Conditions: Non-small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
Lung cancer is the second most commonly diagnosed cancer in the United Kingdom, accounting for 22% of cancer deaths. The main treatments for lung cancer are surgery, radiotherapy or chemoradiotherapy. Current methods, for assessing lung function in lung cancer patients i.e. spirometry and gas transfer are inadequate. We aim to develop a new technique capable of describing regional lung abnormality using hyperpolarized xenon gas MRI.

The study will involve 50 patients diagnosed with lung cancer considered suitable for radical radiotherapy or chemoradiotherapy. Participants will be offered hyperpolarized Xe129 MR at baseline, two weeks after commencement of radiotherapy schedules and four followup visits over one year posttreatment.

Patients will undertake extensive study measures at baseline and followup visits, including chest CT scans, ventilation/perfusion nuclear medicine scans, gadolinium enhanced MRI scans, pulmonary function tests, breathlessness scores, radiotherapy induced lung toxicity assessments and exercise testing. Participation in these full tests takes a day, allowing patients time to rest between tests and allowing for a period of observation following the final hyperpolarized xenon scan.

The investigators will correlate baseline hyperpolarized Xe129 MR imaging with spirometry and breathlessness scores to determine if tolerance for radiotherapy is better predicted by hyperpolarized Xe129 MR imaging. The investigators will evaluate changes in hyperpolarized Xe129 MR imaging before and after radiotherapy (RT) to determine if it provides better monitoring of response compared with spirometry.

The study will take place at the Churchill Hospital, Oxford University Hospitals National Health Service Trust and will be funded by the National Institute for Health Research Oxford Biomedical Research Centre. Hyperpolarized Xe129 MR imaging has the potential to inform individual suitability for radiotherapy schedules better than the investigations used currently. In addition, hyperpolarized Xe129 MR imaging has the potential for better monitoring of treatment response and improved detection of radiation induced lung injury, invaluable to treating patients with radiation induced injury.

Detailed description:
Survival rates for lung cancer are poor. One year survival rate in the United Kingdon for males is 27% and for females 30%, falling to less than 10% at five years. Prognosis for lung cancer is so poor because over two thirds of patients are diagnosed at a late stage when curative treatment is not possible. Early diagnosis and assessment of tolerance for curative treatment would make a significant difference to survival rates.

Histologically, approximately 80% of lung cancer is nonsmall cell lung cancer (NSCLC). The main curative treatment for NSCLC is surgery. Radical radiotherapy and chemoradiotherapy are other potentially curative treatments. These are suitable for patients who present with localized tumours that are surgically unresectable due to involvement of critical local structures or medically inoperable disease due to advanced age or comorbidities. Radiotherapy aims to deliver a high tumouricidal dose to the tumour without damaging the surrounding normal lung tissue. A high dose of radiotherapy improves local control but incurs a risk of inducing toxic effects in the normal lung tissue. If radiationinduced lung toxicity could be better predicted and monitored, radical radiotherapy could be tailored to the individual, which could also have the benefit of avoiding or reducing radiation dose to functional lung tissue.

Currently assessment of patients for radiotherapy involves lung function measurements to provide a clinical indicator as to whether or not the patient would tolerate treatment and maintain sufficient functioning lung posttreatment to continue with activities of daily living without significant impairment. The current gold standard for assessment of lung function is spirometry and gas transfer. Spirometry and gas transfer measure global lung function but provides no information about the different regions of the lung or regarding the support 'framework' of the lung, the parenchyma.Changes in lung function as measured by spirometry or gas transfer do not coherently correlate with symptom severity or reflect a decline in patient health. This weak relationship is probably because the lung is a complex regional organ where localized disturbances of a variety of factors including gas flow (ventilation), blood flow (perfusion) and gas transfer all combine to impair respiratory function.

To address these issues we aim to use hyperpolarized xenon gas (Xe129) magnetic resonance imaging (MRI)and computed tomography (CT)to describe detailed regional and structural lung abnormality in patients with NSCLC. The investigators will correlate this technique with baseline spirometry and dyspnoea scores to determine if respiratory tolerance of radiotherapy is better predicted by hyperpolarized Xe129 MR imaging. The investigators will compare hyperpolarized Xe129 MRI with standard imaging(nuclear medicine scans). The investigators will also evaluate changes in hyperpolarized Xe129 MR imaging before, during and after radiotherapy to determine if it provides improved assessment of radiationinduced lung injury. MRI has advantage of being free from ionizing radiation making it safe and practical for diseases like lung cancer where repeated followup scans are necessary. MR imaging has an enhanced speed of image acquisition compared with CT and lung scintigraphy and offers the potential of dynamic assessment of lungs during respiration. In conventional MRI, the signal originates principally from the protons in water molecules of tissues. Therefore conventional MRI has limited use in respiratory disease because the lung has a very low density of protons, instead being largely composed of air spaces that do not generate MR signal. Hyperpolarised noble gases can resolve this problem. Xenon (Xe129) is an unreactive or inert noble gas. It has a nuclear spin of ½ enabling use in MR imaging to generate a signal. Xe129 is hyperpolarized, that is to say that nuclear spin within the atoms is increased. Hyperpolarization increases the MR signal enabling the Xe129 gas to show up on the MR scan. In portions of the lung that have good airflow, the hyperpolarized Xe129 gas will show up more and be seen more quickly. In addition Xe129 readily dissolves in blood where it emits different MR signal characteristics. This property may be exploited to regionally quantify both ventilation and perfusion within the lung providing a comprehensive assessment of lung function. The need for improved functional imaging to identify preexisting lung disease and predict respiratory tolerance of patients with NSCLC for radiotherapy treatment is clear. Hyperpolarized Xe129 MR imaging has the potential to inform individual suitability for radiotherapy schedules better than the investigations used currently. In addition improved functional imaging is required to monitor treatment response and enable treatment regimes to be tailored to the individual. Hyperpolarized Xe129 MR imaging offers the potential of improved detection of radiationinduced lung injury, invaluable to treating patients with radiation induced injury. It may also provide information that would allow RT to be planned in such a way as to reduce the risk of patients developing radiationinduced lung toxicity (RILT).

The need for improved functional imaging to identify preexisting lung disease and predict respiratory tolerance of patients with NSCLC for radiotherapy treatment is clear. Hyperpolarized Xe129 MR imaging has the potential to inform individual suitability for radiotherapy schedules better than the investigations used currently. In addition improved functional imaging is required to monitor treatment response and enable treatment regimes to be tailored to the individual. Hyperpolarized Xe129 MR imaging offers the potential of improved detection of radiationinduced lung injury, invaluable to treating patients with radiation induced injury. It may also provide information that would allow RT to be planned in such a way as to reduce the risk of patients developing radiationinduced lung toxicity (RILT).

Arms:
arm 1: Xenon gas is inhaled immediately before acquisition of an MR image to enable the lung structure to be seen.

Interventions: intervention 1: Inhalation of hyperpolarized xenon gas
Intervention descriptions: intervention 1: The xenon gas is inhaled immediately before acquisition of an MR image to enable the lung structure to be seen.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
A study to determine regional lung 
function in patients undergoing 
radiotherapy using hyperpolarized 
xenon gas MR imaging       
      
NCT02151604 
27 March 2019 


PROTOCOL Version 3 
IRAS Project ID 42112 
 
27/03/2019 
Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
Clinical Trial Protocol Template version 8.0       © Copyright: The University of Oxford and UOH NHS Trust 2013 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 Page 1 of 60 
 
A study to determine regional lung function in patients undergoing 
radiotherapy using hyperpolarized xenon gas MR imaging 
 
Short title: Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
Ethics Ref: 13/SC/0473 
EudraCT Number: 2011-002028-41 
Sponsor's Protocol Code Number: HPX-2011-003 
NCT: 02151604 
Date and Version No: PROTOCOL Version 3 
27 March 2019 
 
Chief Investigator: 
PROFESSOR FERGUS GLEESON1 (Consultant Radiologist) 
Investigators:  
Mitchell Chen1 (Academic Clinical Fellow in Radiology) 
Tahreema Matin1 (Clinical Research Fellow in Radiology) 
Geoff Higgins3 (Clinician Scientist/Consultant Clinical Oncologist) 
Maria Hawkins3 (Consultant Clinical Oncologist) 
Nikki Pannakis3 (Consultant Clinical Oncologist) 
Naj Rahman2 (Consultant and Associate Professor) 
Vicenti Grau4 (Computational Biologist) 
Ozkan Dogonay (Postdoctoral Student in MR Physics) 
Jenni Lee1 (Churchill Research Programme Director) 
Sponsor:  
Oxford University Hospitals NHS Foundation Trust 
Funder : 
NIHR Oxford Biomedical Research Centre 
 
 
 


PROTOCOL Version 3 
IRAS Project ID 42112 
 
27/03/2019 
Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
Clinical Trial Protocol Template version 8.0       © Copyright: The University of Oxford and UOH NHS Trust 2013 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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1 Department of Radiology, Churchill Hospital, Old Road, Oxford, OX3 7LE 
2 Oxford Centre for Respiratory Medicine, Churchill Hospital, Old Road, Oxford, OX3 7LE 
3 CRUK/MRC Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford 
Cancer Centre, Churchill Hospital, Oxford, OX3 7LE  
4 Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford, OX1 3QD 
 
Signatures: 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than 
the Sponsor, the Investigator Team, host NHS Trust(s), regulatory authorities, and members of 
the Research Ethics Committee.  
 


PROTOCOL Version 3 
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27/03/2019 
Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
Clinical Trial Protocol Template version 8.0       © Copyright: The University of Oxford and UOH NHS Trust 2013 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1. 
KEY TRIAL CONTACTS ............................................................................................................................ 6 
2. 
SYNOPSIS .............................................................................................................................................. 7 
3. 
ABBREVIATIONS .................................................................................................................................... 9 
4. 
BACKGROUND AND RATIONALE ......................................................................................................... 11 
4.1. 
Radiation induced lung toxicity (RILT) ........................................................................................ 11 
4.2. 
Functional imaging can identify lung injury ............................................................................... 12 
4.3. 
Current pulmonary functional imaging is limited ...................................................................... 12 
4.4. 
Rationale for Hyperpolarized Xe-129 MR Imaging in Radiotherapy .......................................... 13 
4.5. 
Hyperpolarized noble gas MR Imaging ...................................................................................... 13 
4.6. 
Methods of Hyperpolarization ................................................................................................... 13 
4.7. 
Hyperpolarized Helium (He-3) MR Imaging ............................................................................... 15 
4.8. 
Hyperpolarized Xenon (Xe-129) MR Imaging ............................................................................. 16 
5. 
PROPOSED RESEARCH ........................................................................................................................ 19 
6. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ....................................................................... 20 
7. 
TRIAL DESIGN ...................................................................................................................................... 22 
7.1. 
Summary of Study Design .......................................................................................................... 22 
7.2. 
Summary Flow Chart of Study Design ........................................................................................ 24 
8. 
PARTICIPANT IDENTIFICATION ........................................................................................................... 27 
8.1. 
Trial Participants ........................................................................................................................ 27 
8.2. 
Inclusion Criteria ........................................................................................................................ 27 
8.3. 
Exclusion Criteria ....................................................................................................................... 27 
9. 
TRIAL PROCEDURES ............................................................................................................................ 27 
9.1. 
Recruitment ............................................................................................................................... 27 
9.2. 
Informed Consent ...................................................................................................................... 28 
9.3. 
Screening and Eligibility Assessment ......................................................................................... 29 
9.4. 
Randomisation, blinding and code-breaking ............................................................................. 29 
9.5. 
Baseline Assessments for patients with a diagnosis of lung cancer .......................................... 29 
9.6. 
Baseline assessment for patients with diagnoses other than lung cancer ................................ 34 
9.7. 
Radiotherapy .............................................................................................................................. 34 
9.8. 
Subsequent Visits for patients with a diagnosis of lung cancer ................................................. 34 
9.9. 
Subsequent Visits for patients with a diagnosis other than lung cancer ................................... 35 
9.10. 
Discontinuation/Withdrawal of Participants from Trial Treatment ........................................... 36 
9.11. 
Definition of End of Trial ............................................................................................................ 36 
10. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ............................................................................ 37 


