Imaging glioblastoma pH using CEST-MRI
| ISRCTN | ISRCTN86522205 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN86522205 |
| Secondary identifying numbers | 35083 |
- Submission date
- 07/08/2017
- Registration date
- 07/08/2017
- Last edited
- 05/07/2021
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English summary of protocol
Background and study aims
Several studies have demonstrated that acidity is greater within tumours that in normal tissue. This effect is predominantly driven by the hypoxic (low oxygen) environment in the tumour cells, and the build-up of lactic/carboxylic acid as the cells generate energy in the absence of oxygen. Extracellular acidity (outside cells) has been linked to increased tumour invasion and angiogenesis (blood vessel formation), reduced immune function and also resistance to radiation and systemic cytotoxic (anti-cancer drug) treatment. Chemical exchange saturation transfer (CEST) MRI is a non-invasive imaging technique that can give a readout of tissue pH (acidity). Besides pH there is evidence that this technique is also sensitive to protein concentration in tumours. This technique is already being assessed in stroke patients to aid the detection of areas with restricted blood supply and there is also a preclinical program in Oxford to develop this technique to evaluate tumours. The main aim of this study is to evaluate images obtained from CEST MRI in patients with glioblastoma, a type of brain cancer. The CEST-MRI data will also be compared with arterial spin labelling (ASL) perfusion MRI (a non-invasive imaging technique which assesses water and nutrient exchange) and tissue-based testing including pH, protein content and hypoxia markers.
Who can participate?
Patients aged 18 or over with glioblastoma who are scheduled for surgery
What does the study involve?
Participants undergo a CEST-MRI scan and ASL Perfusion MRI scan in addition to their standard care anatomical MRI scan. These may be repeated at the next standard care imaging visit if there are concerns over the time period between imaging and surgery. At surgery, biopsies (tissue samples) are taken for analysis. No visits additional to standard care are anticipated.
What are the possible benefits and risks of participating?
There is not expected to be a clinical benefit to those taking part in the study. There are no known risks or side effects to having a MRI, after proper safety considerations have been addressed. MRI is safe and non-invasive and does not involve any ionising radiation (x-rays). Participants are asked safety questions to help determine if they are able to take part. Some people find that the scanner makes them feel uncomfortable (because they have to keep still for a long time), gives them vertigo (dizziness) or claustrophobic (nervous in small spaces). Such feelings go away once the participant is outside the scanner and there are no after-effects of having a MRI scan. The main risk associated with biopsy of glioblastoma is haemorrhage (bleeding). However in this setting, biopsy of the tumour during surgery should not carry any increased risk as the participant’s tumour will be operated on immediately afterward.
Where is the study run from?
Churchill Hospital (UK)
When is the study starting and how long is it expected to run for?
February 2017 to June 2021
Who is funding the study?
Cancer Research UK
Who is the main contact?
Ms Stasya Ng
Contact information
Scientific
IMAGO Trial Office
Oncology Clinical Trials Office
Department of Oncology
Old Road Campus Research Building
Roosevelt Drive
Headington
Oxford
OX3 7DQ
United Kingdom
Study information
| Study design | Non-randomised; Interventional; Design type: Diagnosis, Process of Care, Imaging |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | A single-arm exploratory study examining the feasibility of imaging glioblastoma pH using CEST-MRI |
| Study objectives | Several studies have demonstrated that acidity within tumours is greater that in normal tissue. This effect is predominantly driven by the hypoxic (low oxygen) environment in the tumour cells, and accumulation of lactic/carboxylic acid as the cells generate energy in the absence of oxygen. Extracellular acidity has been linked to increased tumour invasion and angiogenesis (blood vessel formation), reduced immune function and also resistance to radiation and systemic cytotoxic (anti-cancer drug) therapy. Chemical exchange saturation transfer (CEST) MRI is a non-invasive imaging technique that can give a readout of tissue pH (acidity). Besides pH there is evidence that this technique is also sensitive to protein concentration in tumour models. This technique is already being assessed in stroke patients to aid the detection of areas with restricted blood supply and there is also a preclinical program in Oxford to develop this technique to evaluate tumours. The primary objective for this study is to evaluate CEST contrast image obtained from CEST MRI in glioblastoma, a type of brain cancer. As part of this study there are also several exploratory objectives in which the CEST-MRI signature will be correlated with tissue perfusion using arterial spin labelling/ASL perfusion MRI (a non-invasive imaging technique which assesses tissue perfusion/the extent of water and nutrient exchange with tissue) and tissue based testing including pH, protein content and immunohistochemistry to assess for hypoxia markers. |
| Ethics approval(s) | South Central- Oxford A Research Ethics Committee, 18/07/2017, ref: 17/SC/0304 |
| Health condition(s) or problem(s) studied | Brain Cancer |
