching 
Forward 
 
 
 
 

 
 
 
 
V1.0 04.12.25                                  ChemoBrain Prehab Protocol                                      IRAS ID: 356825  
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Resistance Exercise 
Time (seconds) 
Reps 
Sets 
Note 
Front Raises 
20-30 
10 
2-3 
Resistance Band/Weight 
Regression: Less tension/weight / Progression: Increase 
tension/weight 
Side Raises 
20-30 
10 
2-3 
Resistance Band/Weight 
Regression: Less tension/weight / Progression: Increase 
tension/weight 
Seated Squats 
20-30 
10 
2-3 
Resistance Band/Weight 
Regression: Less tension/weight / Progression: Increase 
tension/weight 
Seated Abduction 
Extension 
20-30 
10 
2-3 
Resistance Band 
Regression: Less tension / Progression: Increase tension 
Seated Leg Press 
20-30 
10 
2-3 
Resistance Band 
Regression: Less tension / Progression: Increase tension 
 
Cool Down 
Time (seconds) 
Repetitions 
Sets 
Notes (All body weight) 
Overhead Stretch 
10 
10 
2 
Chair or Standing 
Neck Stretch 
10 
10 
2 
Chair or Standing 
Side Lean Stretch 
10 
10 
2 
Chair or Standing 
Hamstring Stretch 
10 
10 
2 
Chair or Standing 
Ankle Stretch 
10 
10 
2 
Chair or Standing 
 

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Appendix - Functional Fitness Assessment For Elderly Adults 
Normal scores based on age and sex 

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Description and Instructions For The Functional Fitness Assessment 

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