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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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10.1. 
IMP Description ......................................................................................................................... 37 
10.2. 
Production, Storage and Dispensing of IMP .............................................................................. 39 
10.3. 
Compliance with Trial Treatment .............................................................................................. 40 
10.4. 
Accountability of the Trial Treatment ........................................................................................ 40 
10.5. 
Concomitant Medication ........................................................................................................... 40 
10.6. 
Post-trial Treatment ................................................................................................................... 40 
11. 
SAFETY REPORTING ........................................................................................................................ 41 
11.1. 
Definitions .................................................................................................................................. 41 
11.2. 
Causality ..................................................................................................................................... 42 
11.3. 
Procedures for Recording Adverse Events ................................................................................. 42 
11.4. 
Reporting Procedures for Serious Adverse Events .................................................................... 43 
11.5. 
Expectedness ............................................................................................................................. 43 
11.6. 
SUSAR Reporting ........................................................................................................................ 43 
11.7. 
Safety Monitoring Committee ................................................................................................... 44 
11.8. 
Development Safety Update Reports ........................................................................................ 44 
12. 
STATISTICS ...................................................................................................................................... 45 
12.1. 
Description of Statistical Methods ............................................................................................. 45 
12.2. 
The Number of Participants ....................................................................................................... 46 
12.3. 
The Level of Statistical Significance ............................................................................................ 46 
12.4. 
Criteria for the Termination of the Trial .................................................................................... 46 
12.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. ......................................... 46 
12.6. 
Inclusion in Analysis ................................................................................................................... 46 
12.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ........................... 47 
13. 
DATA MANAGEMENT ..................................................................................................................... 48 
13.1. 
Source Data ................................................................................................................................ 48 
13.2. 
Access to Data ............................................................................................................................ 48 
13.3. 
Data Recording and Record Keeping .......................................................................................... 48 
14. 
QUALITY ASSURANCE PROCEDURES .............................................................................................. 49 
15. 
SERIOUS BREACHES ........................................................................................................................ 49 
16. 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................. 49 
16.1. 
Declaration of Helsinki ............................................................................................................... 49 
16.2. 
ICH Guidelines for Good Clinical Practice .................................................................................. 49 
16.3. 
Approvals ................................................................................................................................... 49 
16.4. 
Reporting ................................................................................................................................... 50 


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Clinical Trial Protocol Template version 8.0       © Copyright: The University of Oxford and UOH NHS Trust 2013 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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16.5. 
Participant Confidentiality ......................................................................................................... 50 
16.6. 
Expenses and Benefits ............................................................................................................... 50 
16.7. 
Other Ethical Considerations ..................................................................................................... 50 
17. 
FINANCE AND INSURANCE ............................................................................................................. 52 
17.1. 
Funding ...................................................................................................................................... 52 
17.2. 
Insurance .................................................................................................................................... 52 
18. 
PUBLICATION POLICY ..................................................................................................................... 53 
19. 
REFERENCES ................................................................................................................................... 54 
20. 
APPENDICES ................................................................................................................................... 57 
21. 
AMENDMENT HISTORY .................................................................................................................. 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL Version 3 
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27/03/2019 
Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
Clinical Trial Protocol Template version 8.0       © Copyright: The University of Oxford and UOH NHS Trust 2013 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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1. KEY TRIAL CONTACTS 
 
Chief Investigator 
Professor Fergus V Gleeson 
Radiology Department 
The Churchill Hospital 
Old Road 
Headington 
Oxford 
OX3 7LE 
Email: fergus.gleeson@ oncology.ox.ac.uk 
Tel: 01865235746 
Fax: 01865235006 
Sponsor 
Oxford University Hospitals NHS Trust 
Mrs Heather House 
Research & Development Lead 
Joint Research Office, Block 60 
The Churchill Hospital 
Old Road 
Headington 
OX3 7LE 
Email: ouh.sponsorship@nhs.net 
Tel: 01865 572973 
Fax: 01865 572242 
Co-Investigator 
Dr Mitchell Chen 
Radiology Department 
The Churchill Hospital 
Old Road 
Headington 
Oxford 
OX3 7LE 
Email: mitchell.chen@ouh.nhs.uk 
 
 
 


PROTOCOL Version 3 
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27/03/2019 
Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
Clinical Trial Protocol Template version 8.0       © Copyright: The University of Oxford and UOH NHS Trust 2013 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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2. SYNOPSIS 
 
Trial Title 
A study to determine regional lung function in patients 
undergoing radiotherapy using hyperpolarized xenon gas MR 
imaging 
 
Short title 
Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
HPX-2011-003 
Clinical Phase  
Phase II 
Trial Design 
Cohort Study 
Trial Participants 
Patients considered suitable for radiotherapy that will affect the lung. 
Planned Sample Size 
30 
Treatment duration 
Hyperpolarized xenon gas will be administered for completion of 
hyperpolarized Xe-129 MRI scans. Radiotherapy as per local 
departmental protocols  
Follow up duration 
9 months 
Planned Trial Period 
7 years 
 
Objectives 
Outcome Measures/Endpoints 
Primary 
 
 
To demonstrate that 
hyperpolarized Xe-129 is 
sensitive to change following 
pulmonary radiotherapy, and 
thus may be developed as an 
objective and quantifiable 
method of functional lung 
assessment in patients 
undergoing radiotherapy that 
affects the lung 
 
 
Change in hyperpolarized Xe-129 
MR imaging from baseline to other 
time points post radiotherapy 
initiation. 
 
Secondary 
 
 
To obtain preliminary data 
demonstrating if changes in 
hyperpolarized Xe-129 MR 
imaging correlate with subjective 
and objective responses following 
pulmonary radiotherapy. 
 
 
To obtain preliminary data 
demonstrating if baseline 
hyperpolarized Xe-129 MR 
 
Change in hyperpolarized Xe-129 
MR imaging parameters from 
baseline to other time points post 
radiotherapy initiation compared 
to subjective and objective 
measures of lung function. 
 
 
Comparison of hyperpolarized Xe-
129 MR imaging and four-


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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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imaging is a more reliable clinical 
indicator of patient respiratory 
tolerance to pulmonary 
radiotherapy than conventional 
lung function testing by 
determining the relationship 
between hyperpolarized Xe-129 
MR imaging indices and 
functional patient outcome 
measures (dyspnoea and 
radiation-induced lung toxicity 
assessment). 
 
 
To use functional lung 
information in virtual predictive 
and adaptive radiotherapy 
treatment planning. 
 
 
dimensional CT (4D-CT) at 
baseline.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Retrospective comparison of 
modified radiotherapy treatment 
planning incorporating functional 
lung information from 
hyperpolarized Xe-129 MR imaging 
with conventional radiotherapy 
treatment plans. 
 
Investigational 
Medicinal Product(s) 
Hyperpolarized xenon gas 
Formulation, Dose, 
Route of Administration 
The xenon gas will be hyperpolarized in the Radiology department, 
Churchill Hospital. 
We will administer a maximum of 6 x 1 Litre doses of hyperpolarized 
xenon gas to each participant per hospital visit for Xe-129 lung MR 
imaging. If it is not essential to give 100% xenon for imaging, the gas may 
be diluted with ultrapure nitrogen. The ratio of xenon to nitrogen will 
vary from 10% to 100% but the volume provided to the patient will 
always be 1 L. 
The route of administration is inhalation. 
 
 
 


PROTOCOL Version 3 
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Hyperpolarized Xenon gas MR Imaging in Radiotherapy 
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3. ABBREVIATIONS 
ADC 
Apparent diffusion co-efficient 
AE 
Adverse event 
AR  
Adverse reaction 
BRC 
Biomedical Research Centre 
cm2s-1 
Square centimetres per second (measure of ADC) 
CI 
Chief Investigator 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CRT 
Chemoradiotherapy 
CT 
Computed tomography 
4D-CT 
Four-dimensional computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTA 
Clinical Trials Authorisation 
EBRT 
External beam radiotherapy 
EPI 
Echo Planar Imaging 
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Vital Capacity 
FiXe 
Fraction of inhaled xenon 
FXe 
Fraction of xenon 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
He 
Helium 
IB 
Investigators Brochure 
IMP 
Investigational Medicinal Product 
L 
Litre 
LPV 
Lobar perfusion Value 
MAC 
Maximum Alveolar Concentration 
MHRA 
Medicines and healthcare products regulatory agency 
MLD 
Mean lung dose 
MR/MRI 
Magnetic resonance imaging 
NIHR 
National Institute for Health Research 
NSCLC 
Non-small cell lung cancer 
PO2 
Partial pressure of oxygen 


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Clinical Trial Protocol Template version 8.0       © Copyright: The University of Oxford and UOH NHS Trust 2013 
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PTV 
Planning target volume 
PV 
Perfusion values 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
RILT 
Radiation induced lung toxicity 
RT 
Radical radiotherapy 
SAE 
Serious Adverse Event 
SaO2 
Arterial oxygen saturation 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SPV 
Segmental perfusion value 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
S\V 
Alveolar surface area per unit volume of gas 
TMF 
Trial Master File 
TSG 
Oxford Radcliffe Hospitals Trust / University of Oxford Trials Safety Group 
VPV 
Ventilation perfusion volume 
VDV 
Ventilation defect volume 
Xe 
Xenon 
XTC 
Xenon Transfer Contrast 
 
 
 
 
 
 
 
 
 
 
 
 


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4. BACKGROUND AND RATIONALE 
 
Lung cancer is the second most common cancer in the UK, with approximately 39,000 new cases 
diagnosed each year (1). It is the most common cause of cancer death for both men and women 
in the UK, accounting for 22% of all cancer deaths, which equates to around 34,500 people. 
Survival rates for lung cancer are poor. One year survival rates in the UK for males is 27% and for 
females 30%, falling to less than 10% at five years (2). Prognosis for lung cancer is so poor because 
over two thirds of patients are diagnosed at a late stage when curative treatment is not possible. 
Early diagnosis and assessment of tolerance for curative treatment would make a significant 
difference to survival rates.  
Histologically, approximately 80% of lung cancer is non-small cell lung cancer (NSCLC). The main 
curative treatments for NSCLC are surgery, radical radiotherapy (RT) and radical 
chemoradiotherapy (CRT). 
 
4.1. Radiation induced lung toxicity (RILT) 
 
Radiation induced lung toxicity (RILT) occurs when normal lung tissue is irradiated while treating 
tumours. RILT presents in two phases designated radiation pneumonitis (acute) and fibrosis (late).  
Radiation pneumonitis generally occurs between two and seven months after RT and may present 
clinically with cough, dyspnoea, fever and chest pain or with radiographic changes only. Acute 
pneumonitis is treated with steroids but can be life-threatening even with treatment, though with 
early identification and treatment most patients recover. If untreated, acute pneumonitis can 
progress to permanent fibrosis after more than six months. RILT has been shown to increase in 
frequency after increased radiation dose, increased volume of the lung irradiated, some 
combinations of chemotherapy and RT, previous radiation and steroid withdrawal. 
The risk of developing RILT can be determined by assessment of the mean lung dose (MLD) and 
volume of lung receiving a dose of 5-20 Gy (V5-20) over a course of radical RT (3-10). By reducing 
set-up variability and tumour motion due to respiration, the planning target volume (PTV) margins 
can be reduced, thus reducing the amount of normal lung irradiated and potentially resulting in 
a lower risk of RILT.  
 
 
 


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4.2. Functional imaging can identify lung injury 
 
Radiation planning using only computed tomography (CT) data has traditionally treated all regions 
of the lung equally. However, most gas exchange occurs in the inferior aspects of the lung and 
irradiation of this region is correlated with risk of RILT. By identifying functioning lung that is 
irradiated, ventilation and perfusion imaging may improve prediction and assessment of 
pulmonary toxicity following radiotherapy. Pulmonary perfusion-weighted treatment plan 
optimization may be useful in reducing radiation damage in patients with large perfusion defects.  
External Beam RT (EBRT) planning has traditionally used anatomic imaging to aid localisation of 
the target structures and surrounding normal structures. The risk of RILT with radical RT is based 
on the assumption that lung function is spatially uniform. There is evidence, however, that the 
functional subunits that contribute to whole lung function are not uniformly distributed (11). This 
is confounded by potential variations in lung function due to tumour characteristics and patient 
co-morbidity. Functional imaging of the lung using SPECT 99mTc labelled macroaggregate albumin 
provides 3D information on the distribution of pulmonary blood flow and may equate to areas of 
normal lung function (12). Imaging with hyperpolarized xenon gas MRI has an added advantage, 
as it not only provides 3D information on lung ventilation but potentially also provides 
information on lung perfusion. By identifying functioning lung that is irradiated, ventilation and 
perfusion imaging may improve prediction and assessment of pulmonary toxicity following 
radiotherapy. 
 