| Intervention | Current interventions as of 22/08/2019: Study participants (previously untreated glioblastoma patients for resection/debulking surgery) will undergo a CEST-MRI scan and ASL Perfusion MRI scan in addition to their standard care anatomical MRI scan. These may be repeated at the next standard care imaging visit if there are concerns over the time period between imaging and surgery. At surgery, biopsies will be taken for analysis prior to tumour resection/debulking. No visits additional to standard care are anticipated. Further analysis will explore, by carrying out genomic, transcriptomic and metabolomic profiling of the tumour samples, how the hypoxic tumour signature relates to the degree of CEST imaging contrast. This latter work will focus on transcriptomic metagene approaches to assess for example the expression of a validated hypoxia metagene and its relationship to the CEST MRI signature as well as characterisation of glutamine metabolism and its activation under hypoxic conditions (and hence relationship to the CEST MRI imaging signature). Previous interventions: Study participants (previously untreated glioblastoma patients for resection/debulking surgery) will undergo a CEST-MRI scan and ASL Perfusion MRI scan in addition to their standard care anatomical MRI scan. These may be repeated at the next standard care imaging visit if there are concerns over the time period between imaging and surgery. At surgery, biopsies will be taken for analysis prior to tumour resection/debulking. No visits additional to standard care are anticipated. |
| Intervention type | Other |
| Primary outcome measure | pH-weighted CEST MRI signal, assessed using amide proton transfer ratio analysis, taken at the patient’s imaging visit |
| Secondary outcome measures | Current secondary outcome measures as of 22/08/2019: 1. Protein levels obtained from tissue-based assay using biopsies obtained on the surgery date 2. pH levels obtained from tissue-based assay using biopsies obtained on the surgery date 3. Hypoxia markers obtained from immunohistochemistry using biopsies obtained on the surgery date 4. Cerebral blood flow and bolus arrival time from ASL MRI perfusion scan, taken at the patient’s imaging visit 5. Correlation of tumour metabolite levels and functional genetic pathway expression with CEST-MRI imaging signal Previous secondary outcome measures: 1. Protein levels obtained from tissue-based assay using biopsies obtained on the surgery date 2. pH levels obtained from tissue-based assay using biopsies obtained on the surgery date 3. Hypoxia markers obtained from immunohistochemistry using biopsies obtained on the surgery date 4. Cerebral blood flow and bolus arrival time from ASL MRI perfusion scan, taken at the patient’s imaging visit |
| Overall study start date | 23/02/2017 |
| Completion date | 15/06/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 20; UK Sample Size: 20 |
| Total final enrolment | 19 |
| Key inclusion criteria | 1. Participant is willing, capable of cooperating with the protocol and able to give informed consent for participation in the study 2. Male or female, aged 18 years or above 3. Diagnosed with glioblastoma and scheduled for neurosurgical resection or debulking |
| Key exclusion criteria | Current exclusion criteria as of 16/02/2018: 1. Intolerant of MRI brain (for example: claustrophobia) 2. MRI brain contraindicated (for example: implanted electric and electronic devices, heart pacemakers, insulin pumps, implanted hearing aids, neurostimulators, intracranial metal clips, metallic bodies in the eye) 3. Neoadjuvant chemotherapy/radiotherapy treatment for glioblastoma which would interfere with the interpretation of trial results 4. Pregnancy 5. Other psychological, social or medical condition that the investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results Previous exclusion criteria: 1. Intolerant of MRI brain (for example: claustrophobia) 2. MRI brain contraindicated (for example: implanted electric and electronic devices, heart pacemakers, insulin pumps, implanted hearing aids, neurostimulators, intracranial metal clips, metallic bodies in the eye) 3. Prior treatment for glioblastoma 4. Pregnancy 5. Other psychological, social or medical condition that the investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results |
| Date of first enrolment | 24/10/2017 |
| Date of final enrolment | 31/05/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Headington
Oxford
OX3 7LE
United Kingdom
Sponsor information
University/education
Clinical Trials & Research Governance
Joint Research Office
Boundary Brook House
Headington
Oxford
OX3 7GB
England
United Kingdom
"ROR" |
https://ror.org/052gg0110 |
|---|
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 15/06/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | The intention is to publish this research in a specialist peer reviewed scientific journal. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
05/07/2021: The following changes were made to the trial record:
1. The overall trial end date has been changed from 30/06/2019 to 15/06/2021 and the plain English summary has been updated accordingly.
2. The intention to publish date was changed from 30/04/2022 to 15/06/2022.
19/10/2020: The intention to publish date was changed from 31/01/2021 to 30/04/2022.
04/06/2020: The intention to publish date was changed from 30/06/2020 to 31/01/2021.
22/08/2019: The following changes were made to the trial record:
1. The interventions were changed.
2. The secondary outcome measures were changed.
04/06/2019: The total final enrolment was added.
03/04/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Brain Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasms of eye, brain and other parts of central nervous system" to "Brain Cancer" following a request from the NIHR.
12/11/2018: Sponsor address updated.
31/08/2018: The following changes were made to the trial record:
1. The recruitment start date was changed from 31/07/2018 to 31/05/2019.
2. The overall trial start date was changed from 30/11/2018 to 30/06/2019.
3. The intention to publish date was changed from 30/11/2019 to 30/06/2020.
16/02/2018: The following changes were made to the trial record:
1. The exclusion criteria were updated.
2. The recruitment start date was changed from 14/09/2017 to 24/10/2017.