4.3. Current pulmonary functional imaging is limited 
 
Currently assessment of patients for radiotherapy involves lung function measurements to 
provide a clinical indicator as to whether or not the patient would tolerate treatment and 
maintain sufficient functioning lung post-treatment to continue with activities of daily living 
without significant impairment. The current gold standard for assessment of lung function is 
spirometry and gas transfer. Spirometry and gas transfer reflect global lung function but provides 
no information about the different regions of the lung or regarding the support ‘framework’ of 
the lung, the parenchyma. Changes in lung function as measured by spirometry do not coherently 
correlate with symptom severity or reflect a decline in patient health (13). This weak relationship 
is probably because the lung is a complex regional organ where localized disturbances of a variety 
of factors including gas flow (ventilation), blood flow (perfusion) and gas transfer all combine to 
impair respiratory function. 
Some imaging techniques can detect regional lung health, however each has limitations. 
Computed X-ray tomography (CT) provides structural, rather than functional readout and exposes 
patients to both radiation and contrast. FDG-PET provides an individualized estimate of radiation 
response, but not pulmonary function information. Scintigraphy (SPECT) with radioactive gas, can 


PROTOCOL Version 3 
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detect regional lung function changes from irradiation. However, SPECT has low spatial resolution 
and exposes the patient to ionizing radiation. Both SPECT and PET also expose patients to ionizing 
radiation. 
 
4.4. Rationale for Hyperpolarized Xe-129 MR Imaging in Radiotherapy 
 
Hyperpolarized Xe-129 MR imaging will provide regional functional information about the lung 
that may be useful in predicting RILT post radiotherapy. It is feasible to co-register hyperpolarized 
Xe-129 MRI with RT planning scans. Incorporating information from hyperpolarized Xe-129 MR 
imaging into radiotherapy planning has the potential to minimise and predict RILT. 
Hyperpolarized Xe-129 MR imaging offers the potential to inform the radiotherapy planning 
process so that parts of the lung demonstrated to function well are spared at the expense of less 
functional/diseased parts. This may reduce radiotherapy side effects and enable individuals who 
would otherwise be unsuitable for radical treatment to receive potentially curative therapy. 
 
4.5. Hyperpolarized noble gas MR Imaging 
 
The first hyperpolarized gas MR images were obtained using Xe-129 in a mouse heart lung 
preparation by Albert et al. (14), followed shortly by hyperpolarized He-3 images of human lungs 
by MacFall et al. (15). In subsequent years, hyperpolarized He-3 MR imaging became the focus of 
investigation due to inherent advantageous physical properties. He-3 has a larger magnetic 
moment than Xe-129 giving an increased signal to noise ratio. Also, until recently polarization 
methods were capable of achieving 30-50% polarization levels for He-3 but only 10 % for Xe-129 
(16, 17).  Both of these factors contributed to a stronger MR signal for He-3 compared with Xe-
129. In contrast, Patz et al. has described a modified polarization method, which enables 55% 
polarization levels of Xe-129 to be achieved at a production rate of 5.5 litres/hour (18). These 
levels of polarization are comparable to those previously published for He-3, making Xe-129 an 
increasingly attractive agent given its large natural abundance and wide availability.  
 
 
 
4.6. Methods of Hyperpolarization 
 
In their natural form, noble gases (Xe-129 and He-3) have low magnetic moments generating a 


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weak MR signal.  Compared to protons, which are abundant throughout the body, there is a limit 
to the amount of noble gas that can be administered into the lungs. Laser optical pumping is a 
technique employed to enhance the nuclear polarization of noble gases via a process called 
hyperpolarization. This technique was developed over 50 years ago and has been extensively 
applied within the field of physics research (19, 20). Hyperpolarization results in the polarization 
of noble gases 100, 000 times greater than the polarization of hydrogen nuclei in conventional 
MRI. This large net polarization gives rise to a large MR signal. In this way hyperpolarization 
compensates for the low physical density of noble gases introduced to the lungs permitting good 
visualization of the airspaces. The MR signal is generated by the hyperpolarization of He-3/Xe-129 
and is completely independent of the field strength, unlike conventional MRI (21-24). It is 
therefore possible to perform hyperpolarized Xe-129 MR imaging in a lower field strength with 
the benefit of reduced susceptibility artefacts. However most studies to date have been 
undertaken with 1.5T systems due to availability. 
Comprehensive details of hyperpolarization methods have been previously published (20, 25-29). 
There are two methods of laser optical pumping including alkali-metal spin exchange (30) and 
metastability exchange (19). Hyperpolarization of Xe-129 can only be performed by the spin 
exchange technique. Both methods employ circularly polarized light at different wavelengths. In 
brief, the spin exchange technique (Figure 1.) involves heating a glass cell containing He-3 or Xe-
129 and rubidium metal to produce rubidium vapour. The rubidium atoms absorb circularly 
polarized laser light illuminating the cell, resulting in high polarization of rubidium by “optical 
pumping”. Collision between the polarized rubidium atoms and noble gas atoms transfers the 
polarization by “spin exchange”. The product is hyperpolarized He-3 or Xe-129 atoms. 
 
 
 
 
 
Figure 1. from (16). 
Challenges faced when imaging hyperpolarized noble gases include the following: - 
1. The hyperpolarization generating the MR signal is “non-renewable”. Some polarization 
will be consumed during image acquisition and may only be replenished by the 
introduction of additional hyperpolarized gas. 


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2. The paramagnetic properties of oxygen within the lungs leads to a loss of polarization 
and decay of MR signal. However, this characteristic can be utilized beneficially to 
measure intrapulmonary PO2. 
3. He-3 is highly diffusive resulting in MR signal loss. 
 
MR pulse sequences have been developed to account for these factors and enable regional 
imaging of lung structure and function down to the level of the secondary pulmonary lobule. 
 
4.7. Hyperpolarized Helium (He-3) MR Imaging 
 
To date, hyperpolarized helium (He-3) gas MRI has been the focus of ventilation imaging research. 
However He-3 is expensive and limited in world supply necessitating further investigation into 
other suitable gases, namely Xe-129. The techniques and findings from previous research with 
hyperpolarized He-3 MR imaging form the basis of the current study. A summary of the current 
literature has been therefore been included. 
In normal individuals, the inhaled hyperpolarized He-3 gas is distributed homogenously 
throughout the lung airspaces. In contrast, localized regions deficient in hyperpolarized gas and 
therefore MR signal represent ventilation defects. These have been shown in a range of lung 
pathologies e.g. asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (31) and 
bronchiolitis obliterans (32, 33). The size and extent of ventilation defects demonstrated with 
hyperpolarized gas MR correlate with spirometry (16, 31). Furthermore, hyperpolarized gas MRI 
has shown increased sensitivity in detecting ventilation abnormalities compared with spirometry 
and lung ventilation scintigraphy (16, 34).  
“Dynamic ventilation images” may be obtained with hyperpolarized gas MRI by employing 
ultrafast pulse sequences (35-38). Dynamic ventilation imaging allows the distribution and 
severity of air trapping to be assessed directly (37, 38) and has been performed to evaluate air 
trapping in patients with bronchial asthma (37) and cystic fibrosis (38).  
Several methods for the quantitative measurement of regional lung ventilation using 
hyperpolarized He-3 MRI have been suggested in experimental animal studies (39-41). In a rat 
model of emphysema, the ventilation abnormalities detected preceded the histological changes 
seen in lung alveoli (42). This study, demonstrated detectable lung functional changes before 
structural abnormalities and further supports hyperpolarized gas MR functional imaging for 
earlier diagnosis in pathological disease processes. 
The diffusion coefficient of a particular gas determines the average distance its atoms move in a 
given period of time. The lung microstructure acts to restrict the diffusion of hyperpolarized noble 
gas atoms enabling the average short time diffusion coefficient, (apparent diffusion coefficient, 
ADC) to be measured with MRI (43). Increased ADC values have been reported with 


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hyperpolarized He-3 MR imaging in emphysema, reflecting the increased free movement of He-3 
gas atoms permitted by alveolar tissue destruction (43-46).  In this way, regional ADC values can 
be used as a surrogate measure of alveolar airspace size. Precise correlations between 
hyperpolarized gas MRI ADC measurements and histological measurements of alveolar size have 
been reported (47-49). ADC values with hyperpolarized He-3 MR imaging have proven highly 
reproducible (50, 51), and been shown to correlate strongly with lung function tests (44).  
Another potential application of ADC measurements is the assessment of radiation induced lung 
injury. Post radiation therapy, lower hyperpolarized He-3 ADC values may represent reduced 
alveolar volumes associated with fibrosis of the interstitium (52). 
In the presence of oxygen within the lung, hyperpolarized noble gases undergo hastened loss of 
polarization resulting in a predicted reduced MR signal (53). This known paramagnetic effect of 
oxygen on He-3 gas may therefore be utilized to quantitatively measure intrapulmonary PO2 (54, 
55). Reproducibility of intrapulmonary PO2 measurements has been confirmed. 
 
4.8. Hyperpolarized Xenon (Xe-129) MR Imaging  
 
Xenon (Xe) is an inert, non-toxic noble gas. Atmospheric air contains approximately 0.04 mol% of 
xenon. The xenon isotope Xe-129 is employed for hyperpolarized xenon MR imaging. The natural 
abundance of Xe-129 in atmospheric Xe is 26%, and can be extracted relatively easily. 
Previous applications of xenon include use as an anaesthetic at high concentrations (at > 3 times 
the concentration to be used in this study and with ongoing delivery rather than a single breath), 
in scintigraphic and CT brain perfusion studies and as an inhaled contrast agent in CT (56, 57). Xe-
129 is ten times more soluble than He-3 in water and one hundred times more soluble in lipid-
rich tissue. Xenon’s vastly increased solubility in blood and lipid-rich tissue demonstrates a 
partition coefficient of approx 0.1 (58). This property of Xe-129 may be exploited to evaluate gas 
exchange between alveoli and capillaries, and to provide information regarding the diffusion 
capacity (18, 59-65). In addition to assessment of ventilation and ADC in the gas spaces possible 
with He-3, Xe-129 allows for dissolved-phase imaging (14).  
Following inhalation, approximately only 2% of Xe-129 is dissolved into the lung parenchyma or 
blood.  The blood circulation distributes dissolved Xe-129 throughout the body enabling perfusion 
imaging in different organs. The MR signal characteristics of Xe-129 are strongly influenced by its 
environment such that the signal from dissolved-phase Xe-129 is significantly different to that of 
the gas-phase. A chemical shift of signal in the dissolved-phase is seen of approximately 200 parts 
per million from that of the gas-phase.  Chemical shifting imaging in the lungs and other body 
organs has been demonstrated in rat models (66, 67). Investigation of hyperpolarized Xe-129 MR 
signal characteristics has revealed different signals corresponding to Xe-129 compartmentalized 
within fat, tissue and red blood cells. Simultaneous ventilation perfusion studies of the lung are 


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possible through collection of gas and dissolved-phase signal within a single acquisition of images. 
Initially Albert et al demonstrated imaging of the lung airspaces using hyperpolarized Xe-129 
introduced into the trachea of a mouse heart-lung model (14). High signal intensity was achieved 
using 25ml (3atm) of Xe-129 polarized to approximately 25%. This was followed by a combined 
imaging and spectroscopic approach by Mugler et al. Comparison was made between 
hyperpolarized Xe-129 and conventional H1 MR images in two human volunteers following 
inhalation of hyperpolarized Xe-129, polarized to 2%. Significant correlation was shown between 
the gas space signal absence in conventional MRI and the gas space signal in hyperpolarized Xe-
129 images (62). 
The dynamics of Xe-129 within the chest have been further studied in a dog (17). This study 
demonstrated a decay of the Xe-129 MR signal within the gas-phase. This was observed to provide 
a measure of Xe-129 absorption into the tissue. Time constants for saturation were determined 
as 61ms and 70ms for tissue and red blood cells respectively. 
Hyperpolarized Xe-129 MR imaging may be applied as a non-invasive measure of lung function 
parameters specific to emphysema. The alveolar surface area per unit volume of gas (S/V) 
represents a primary measure of emphysema that may be evaluated using the chemical shift 
saturation recovery method (18, 59, 65). Another strategy using hyperpolarized Xe-129 MR is the 
xenon transfer contrast (XTC) method that may be adapted to derive values of S/V (18, 65). In 
addition, the XTC method has been used successfully to measure lung septal thickness in animals 
(63, 68) and humans (65) and evaluate the severity and progression of emphysema (47). 
ADC values may also be determined with hyperpolarized Xe-129 MR imaging. However, Xe-129 
has a much lower diffusivity than He-3 and demonstrates a lower diffusion coefficient. This offers 
an advantage over He-3 since measurement of alveolar and small airways dimensions is possible 
by applying diffusion weighted imaging (65, 69). 
Hyperpolarized Xe-129 is also susceptible to the paramagnetic effect of oxygen within the 
pulmonary airspaces. The resultant loss of polarization and predicted decay in MR signal may be 
used to measure intrapulmonary PO2. However, this is slightly more complex than when 
measuring with He-3 because additional signal loss due to diffusion of Xe-129 into alveolar tissue 
needs to be taken into account (18). An equivalent PO2 is determined accounting for signal decay 
due to the presence of oxygen and Xe-129 diffusion. 
At our Oxford centre, we have already commenced studies using hyperpolarized Xe-129 MR 
imaging in normal healthy volunteers and patients with chronic obstructive pulmonary disease 
(COPD). To date, we have administered 51 doses of 1L hyperpolarized xenon gas to 16 study 
participants for completion of hyperpolarized Xe-129 MR imaging. These have all been well 
tolerated with no serious adverse events.  Preliminary results have shown that hyperpolarized Xe-
129 MRI is a viable functional lung imaging modality. Images acquired from a normal healthy 
volunteer and patient with COPD using our scanner are shown below in Figures 2, 3. 


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5. 
PROPOSED RESEARCH 
 
We aim to use hyperpolarized xenon gas (Xe-129) magnetic resonance imaging (MRI) and 
computed tomography (CT) imaging as a new technique capable of objectively and quantitatively, 
describing regional and structural lung abnormality in patients that will be undergoing 
radiotherapy affecting the lung. We will correlate this technique with baseline physiological and 
functional measures to determine if respiratory tolerance for radiotherapy is better predicted by 
hyperpolarized Xe-129 MR imaging. We will also evaluate changes in hyperpolarized-Xe-129 MR 
imaging before, during and after radiotherapy to determine if it provides improved assessment 
of radiation-induced lung injury. 
MR imaging has an enhanced speed of image acquisition compared with CT and lung scintigraphy 
and offers the potential of ultra-fast sequences allowing dynamic assessment of lungs during 
respiration. In conventional MRI, the signal originates principally from the protons in water 
molecules of tissues. Therefore conventional MRI has limited use in respiratory disease because 
the lung has a very low density of protons, instead being largely composed of air spaces that do 
not generate MR signal. Hyperpolarized noble gases can resolve this problem. Helium (He-3) and 
Xenon (Xe-129) are unreactive or inert noble gases. The both have a nuclear spin of ½ enabling 
use in MR imaging to generate a signal.   
The study will focus on hyperpolarized Xe-129 MR imaging as xenon is available in unlimited 


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supply in nature and has certain advantageous properties over He-3 including increased lipid 
solubility. Xe-129 is hyperpolarized, that is to say that nuclear spin within the atoms is increased. 
Hyperpolarization increases the MR signal enabling the Xe-129 gas to show up on the MR scan. In 
portions of the lung that have good airflow, the hyperpolarized Xe-129 gas will show up more and 
be seen more quickly. In addition Xe-129 readily dissolves in blood where it emits different MR 
signal characteristics. This property may be exploited to regionally quantify both ventilation and 
perfusion within the lung providing a comprehensive assessment of lung function. 
The need for improved functional imaging to identify pre-existing lung disease and predict 
respiratory tolerance of patients undergoing radiotherapy affecting the lung is clear. 
Hyperpolarized Xe-129 MR imaging has the potential to inform individual suitability for 
radiotherapy schedules better than the investigations used currently. In addition improved 
functional imaging is required to monitor treatment response and enable treatment regimes to 
be tailored to the individual. Hyperpolarized Xe-129 MR imaging offers the potential of improved 
detection of radiation-induced lung injury, invaluable to treating patients with radiation induced 
injury. It may also provide information that would allow RT to be planned in such a way as to 
reduce the risk of patients developing RILT.  
 
6. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
Objectives 
Outcome Measures/Endpoints 
Primary 
 
 
To demonstrate that 
hyperpolarized Xe-129 is 
sensitive to change following 
pulmonary radiotherapy, and 
thus may be developed as an 
objective and quantifiable 
method of functional lung 
assessment in patients 
undergoing radiotherapy that 
affects the lung 
 
 
Change in hyperpolarized Xe-129 
MR imaging from baseline to other 
time points post radiotherapy 
initiation. 
 
Secondary 
 
 
To obtain preliminary data 
demonstrating if changes in 
hyperpolarized Xe-129 MR 
imaging correlate with subjective 
and objective responses following 
pulmonary radiotherapy. 
 
 
To obtain preliminary data 
demonstrating if baseline 
hyperpolarized Xe-129 MR 
imaging is a more reliable clinical 
 
Change in hyperpolarized Xe-129 
MR imaging parameters from 
baseline to other time points post 
radiotherapy initiation compared 
to subjective and objective 
measures of lung function. 
 
 
Comparison of hyperpolarized Xe-
129 MR imaging and four-
dimensional CT (4D-CT) at 
baseline.  


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indicator of patient respiratory 
tolerance to pulmonary 
radiotherapy than conventional 
lung function testing by 
determining the relationship 
between hyperpolarized Xe-129 
MR imaging indices and 
functional patient outcome 
measures (dyspnoea and 
radiation-induced lung toxicity 
assessment). 
 
 
To use functional lung 
information in virtual predictive 
and adaptive radiotherapy 
treatment planning. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retrospective comparison of 
modified radiotherapy treatment 
planning incorporating functional 
lung information from 
hyperpolarized Xe-129 MR imaging 
with conventional radiotherapy 
treatment plans. 
 
 
 


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7. TRIAL DESIGN 
7.1. Summary of Study Design 
This will be an open, single-centred study in the UK. The study group will include 30 patients who 
are considered suitable for radiotherapy that will affect the lung. Participants considered for 
radiotherapy that will affect the lung include those with a diagnosis of lung cancer and those with 
other diagnoses, for example, oesophageal cancer, chest wall tumours and lymphoma. All 
potential participants for this study undergo an enrolment visit (Visit 1).  This is an opportunity to 
discuss the study in more detail, and for those choosing to take part to gain informed, written 
consent.  Eligibility criteria will be checked.  All female participants of child-bearing age will have 
had pregnancy excluded as part of their routine clinical care in Oncology prior to starting 
radiotherapy. Volunteers will be invited to undertake a ‘dummy run’ of Xe-129 lung MRI imaging, 
during which they lie on a couch similar to that used during the MRI, and practice the manoeuvre 
required when breathing in xenon from a 1L bag during subsequent lung imaging.  During the 
dummy run this will simply be air or oxygen in the 1L bag.   
The enrolment and baseline visits are compulsory for all participants. Participants will be required 
to complete at least one follow-up visit from the  “half-way through” following commencement 
of radiotherapy, end of treatment and 3-months post-radiotherapy visits. The three follow-up 
visits will be offered to all patients, however completion of only one visit post-commencement of 
radiotherapy will be compulsory. 
At the first baseline imaging visit (Visit 2), patients will be offered hyperpolarized xenon MR 
imaging, gadolinium-enhanced lung MRI and ventilation/perfusion nuclear medicine scan of the 
chest (optional) in addition to routine thoracic CT imaging. This enables co-registration between 
imaging modalities and correlation with physiological variables. Hyperpolarized xenon MR 
imaging involves acquisition of up to four MR sequences during one scanning session i.e. the 
participant will undergo up to four hyperpolarized xenon breath holds during each visit. The four 
inhalations may be different sequences or the same sequence may be repeated to assess 
reproducibility. Previous studies have shown that the signal from each xenon breath hold clears 
within seconds of exhalation. Participants will receive radiotherapy schedules according to 
departmental protocols. Patients will be offered hyperpolarized xenon MRI half-way through 
their radiotherapy schedule (Visit 3). At this time point no other imaging tests will be completed. 
In addition to routine thoracic CT, further hyperpolarized Xe-129 MRI and gadolinium-enhanced 
lung MRI will be offered on the final day of treatment and 3 months following completion of 
radiotherapy (Visits 4 & 5). 
During each visit, patients are scheduled to undergo up to four hyperpolarized Xe-129 breath 
holds to complete MRI scanning. In the event that breathing and scanning are not entirely 
synchronised, one or two xenon breath holds may need to be repeated; so in total, each 
participant will undergo up to a maximum of 24 hyperpolarized Xe-129 breath holds during the 
four imaging visits over the 9 month study period.  


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All patients enrolled with lung cancer will undergo clinical assessment involving objective 
physiological measures (pulmonary function testing and pulse oximetry) and patient orientated 
functional measures (dyspnoea scores, CTCAE version 4. Radiotherapy-induced lung toxicity 
assessment) at baseline, on the final day of radiotherapy treatment and 3 months post treatment. 
These assessments will not be completed at the two week following commencement of 
radiotherapy schedule visit.  
Patients to be treated with radiotherapy affecting the lung that do not have lung cancer, such as 
oesophageal cancer, chest wall tumours, lymphoma affecting the mediastinum and others, will 
undergo clinical assessment (excluding full pulmonary function testing) and Xe-129 lung MRI 
imaging only at each visit. 
Participation in these full tests takes up to a day, allowing patients time to rest between tests. All 
participants will be monitored for at least 30 minutes after the final hyperpolarized xenon dose 
before they are discharged home. It is likely approximately 3 hours will have elapsed since 
administration of the first hyperpolarized xenon dose by this time.  Participants will receive a 
telephone consultation 24 hours after completion of hyperpolarized Xe-129 MRI to review any 
AEs that have occurred in the interim following discharge. Furthermore, participants will attend 
hospital and see the Oncology clinical team on a daily basis during radiotherapy when they will 
have the opportunity to report any AEs relating to hyperpolarized Xe-129 gas. The study schedule 
includes follow-up by both the study team and Oncology clinical team in out-patient clinic at 
regular intervals throughout the 9 month trial duration. This will allow for review of possible 
AE/SAE two weeks after each hyperpolarized xenon scanning session. 
Following the final xenon administration at the 3-month post-radiotherapy follow-up visit, 
participants will also receive a telephone consultation two weeks later to review AE/SAEs. 
 
 


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7.2. Summary Flow Chart of Study Design 
 
 


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8. PARTICIPANT IDENTIFICATION 
8.1. Trial Participants 
Study participants considered suitable for radiotherapy or chemoradiotherapy (concurrent or 
sequential schedule) affecting the lung will be recruited. 
8.2. Inclusion Criteria 
• Participant is willing and able to give informed consent for participation in the trial. 
• Male or Female, aged 18 years or above. 
• Patients where radiotherapy or chemoradiotherapy (concurrent or sequential schedule) 
affecting the lung is considered appropriate by the treating clinical Oncologist. 
• WHO performance status 0-2 
• Able (in the Investigators opinion) and willing to comply with all study requirements. 
8.3. Exclusion Criteria 
The participant may not enter the trial if ANY of the following apply: 
• Inability to give written informed consent. 
• Female participant who is pregnant, lactating or planning pregnancy during the course of 
the trial. 
• Previous radiotherapy to the chest. 
• The presence of another condition where the disease itself or treatment may interfere 
with the study endpoints. 
• Any psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule. 
• Inability to lie flat for imaging. 
• Contraindications to MRI examination including indwelling pacemaker, non-MRI 
compatible metallic implant, severe claustrophobia, intra-ocular foreign body. 
• Contraindications 
for 
gadolinium 
enhanced 
lung 
MRI 
scan 
– 
known 
hypersensitivity/allergy to the injection of MultiHance (contains gadobenate dimeglumine 
and small quantities of benzyl alcohol) that is given as part of this scanning or an adverse 
reaction to an injection given during previous MRI scanning, severe renal impairment. 
• Epilepsy requiring on-going medical treatment, or a seizure within the past year. 
9. TRIAL PROCEDURES 
9.1. Recruitment 


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Potential participants will be identified from out-patient Lung cancer or Oncology clinic 
appointments. Potential participants will be approached by a member of their clinical team within 
the hospital setting. Any potential participant fulfilling the inclusion criteria will be informed of 
the trial by a member of their clinical team. If a patient expresses an interest in the study, they 
will be given a patient information leaflet and will be asked to give their permission to be 
contacted by the study team. The leaflet will also provide contact details for the study team 
should the patient wish to initiate contact. 
A member of the study team will contact the participant to arrange an enrolment visit (Visit 1). 
This may be arranged to coincide with a scheduled out-patient clinic appointment for 
convenience. Enrolment will involve checking that the patient is eligible for the study, completion 
of informed consent and study registration. This will be an opportunity to discuss the study in 
detail, familiarise the participant with the Radiology department where the majority of study 
measures will take place and to complete a “dummy run” of Xe-129 lung MR imaging as previously 
described in section 7.1. 
9.2. Informed Consent 
The participant must personally sign and date the latest approved version of the Informed 
Consent form before any trial specific procedures are performed. This will be done in accordance 
with the national and local regulatory requirements. 
Patients who express an interest in participating in the trial when a member of their clinical team, 
usually their Oncologist/Respiratory Physician, discusses it with them will be provided with an 
information leaflet and will be asked to give their permission to be contacted by the study team. 
The leaflet will also provide contact details for the study team should the patient wish to initiate 
this contact. Written and verbal versions of the participant information sheet and informed 
consent form will be presented detailing no less than: the exact nature of the study; the 
implications and constraints of the protocol; the known side effects and any risks involved in 
taking part. It will be clearly stated that the participant is free to withdraw from the study at any 
time for any reason without prejudice to future care, and with no obligation to give the reason 
for withdrawal. 
Patients are given an MRI safety leaflet, and a contact number to discuss any aspect of the visit 
and scanning prior to giving consent. 
The participant will be allowed as much time as wished to consider the information (at least 24 
hours with written information to allow the patient to carefully consider participation but avoid 
any delay of radiotherapy treatment), and the opportunity to question the Investigator, their GP 
or other independent parties to decide whether they will participate in the study. The informed 
consent procedure will conform to the ICH guidelines on Good Clinical Practice. This implies that 
“the written informed consent form should be signed and personally dated by the patient or by 
the patient’s legally acceptable representatives”. A copy of the signed Informed Consent will be 
given to the participants.  The original signed form will be retained at the study site. A copy of the 


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signed Informed Consent will also be scanned onto the Radiology CRIS system and linked to the 
participant’s Xe-129 MR imaging event. 
The person who obtained the consent must be suitably qualified and experienced with up to date 
GCP/informed consent training, and have been authorised to do so by the Chief/Principal 
Investigator.  
9.3. Screening and Eligibility Assessment 
Potential participants will be approached by their Oncologist or Respiratory Physician within the 
hospital setting. Any potential participant fulfilling the inclusion criteria will be informed of the 
trial by a member of their clinical team. If a patient expresses an interest in the study, they will 
be given a patient information leaflet and will be asked to give their permission to be contacted 
by the study team. The leaflet will also provide contact details for the study team should the 
patient wish to initiate contact. 
Prior to registration or any study measures being undertaken, documented informed consent will 
be completed as detailed in section 9.2.  
All participants will undergo clinical assessment including medical history and baseline study 
measures (section 9.5) over 1 -2 hospital visits as outlined below: - 
Demographics 
The date of birth, gender and smoking habits will be recorded.  
Medical History 
This forms part of the patient’s routine clinical care. 
All female participants of child-bearing age will have had pregnancy excluded as part of their 
routine clinical care in Oncology prior to starting radiotherapy.  
9.4. Randomisation, blinding and code-breaking 
This study is not a randomised trial.  All patients undergoing hyperpolarized MR imaging will 
breathe Xe-129.  
9.5. Baseline Assessments for patients with a diagnosis of lung cancer 
 
Arterial oxygen saturations (SaO2) – measured after a period sitting quietly and resting. The 
average reading over a two-minute period is recorded. 
Pulmonary Function Tests 


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Pulmonary function tests will be carried out, including spirometry, lung volumes and carbon 
monoxide transfer factor. Recordings will be compared to predicted values determined from 
standard published data.   
Spirometry will involve the participant breathing out as fast as they can for as long as they can, at 
least three times. The maximal amount breathed out in one second (forced expiratory volume in 
one second, FEV1) and total amount breathed out (forced vital capacity, FVC) will be recorded. 
Recorded values will be compared to predicted values determined from standard reference 
tables. Spirometry may be repeated following bronchodilator or steroid therapy to assess for 
reversibility as indicated by improvement FEV1 if a clinical history of asthma or chronic obstructive 
pulmonary disease (COPD) is present.   
Analysis will be based on change in % predicted values over time. 
Dyspnoea 
Dyspnoea (breathlessness) will be measured using the Dyspnoea-12 score (70), a seven-point 
Likert scale and a visual analogue score. 
Analysis will be based on the change in score from the baseline over time. 
Radiation-induced lung toxicity (RILT) 
RILT will be assessed using the common terminology criteria for adverse events (CTCAE version 
4). This is completed as part of standard routine care to enable assessment of functional 
impairment relating to radiotherapy-induced lung toxicity. 
Analysis will be based on the change in score from the baseline over time. 
Ventilation/perfusion nuclear medicine scan (SPECT/CT)  
Ventilation/perfusion nuclear medicine scan will be completed at baseline only and is an optional 
study measure. This scan is performed using the 16-slice GE Discovery 670 scanner as per local 
protocol. The nuclear medicine scan involves three components: - 
• Ventilation imaging – this involves the patient breathing in a gaseous tracer in aerosol 
form e.g. technetium-labeled diethylenetriamine pentaacetate (99mTc-DTPA) via a 
mouthpiece or mask.  
• Perfusion imaging – this involves insertion of a cannula, and then an injection of a small 
volume, < 5 mL, of radioactive technetium labelled macro aggregates of albumin (99mTc-
MAA).  A gamma camera acquires images for both ventilation and perfusion components. 
Patients do not have to move to a different bed between the nuclear medicine and CT 
scans, so it is associated with minimum disruption.   
Participants will be screened for contraindications to nuclear medicine scanning including known 
hypersensitivity to albumin or preference to avoid blood donation product. If a contraindication 


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to the nuclear medicine scan is identified, it will not be performed. This will not exclude the 
patient from participating in the study. 
 
 
Computed Tomography (CT) 
Thoracic CT will be performed at the Churchill Hospital. An injection of iodinated contrast will be 
administered through the same cannula that was inserted for the nuclear medicine scan. Scanning 
takes place 50-60 seconds post injection as per standard imaging protocol. CT images will be 
acquired during a single breath hold performed triggered to lung volume. The patient lies on their 
back, whilst scanning takes place. 
Participants will be screened for contraindications to iodinated contrast prior to completion of 
this study measure. These include: - 
• Marked renal failure not on dialysis 
• Known allergy to contrast medium, history of anaphylaxis 
• Known or suspected thyroid carcinoma 
• Inability to gain intra-venous access 
If contraindication to iodinated contrast is identified, all thoracic CT scans will be performed 
without contrast. This will not exclude the patient from participating in the study. 
 
Software will be used to determine areas of lung attenuation, such as delineating areas < -950 HU 
validated by visual inspection by an experienced thoracic radiologists, and/ or other measures of 
local texture in CT imaging.  Comparisons with manual region of interest performed on an image 
display software (OsiriX) will be made. 
Hyperpolarized Xe-129 MR Imaging 
The patient lies on their back in an MR scanner, and has conventional safety monitoring 
throughout the scan (direct visual observation, arterial oxygen saturations and heart rate 
monitoring). They wear a lightweight vest containing the imaging coils over their clothes that is 
necessary for acquiring images. 
Before the first Xe-129 MR scan involving inhalation of up to 1L of xenon, patients will be asked 
to breath in a small volume of xenon of approximately 100mL mixed with medical grade nitrogen 
for a total volume of 1L. The patient will be instructed to perform a standard breath hold for a 
short period of time (approximately 2 seconds). This is a set-up procedure for the scan enabling 
optimization of Xe-129 MR parameters according to patient height and weight as well as a 
practice run for the patient. The output from calibration (flip angle measurement) enables the 
best quality Xe-129 MR images to be acquired for each individual and is not be used to evaluate 
the study endpoints. 


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For the actual Xe-129 MRI scan, the patient breathes out, and then breathes in from a bag 
containing up to 1L of xenon, balance nitrogen. The total volume of gas participants inhale for Xe-
129 MRI scans is 1L, however this may consist of a mixture of 50-100% hyperpolarized xenon and 
up to 50% nitrogen i.e. 500 mL to 1L of hyperpolarized xenon is mixed with medical grade nitrogen 
to make up a total volume of 1L. Breathing in xenon is challenging for some people because it has 
a density 4.55 time greater than air, which increases airways resistance (72). Therefore patients 
are sometimes given assistance with the respiratory manoeuvre by physically compressing the 
bag during inhalation.  The patient receives a bag full of air or oxygen to practice this breathing 
manoeuvre before breathing xenon.  Scanning then takes place during a breath hold for 
approximately 20 seconds, or during an inhalation-exhalation manouevre. This manoeuvre with 
scanning will be repeated up to four times to enable acquisition of all Xe-129 MRI sequences.  The 
four inhalations may be different sequences or the same sequence may be repeated to assess 
reproducibility. There are currently three confirmed sequences (ventilation, ADC and dissolved 
phase) with further sequences under technical development that will be introduced during the 
course of the study period.  
If the patient fails to breathe in sufficient xenon at the required time, the investigator may suggest 
that the procedure is repeated once or twice. One patient will not exceed six inhalations of xenon 
in a single day. In the unlikely occurrence of an adverse event, a radiographer will be able to access 
the participant immediately.  Participants are monitored for at least 30 minutes after the final 
hyperpolarized xenon dose before they are discharged home. It is likely approximately 3 hours 
will have elapsed since administration of the first hyperpolarized xenon dose by this time.  
Participants will receive a telephone consultation 24 hours after completion of hyperpolarized Xe-
129 MRI to review any AEs that have occurred in the interim following discharge. Furthermore, 
participants will attend hospital and see the Oncology clinical team on a daily basis during 
radiotherapy when they will have the opportunity to report any AEs relating to hyperpolarized 
Xe-129 gas. The study schedule includes follow-up by both the study team and Oncology clinical 
team in out-patient clinic at regular intervals throughout the 9 month trial duration. This will allow 
for review of possible AE/SAE two weeks after each hyperpolarized xenon scanning session. 
Following the final xenon administration at the 3-month post-radiotherapy follow-up visit, 
participants will also receive a telephone consultation two weeks later to review AE/SAEs. 
Hyperpolarized Xe-129 MR imaging will be performed using xenon hyperpolarized by a xenon 
hyperpolarizer (Polarean 9880) and imaged on a 1.5T MRI scanner. A dedicated Xe-129 chest coil 
will be used. Images will be obtained in the coronal plane. During each scanning session, up to 
four hyperpolarized Xe-129 MR sequences will be acquired with the participant undergoing four 
separate xenon breath holds. Hyperpolarized Xe-129 MR will be repeated at baseline to assess 
reproducibility. Total scanning time will be approximately half a day during each visit. The 
participant will spend a total of approximately 1 ½ hour within the MRI scanner during each visit. 
Image acquisition strategy will include: - 
• Short echo proton MRI for co-registration purposes. 


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• Static ventilation  
• Dynamic ventilation. 
• Diffusion Imaging (ADC). 
• Intrapulmonary PO2   
• Dissolved phase imaging. 
 
If the study team fails to acquire all the required Xe-129 MRI sequences during a single scanning 
session as a result of technical difficulties or non-synchronisation of patient breathing and 
scanning, the patient may be requested to return within a few days to complete Xe-129 lung MRI 
scanning and ensure acquisition of all sequences for that study visit. This may take up to half a 
day and may involve repeating one or two Xe-129 MR sequences previously acquired since these 
cannot be analysed accurately if they have not all been performed at the same time point. 
Analysis 
All analyses will be performed by two experienced Thoracic Radiologists Fergus Gleeson (FG) and 
Rachel Benamore (RB) blinded to clinical data and all other investigation results to avoid bias. 
1. Accurate co-registration of global and regional data from hyperpolarized Xe-129 MRI and 
CT chest, by correlating Xenon MRI Ventilation and ADC maps with CT identified areas of 
emphysema using CT density maps (measure in Hounsfield units). 
Multivariate analysis to correlate global ventilation and ACD data from hyperpolarized Xe-
129 MRI with key patient-centred outcome measures – dyspnoea-12 score, RILT 
assessment.  
Gadolinium enhanced lung MRI 
This will be performed on a 1.5T MRI scanner according to local standard protocols. An injection 
containing gadolinium is given via the cannula (this will be the same one used for nuclear medicine 
and CT scans) and lung MRI carried out during a short breath hold.  Since patients do not need to 
move from the bed following Xe-129 lung MRI there is minimal inconvenience and disruption for 
the patient.   
Description of MultiHance (gadolinium injection) 
MultiHance contains gadolinium, which is a rare earth metal that improves images of pulmonary 
arteries during lung MRI.  Gadolinium is given in the form of gadobenate dimeglumine.   The dose 
of MultiHance is around 0.2 ml/ kg body weight.  There is no interaction or interference between 
MultiHance and inhalation of hyperpolarized Xe-129 gas, allowing this study measure to be 
performed straight after the hyperpolarized Xe-129 MRI scan safely. 
Safety considerations for MultiHance 
MultiHance is commonly used in clinical practice for perfusion imaging during MRI where it is safe 
and well tolerated.  Common side effects (more than 1/100 but fewer than 1/10) are headache, 


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nausea, feeling hot and local reactions such as swelling or pain at the injection site. Rarely (more 
than 1/ 10,000 but fewer than 1/ 1,000) allergic reactions can arise leading to shock, itching, skin 
rashes, urticarial, fainting, a swollen face and neck and wheezing, or other serious effects 
including tinnitus, pancreatitis, pulmonary oedema, intracranial hypertensions or hemiparesis. 
9.6. Baseline assessment for patients with diagnoses other than lung cancer 
Patients with diagnoses other than lung cancer, for example, oesophageal cancer, chest wall 
tumours and lymphoma will undergo the following baseline assessments only: - 
• 
Arterial oxygen saturations (SaO2) 
• Dyspnoea 
• Radiation-induced lung toxicity (RILT) 
• Hyperpolarized Xe-129 MR Imaging 
Full details about each of the study measures has been provided above in Section 9.5. 
9.7. Radiotherapy 
Radiotherapy treatment will be CT planned and delivered as per local departmental radiotherapy 
protocols. The treating Oncologist will not have access and be blinded to the baseline Xe-129 MRI 
images whilst planning radiotherapy. Entry into this study will not delay patients commencing 
radiotherapy, and their treatment will not be altered as a result of their enrolment into this study. 
The appropriate beam energy will be selected to optimize the RT dose distribution in the target 
volume and minimize dose to non-target tissues. 
9.8. Subsequent Visits for patients with a diagnosis of lung cancer 
At each hospital visit, study patients will be asked whether they have had any:  
• Hospitalisations 
• Consultations with other medical practitioners 
• Disability or incapacity or other adverse event that has occurred since their last visit 
All study measures will be performed and analysed as detailed previously in sections 9. and 12. of 
this document. 
Although all three follow-up visits will be offered to participants, only one visit post-
commencement of radiotherapy will be compulsory. 
Half-way through radiotherapy schedules 
  


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The only study measure to be completed will be hyperpolarized Xe-129 MR imaging involving up 
to a maximum of six xenon breath holds. Adverse events and serious adverse events will be 
reviewed. 
Final day of treatment and 3-months following completion of radiotherapy: - 
• AE/SAE review 
• Arterial oxygen saturation  
• Dyspnoea & CTCAE version 4 RILT assessment 
• Full pulmonary function tests 
• Thoracic CT 
• Hyperpolarized Xe-129 MR imaging involving up to a maximum of six xenon breath holds 
• Gadolinium enhanced lung MRI  
 
Two weeks after final xenon administration at 3-month post-radiotherapy 
 
• AE/SAE review via telephone consultation 
 
9.9. Subsequent Visits for patients with a diagnosis other than lung cancer 
 
At each hospital visit, study patients will be asked whether they have had any:  
• Hospitalisations 
• Consultations with other medical practitioners 
• Disability or incapacity or other adverse event that has occurred since their last visit 
All study measures will be performed and analysed as detailed previously in sections 9. and 12. of 
this document. 
Although all three follow-up visits will be offered to participants, only one visit post-
commencement of radiotherapy will be compulsory. 
Half-way through radiotherapy schedules 
 The only study measure to be completed will be hyperpolarized Xe-129 MR imaging involving up 
to a maximum of six xenon breath holds. Adverse events and serious adverse events will be 
reviewed. 
Final day of treatment and 3-months following completion of radiotherapy: - 
• AE/SAE review 
• Arterial oxygen saturation  
• Dyspnoea & CTCAE version 4 RILT assessment 
• Hyperpolarized Xe-129 MR imaging involving up to a maximum of six xenon breath holds 


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Two weeks after final xenon administration at 3-month post-radiotherapy 
 
• AE/SAE review via telephone consultation 
 
9.10. 
Discontinuation/Withdrawal of Participants from Trial Treatment 
Each participant has the right to withdraw from the trial at any time.  In addition, the Investigator 
may discontinue a participant from the trial at any time if the Investigator considers it necessary 
for any reason including: 
• Pregnancy 
• Ineligibility (either arising during the trial or retrospectively having been overlooked at 
screening) 
• Significant protocol deviation 
• An adverse event which requires discontinuation of the trial medication or results in 
inability to continue to comply with trial procedures 
• Disease progression which requires discontinuation of the trial medication or results in 
inability to continue to comply with trial procedures 
• Withdrawal of Consent 
• Loss to follow up 
Withdrawal from the study will not result in exclusion of the data for that participant from analysis 
provided all baseline study measures have been completed. 
The reason for withdrawal will be recorded in the CRF. If the participant is withdrawn due to an 
adverse event, the Investigator will arrange for follow-up visits or telephone calls until the adverse 
event has resolved or stabilised. 
9.11. 
Definition of End of Trial 
The end of trial is the date of the last hospital visit of the last participant. 
 


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10. INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
10.1. 
IMP Description 
No treatments are given as a part of the proposed study since the appropriate radiotherapy 
schedule is taking place as part of patients’ routine clinical care.   
Hyperpolarized Xe-129 lung MRI requires breathing in an investigational medical product, 
hyperpolarized xenon gas, Xe-129, which is described in detail below.   
Xenon is an inert gas that is present in the atmosphere in low concentrations.  It has no smell or 
taste.  Breathing xenon or undergoing an MRI scan does not involve exposure to ionising radiation.  
We will administer a maximum of 6 x 1 Litre doses of hyperpolarized xenon gas to each participant 
per hospital visit for Xe-129 lung MR imaging. If it is not essential to give 100% xenon for imaging, 
the gas may be diluted with ultrapure nitrogen. The ratio of xenon to nitrogen will vary from 10% 
to 100% but the volume provided to the patient will always be 1 L. 
The route of administration is inhalation. All female participants of child-bearing age will have had 
pregnancy excluded as part of their routine clinical care in Oncology prior to starting radiotherapy.  
Physiological effects  
At low concentrations such as those that will be used in this study, Xenon has effects similar to 
nitrous oxide (laughing gas).  Nine out of 10 patients experience light headedness, paraesthesia, 
euphoria or a mild ‘drunk’ feeling, which in short lived and resolves within 2-3 minutes of 
breathing the gas (73-75). 
Side effects   
Xenon has been found to be extremely safe and well tolerated, both during single breath-hold 
experiments such as ours (n=26 (76)and n=44 (72)) and during 4 minute 20 second continuous 
breathing (n=1,830) (74).  In a prospective study examining safety and tolerability of xenon, 32% 
of 44 volunteers experienced mild gastrointestinal symptoms (72).  One volunteer experienced 
drowsiness, sleepiness and numbness, which resolved in about 7 minutes (72). She had 
considerable co-morbidity, including multiple sclerosis, B12 deficiency and Graves’ disease.  In a 
large retrospective study involving breathing xenon for cerebrovascular imaging during a 4 
minutes 20 seconds period (in contrast to our single breath exposure), the incidence of pauses in 
breathing for >15 seconds was 0.6%, headache (usually mild) 0.4%, nausea or vomiting 0.2%, 
change in sensorium 0.1% and 0.05% hallucinations (74).  0.2% of patients had a seizure, but 3 of 
4 of these patients were being investigated for unexplained seizures, and diagnostic information 
was not available for the fourth patient.  Patients with multiple sclerosis had increased emotional 
lability.  These side effects nearly all occurred towards the end of the exposure period.  Pauses in 
breathing almost invariably were terminated by an instruction to take a breath. 
Safety considerations   


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At high concentrations xenon has anaesthetic properties.  The minimum alveolar concentration 
(MAC) of xenon at sea level is 70% (77).  Our patients will breathe a fraction of inhaled xenon 
(FiXe) considerably lower than this, and will inhale a single breath and therefore not approach the 
gas equilibrium that is required when defining MAC.  Our patients will inhale 1L from residual 
volume, resulting in an approximate fraction of xenon (FXe) of 10-30%. The alveolar FXe would 
tend to be marginally lowered due to Xe in the anatomical deadspace of the large airways, and 
marginally raised due to Xe not entering non- or slowly communicating air spaces within the lungs.  
Thus the FXe that our patients will be exposed to is considerably below the dose required to 
induce anaesthesia, and well within safe limits.  It is not possible for patients to breathe more 
than 1 L of xenon, since they are given a single bag of the gas. This procedure may be repeated 
up to four times during one imaging session. In the event that breathing and scanning are not 
entirely synchronised, one or two xenon breath holds may need to be repeated; so in total, each 
participant will undergo a maximum of 24 hyperpolarized Xe-129 breath holds during the four 
imaging visits over the 9-month study period. 
A further safety consideration is patients’ oxygenation, since they will be inhaling 1 L of anoxic 
gas, followed by a breath hold. However, participants will only be exposed to this low oxygen 
fraction for a single breath hold.  The breath hold is approximately 30 seconds, although patients 
are free to take another breath sooner if they cannot manage this long. The amount of oxygen 
available in 3.5 L of 11% oxygen is 385 mL, which is considerably more than the oxygen 
requirement for the duration of the breath hold (assuming oxygen use is 250 mL/ min). These 
calculations assume all gas within the lungs is in communication with inhaled gas, which is often 
not the case in respiratory disease, however the safety margins are extremely large.  Reassuringly, 
studies in chronic obstructive pulmonary disease (COPD) patients using this breathing technique 
observed a mean fall in oxygen saturations of only 1.2 % of baseline during observation at 2 
minute intervals for 10 minutes (72).  In the unlikely event that a patient desaturates by more 
than 10% immediately following Xe inhalation, this manoeuvre will not be repeated.   
Our patients will be carefully observed and monitored throughout the study, including direct 
visual observation, heart rate, respiratory rate and arterial oxygen saturations. The minimum 
number of people in attendance during a scan is two.  This includes a doctor or allied health care 
professional such as a nurse or radiographer, who is solely responsible for patient monitoring, 
safety and well-being.  They will be aware of potential risks of Xe, and appropriately trained in 
how to respond to any adverse sequelae arising.  It also includes a technician/ radiologist who is 
responsible for acquiring images.  In the event of any untoward medical event occurring mid-scan, 
staff can reach the patient immediately.  As in all clinical areas throughout the Oxford Hospital 
Trust, emergency drugs and equipment are readily available and staff are trained in their use.  
This includes supplementary oxygen and resuscitation equipment.   
All participants will be monitored for at least 30 minutes after the final hyperpolarized xenon dose 
before they are discharged home. It is likely approximately 3 hours will have elapsed since 
administration of the first hyperpolarized xenon dose by this time.  Participants will receive a 
telephone consultation 24 hours after completion of hyperpolarized Xe-129 MRI to review any 


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AEs that have occurred in the interim following discharge. Furthermore, participants will attend 
hospital and see the Oncology clinical team on a daily basis during radiotherapy when they will 
have the opportunity to report any AEs relating to hyperpolarized Xe-129 gas. The study schedule 
includes follow-up by both the study team and Oncology clinical team in out-patient clinic at 
regular intervals throughout the 9-month trial duration. This will allow for review of possible 
AE/SAE two weeks after each hyperpolarized xenon scanning session. 
Following the final xenon administration at the 3-month post-radiotherapy follow-up visit, 
participants will also receive a telephone consultation two weeks later to review AE/SAEs. 
A ‘Physician information sheet’ documenting possible effects of Xe and appropriate medical 
responses has been drawn up, and will be provided to all those involved in Xe imaging.   
10.2. 
Production, Storage and Dispensing of IMP 
 
Xe-129 will be isolated from a gas mixture of 1.0% xenon, 10% nitrogen and 89% helium, 
manufactured in the USA and supplied by Spectra Gases Ltd, Littleport Cambridgeshire.  It will be 
polarised via spin exchange optical pumping by laser, using the Polarean 9800 hyperpolarisation 
system.  Xe-129 will then be frozen to isolate it from other gases and sublimated into Tedlar plastic 
bags for administration to participants via inhalation.  The gas is labelled in accordance with EU 
trial directive requirements. 
Each batch of Xe-129 will be tested using a Polarean 2881 polarization measurement system to 
ensure sufficient xenon gas is hyperpolarized to enable lung imaging.  All staff involved in the 
process of Xe-129 manufacture will be trained to ensure that the manufacture is conducted safely 
to the correct technical specification.  The manufacturing facility is licensed by the MHRA and 
each batch is manufactured to GMP standard and certified for release to the investigator by a 
Qualified Person according to the approved Standard Operating Procedures. 
Calibration 
Calibration involves the patient breathing a small volume of xenon of approximately 100mL mixed 
with medical grade nitrogen for a total volume of 1L. The patient will be instructed to perform a 
standard breath hold for a short period of time (approximately 2 seconds). This is a set-up 
procedure for the scan enabling optimization of Xe-129 MR parameters according to patient 
height and weight as well as a practice run for the patient. The output from calibration (flip angle 
measurement) enables the best quality Xe-129 MR images to be acquired for each individual and 
is not be used to evaluate the study endpoints. 
For calibration, hyperpolarization will take up to 10 minutes. The same manufacturing process as 
clearly described by SOPs to produce up to 1L of hyperpolarized Xe-129 will be adhered to. The 
only difference is the length of hyperpolarization time resulting in a much smaller volume (100mL) 
of hyperpolarized xenon gas being produced. Xe-129 will be isolated from other gases and 


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sublimated into Tedlar plastic bags in Radiology for administration to participants via inhalation 
in the MR suite. To make a total volume of 1L, medical grade nitrogen is added. These small 
calibration doses are not considered to be IMPs and do not require QP release. 
10.3. 
Compliance with Trial Treatment 
 
Compliance auditing is not relevant to use of hyperpolarized xenon: a dose is only given by 
radiographers/ radiologists during the MR regional lung imaging itself. However, the volume of 
Xe-129 inhaled will be recorded on the CRF. 
10.4. 
Accountability of the Trial Treatment 
 
Medical grade xenon and nitrogen will be supplied by Spectra Gases Ltd, Littleport 
Cambridgeshire to Oxford Thoracic Imaging Centre where the gas will be polarized.  The duration 
of hyperpolarization will be up to 70 minutes. Hyperpolarized xenon may be kept frozen for a 
short time (less than 30 minutes) before thawing. After thawing, bags of hyperpolarized xenon 
will be labeled with the patient’s ID and the expiry date and time. Hyperpolarized xenon will be 
used within 30 minutes of thawing.   
10.5. 
Concomitant Medication 
Patients’ medications will be recorded at baseline and at each follow-up visit. 
10.6. 
Post-trial Treatment 
 
The proposed study is an interventional study. As such all participants will receive best standard 
care throughout and this will continue without interference following study completion. 
 
 
 


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11. SAFETY REPORTING 
11.1. 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a 
medicinal product has been administered, including occurrences 
which are not necessarily caused by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
The phrase "response to an investigational medicinal product" 
means that a causal relationship between a trial medication and 
an AE is at least a reasonable possibility, i.e. the relationship 
cannot be ruled out. 
All cases judged by either the reporting medically qualified 
professional or the Sponsor as having a reasonable suspected 
causal relationship to the trial medication qualify as adverse 
reactions. 
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 
hypothetically 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 trial treatments, based on the information 
provided. 


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Suspected Unexpected 
Serious 
Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out: 
• in the case of a product with a marketing authorisation, in the 
summary of product characteristics (SmPC) for that product 
• in the case of any other investigational medicinal product, in 
the investigator’s brochure (IB) relating to the trial in 
question. 
 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and 
“severe”, the following note of clarification is provided: “Severe” is often used to describe 
intensity of a specific event, which may be of relatively minor medical significance. “Seriousness” 
is the regulatory definition supplied above. 
Any pregnancy occurring during the clinical trial and the outcome of the pregnancy should be 
recorded and followed up for congenital abnormality or birth defect, at which point it would fall 
within the definition of “serious”. 
11.2. 
Causality 
 
The relationship of each adverse event to the trial medication must be determined by a medically 
qualified individual according to the following definitions: 
Related: The adverse event follows a reasonable temporal sequence from trial medication 
administration. It cannot reasonably be attributed to any other cause. 
Not Related: The adverse event is probably produced by the participant’s clinical state or by other 
modes of therapy administered to the participant. 
11.3. 
Procedures for Recording Adverse Events 
 
All AEs observed by the investigator or reported by the patient during and for 24 hours after Xe-
129 lung MRI are reported on the case report forms. A member of the research team will contact 
the participant by telephone 24 hours after completion of hyperpolarized Xe-129 MR imaging to 
record any AEs that may have occurred after leaving the hospital. These will be clearly 
documented on the patient CRFs. Thereafter only adverse events where there is a reasonable 
possibility of a relationship to inhaled xenon (adverse reactions) as judged by the chief 
investigator, and any adverse event considered by the chief investigator to be of medical interest/ 
importance are reported.  These events will be reported on the case report forms. 


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The following information will be recorded: description, date of onset and end date, severity, 
assessment of relatedness to trial medication, other suspect drug or device and action taken.  
Follow-up information should be provided as necessary. 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe. 
AEs considered related to inhaled xenon as judged by a medically qualified investigator or the 
Sponsor will be followed either until resolution, or the event is considered stable. 
It will be left to the investigator’s clinical judgment whether or not an AE/ AR is of sufficient 
severity to require the patient’s removal from Xe-129 MRI scanning.  A patient may also 
voluntarily withdraw from study procedures if they tolerate it poorly.  Further details of 
withdrawal are presented in Section 9.8.   
In the event of symptoms arising, patients will be given appropriate care and medical supervision 
until symptoms resolve, or the condition becomes stable.  Every effort will be made to gather 
outcome data on patients through study follow-up, or general practitioner/ hospital staff unless 
the patient is specifically withdrawn consent to such efforts. 
11.4. 
Reporting Procedures for Serious Adverse Events 
 
All SAEs (other than those defined in the protocol as not requiring reporting) following Xe-129 
lung MRI scanning must be reported on the SAE reporting form to R&D within 24 hours of the Site 
Study Team becoming aware of the event. R&D will perform an initial check of the report, request 
any additional information, and ensure it is reviewed by the Medical Monitor on a weekly basis.  
It will also be reviewed at the next Trial Safety Group meeting.  All SAE information must be 
recorded on an SAE form and faxed, or scanned and emailed, to R&D.  Additional and further 
requested information (follow-up or corrections to the original case) will be detailed on a new 
SAE Report Form and faxed/emailed to R&D. 
11.5. 
Expectedness 
 
Expectedness will be determined according to the Investigators’ Brochure. 
After breathing gas containing xenon, feelings of light-headedness, paraesthesia, euphoria or mild 
‘drunk’ feeling are common, occurring in 9 out of 10 people.  These symptoms last for just a few 
minutes, just like breathing ‘laughing gas’. The expected adverse reactions are described in the 
Investigators’ Brochure. 
11.6. 
SUSAR Reporting 
 


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All SUSARs will be reported by the CI to the relevant Competent Authority and to the REC and 
other parties as applicable. For fatal and life-threatening SUSARS, this will be done no later than 
7 calendar days after the Sponsor or delegate is first aware of the reaction. Any additional relevant 
information will be reported within 8 calendar days of the initial report. All other SUSARs will be 
reported within 15 calendar days. 
Treatment codes will be un-blinded for specific participants.  
Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the 
same Sponsor, whether or not the event occurred in the current study. 
11.7. 
Safety Monitoring Committee 
 
The Oxford University Hospitals Trust / University of Oxford Trials Safety Group (TSG) will conduct 
a review of all SAEs for the trial reported during the quarter and cumulatively. The aims of this 
committee include: 
• To pick up any trends, such as increases in un/expected events, and take appropriate 
action 
• To seek additional advice or information from investigators where required 
• To evaluate the risk of the trial continuing and take appropriate action where necessary 
11.8. 
Development Safety Update Reports 
 
The CI will submit (in addition to the expedited reporting above) DSURs once a year throughout 
the clinical trial, or on request, to the Competent Authority (MHRA in the UK), Ethics Committee, 
Host NHS Trust and Sponsor. 
 
 
 


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12. STATISTICS 
12.1. 
Description of Statistical Methods 
 
Early studies (73, 78), including work from our own group (79), using Xe-129 lung MRI have 
demonstrated that this technique provides valuable information regarding global pulmonary 
parenchymal apparent diffusion coefficients (ADCs – measures of increased air spaces) in COPD, 
demonstrating important differences compared to age matched controls or young, healthy 
volunteers.  Our scanner has excellent anatomical resolution compared to those used in most 
previous work, enabling us to perform regional analysis, down to the level of the secondary 
pulmonary lobule and to determine bronchial wall thickness.   
The primary outcome measure for determining Xe-129 lung MRI changes following radiotherapy 
will be evaluating the change in Xe-129 lung MRI imaging from baseline to other time points post-
radiotherapy initiation. 
We will also compare global Xe-129 lung MRI ADC measures between patients from other 
diagnostic groups (initially patients with NSCLC considered suitable for surgery, patients with 
COPD and patients with normal lungs who are well, but who are having chest CT imaging due to 
a prior testicular malignancy: these studies are covered by separate consent).  We will carry out 
the following completely novel analyses: -  
Technique development 
• 
Assessments of detailed regional data, with regional ADC and bronchial wall thickness 
measurements. 
• 
Accurate co-registration of global and regional data from Xe-129 lung MRI and chest CT, 
by correlating lung masks obtained from CT and proton MRI scans. Analysis of the 
correlation of MRI ADCs with CT lung tissue density (measured in Hounsfield units). 
• 
Development of perfusion data (blood flow through the lungs) obtained using dissolved 
phase Xe-129 lung MRI, and validation against the current gold standard –
ventilation/perfusion nuclear medicine scanning. 
• 
Development of novel and automated analysis methods, based on computational models 
of lung function and combined anatomical and functional information from CT and MRI 
scans, following current work at the Computational Biology Group. 
• 
Comparison of hyperpolarized Xe-129 MR imaging and four-dimensional CT (4D-CT) at 
baseline. 
Demonstration of superiority over standard lung function assessment tools 
• 
Multivariate analysis to correlate global and regional (lobar) data from Xe-129 lung MRI 
with key patient-centred outcome measures – dyspnoea assessment using the Dyspnoea-


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12 score (70) and MRC breathlessness score.  We will test the hypothesis that Xe-129 lung 
MRI has a closer correlation with these measures than FEV1 or gas transfer. 
12.2. 
The Number of Participants 
 
The total sample size will be 30. 
It is not possible to perform a detailed power calculation regarding sample size because this is the 
first time regional lung hyperpolarized Xe-129 MR indices have been correlated with physiological 
and functional outcomes in patients considered suitable for radiotherapy affecting the lung. We 
have taken the number of potential participants who are referred to our Oxford centre and 
considered suitable for radiotherapy affecting the lung over the last year into careful 
consideration and are confident that this sample size is feasible. 
In our development work with this technology using He-3 gas, we have shown in 24 patients with 
COPD that hyperpolarized gas MR imaging identifies more lung regions affected by emphysema 
(defined from ADC values >0.34 cm2/s) than does the severity of emphysema quantified by 
thoracic CT (defined from lung attenuation <960HU, a standard CT index). 
To date most studies employing hyperpolarized Xe-129 have been on animal models and healthy 
volunteers and have reported it as a viable functional lung imaging modality (18, 65). The sample 
size proposed for this trial will be sufficient to be informative in our planned analyses and direct 
future investigation. 
12.3. 
The Level of Statistical Significance 
The level of significance will be set at p<0.05. 
12.4. 
Criteria for the Termination of the Trial 
The study will terminate following recruitment and completion of follow-up of at least 30 
patients, or should a significant safety concern emerge.  
12.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. 
 
Efforts to measure all data as outlined in the trial protocol will be made. If a patient provides data 
from only one Xe-129 MRI scan, this will be included in analysis for mapping, but not for 
reproducibility. The data will be reviewed by Fergus Gleeson, to confirm that it is robust, and any 
deviation from expected results will be reviewed to determine if this is due to scanning error, or 
other artefact.  
12.6. 
Inclusion in Analysis 


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All evaluable participants will be included in the analysis. Participants will be deemed not to be 
evaluable for reproducibility if either or both baseline Xe-129 MRI scans are not assessable. 
12.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
This is an interventional study; exploratory analyses in addition to those above may be conducted 
to further the development of the technique. These will be described in full in the final study 
report. Patient observations will cease at the time of termination of the trial. 
 


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13. DATA MANAGEMENT 
13.1. 
Source Data 
 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 
previous and concurrent medication may be summarised into the CRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there 
is no other written or electronic record of data).  In this study the CRF will be used as the source 
document for initial clinical assessment, dyspnoea scores, RILT assessment and follow-up 
assessment. Safety assessment forms completed during hyperpolarized Xe-129 MRI scans to 
monitor patients’ vital observations will also be source data. All documents will be stored safely 
in confidential conditions. On all trial-specific documents, other than the signed consent, the 
participant will be referred to by the trial participant number/code, not by name. 
13.2. 
Access to Data 
 
Direct access will be granted to authorised representatives from the Sponsor, host institution and 
the regulatory authorities to permit trial-related monitoring, audits and inspections. 
13.3. 
Data Recording and Record Keeping 
 
Trial records will be kept in accordance with the Radiology Department SOPs. All trial data 
excluding imaging data will be entered onto a password secured database (OpenClinica). The 
participants will be identified by a unique trial specific number and/or code in any database. The 
name and any other identifying detail will NOT be included in any trial data electronic file. The 
Data Protection Act will be adhered to at all times. Paper records concerning the trial subjects will 
be kept in locked filing cabinets in the Radiology Department. 
Imaging data will be stored on a dedicated research server in the Radiology Department, Churchill 
hospital for a minimum of 5 years.  
All data will be checked for missing or unusual values (range checks) and for consistency within 
participants over time. If any such problems are identified, a photocopy of the problematic CRF(s) 
will be reviewed for checking and confirmation or correction, as appropriate. Any data, which are 
changed, will be crossed through with a single line, initialed and dated. 
 


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14. QUALITY ASSURANCE PROCEDURES 
The trial will be conducted in accordance with the current approved protocol, ICH GCP, relevant 
regulations and standard operating procedures. 
Regular monitoring will be performed according to ICH GCP by the sponsor. Data will be evaluated 
for compliance with the protocol and accuracy in relation to source documents. Following written 
standard operating procedures, the monitors will verify that the clinical trial is conducted and 
data are generated, documented and reported in compliance with the protocol, GCP and the 
applicable regulatory requirements. 
15. SERIOUS BREACHES 
The Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the 
notification of "serious breaches" to the MHRA within 7 days of the Sponsor becoming aware of 
the breach. 
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to a 
significant degree –  
(a) The safety or physical or mental integrity of the subjects of the trial; or 
(b) The scientific value of the trial”. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working 
day. In collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if 
appropriate, the Sponsor will report it to the REC committee, Regulatory authority and the NHS 
host organisation within seven calendar days. 
16. ETHICAL AND REGULATORY CONSIDERATIONS 
16.1. 
Declaration of Helsinki 
 
The Investigator will ensure that this trial is conducted in accordance with the principles of the 
Declaration of Helsinki.  
16.2. 
ICH Guidelines for Good Clinical Practice 
 
The Investigator will ensure that this trial is conducted in full conformity with relevant regulations 
and with the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) July 1996. 
16.3. 
Approvals 
 


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The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to an appropriate Research Ethics Committee (REC), regulatory 
authorities (MHRA in the UK), and host institution(s) for written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
16.4. 
Reporting 
 
The CI shall submit once a year throughout the clinical trial, or on request, an Annual Progress 
Report to the REC, host organisation and Sponsor.  In addition, an End of Trial notification and 
final report will be submitted to the MHRA, the REC, host organisation and Sponsor. 
16.5. 
Participant Confidentiality 
 
The trial staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by initials and a participants ID number on the CRF and any electronic database.  
All documents will be stored securely and only accessible by trial staff and authorised personnel. 
The trial will comply with the Data Protection Act, which requires data to be anonymised as soon 
as it is practical to do so. 
16.6. 
Expenses and Benefits 
 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on 
production of receipts or a mileage allowance provided as appropriate. Refreshments and 
newspapers will be provided during each visit. 
16.7. 
Other Ethical Considerations 
 
This type of imaging research raises several ethical issues. The proposed hyperpolarized Xe-129 
MR, gadolinium-enhanced lung MRI and optional ventilation/perfusion nuclear medicine scan will 
be provided in addition to any routine scans. Additional imaging may or may not add any 
information that will benefit the individual patient.  Nuclear medicine and CT examinations 
involve ionizing radiation and there is a small but quantifiable risk associated with administration 
of iodinated contrast. These issues will be addressed as follows:  
• Baseline and follow-up CT scans form part of standard routine patient care. Nuclear 
medicine scans are considered negligible exposure in comparison to doses from 
radiotherapy itself. However, any additional exposure will be formally justified. 


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• Patient Information Sheets will be provided describing the study and what it involves in 
non−technical language, as far as possible. Patients and patient’s carers will be involved 
in development of the leaflet.  
• Written informed consent will be obtained in an appropriate setting. The study will be 
introduced to the patient by a member of staff already known to the patient although 
consent will be performed by one of the study investigators.  
• Potential hazards of hyperpolarized Xe-129, optional ventilation/perfusion nuclear 
medicine scan and CT will be explained to the patient. The potential reactions to iodinated 
contrast or gadolinium will be explained to the patient. If the patient has experienced a 
contrast reaction before then contrast will not be used. 
• Patient inconvenience will be minimised by scheduling study investigations on the same 
day as routine clinic appointments, as far as possible. If a separate visit is necessary the 
patient will be compensated for any travel expenses.  
• Patients will be informed that findings from the study may not benefit them directly but 
will be used to improve future assessment of lung function and monitoring of treatment 
response.  
• Findings from imaging, e.g. incidental finding of distant metastasis which may influence 
patient management will be communicated to the referring clinician who will then advise 
the patient appropriately.  
 
 
 


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17. FINANCE AND INSURANCE 
17.1. 
Funding 
 
The trial sponsor will be the Oxford University Hospitals NHS Foundation Trust. 
Tel: + 44 (0) 1865 572 235  
Fax: + 44 (0) 1865 572 242 
The funder for this study will be the Oxford Biomedical Research Centre. Polarean has provided 
support for the trial by servicing the Xenon hyperpolarizer and GE Healthcare provided 
modifications to the Churchill Hospital MRI scanner to enable reading of the hyperpolarized xenon 
signal. 
The chief investigator is responsible for applying for local Trust management approval to conduct 
the trial in accordance with local arrangements and policies. Trust approval and indemnity must 
be confirmed in writing before patient recruitment commences on the Investigator site. 
The Oxford University Hospitals NHS Foundation Trust will authorise trial commencement once 
satisfied that all arrangements and approvals for the proper conduct of the trial are in place. 
17.2. 
Insurance 
 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If you are 
harmed whilst taking part in a clinical trial as a result of negligence on the part of a member of 
the trial team this liability cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS 
Foundation Trust, therefore, cannot agree in advance to pay compensation in these 
circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 
 
 
 


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18. PUBLICATION POLICY 
The final results of the trial will be submitted to a peer-reviewed journal for publication. Authors 
will be the Principal Investigator, the Co-Investigator, the Statistician and other members of the 
research team. No data on individual patients will be published without the permission of the 
Principal Investigator. Authors shall acknowledge that the study was performed with the support 
of the NIHR Oxford Biomedical Research Centre and Oxford Cancer Imaging Centre. 
 
 


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of diffusion of (3)He gas in healthy and diseased lungs. Magn Reson Med. 2000 Aug;44(2):174-9. 


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44. 
Salerno M, de Lange EE, Altes TA, Truwit JD, Brookeman JR, Mugler JP, 3rd. Emphysema: 
hyperpolarized helium 3 diffusion MR imaging of the lungs compared with spirometric indexes--initial 
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Swift AJ, Wild JM, Fichele S, Woodhouse N, Fleming S, Waterhouse J, et al. Emphysematous 
changes and normal variation in smokers and COPD patients using diffusion 3He MRI. Eur J Radiol. 2005 
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Appl Physiol. 2005 Nov;99(5):1992-7. 
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20. APPENDICES 
 


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Appendix 
Appendix code 
Patient information sheet 
A 
Patient consent form 
B 
Physician’s information sheet C 
 
21. AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) 
of 
changes 
Details of Changes made 
1 
1.1 
06/01/2014 
TM 
1. Clarified exclusion of pregnancy 
in female participants of child-
bearing age by Oncology prior to 
radiotherapy 
and 
therefore 
hyperpolarized Xe-129 lung MRI. 
2. Follow-up of participants after 
hyperpolarized Xe-129 MRI scan 
clarified including monitoring for 
at least 30 minutes each visit. 
3. Clarification of AE/SAE review 
including telephone consultation 
two weeks after final xenon 
administration at 1-year post-
radiotherapy visit. 
2 
2 
11/08/2016 
TM/FVG 
1. The number of participants has 
been reduced to 30 in total. 
2. The number of study visits have 
been reduced to a maximum of 
five: - 
a) Visit 
1 
– 
enrolment 
(compulsory) 
b) Visit 
2 
– 
Baseline 
(compulsory) 
c) Visit 3 – Half-way through 
radiotherapy schedule  
d) Visit 4 - Final day of 
radiotherapy treatment  
e) Visit 5 – 3-months post-
radiotherapy. 
Participants will be required 
to complete at least one 
follow-up visit, the others are 
optional. 


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3. Study 
measures 
have 
been 
reduced: - 
a) Ventilation/perfusion 
nuclear medicine scan is 
only to be completed at 
baseline and is optional 
b) Exercise tests have been 
removed 
from 
the 
protocol 
4. Clarification of study measures to 
be completed by patients with 
and without a diagnosis of lung 
cancer 
5. The study duration has been 
reduced to nine months to 
account for the reduced follow-
up period 
6. The planned trial period has been 
increased to 5 years 
7. The primary objective has been 
amended to account for the 
reduced 
number 
of 
study 
visits/follow-up 
period. 
The 
change in hyperpolarised Xe-129 
MRI will now be determined 
between baseline and time points 
post-radiotherapy initiation. 
8. The inclusion criteria have been 
amended to include any patient 
considered for radiotherapy or 
chemotherapy affecting the lung. 
9. The 
name 
of 
the 
xenon 
hyperpolariser 
model 
and 
manufacturer 
(Polarean) 
has 
been amended. 
10. Clarification that thoracic CT will 
be performed at the Churchill 
hospital 
11. The maximum total number of 
xenon 
inhalations 
has 
been 
reduced to 24 to account for the 
reduced number of study visits. 
12. Clarification of type of Xe-129 MR 
sequences to be acquired. 
 
1 
3 
27/03/2019 
MC 
1. Updated list of 
investigators and main 
contact 
2. The planned trial period 
has been increased to 7 
years. 
 


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Protocol amendments must be submitted to the Sponsor for approval prior to submission to the 
REC committee or MHRA.