An observational study in Glioblastoma Multiforme, Adult, Radiation Toxicity and Quality of Life, sponsored by Brighton and Sussex University Hospitals NHS Trust. Completed at 1 site in United Kingdom. Open to participants aged 65 Years and older. Per ClinicalTrials.gov, last updated 2023-01-04.
Sponsored by Brighton and Sussex University Hospitals NHS Trust · Observational
The investigators' aim with the BRITER study is to produce a way of predicting who might be more or less likely to suffer side effects from radiotherapy prior to starting treatment for a glioblastoma (GBM), a type of brain tumour.
GBM is the commonest primary malignant brain tumour. Treatment options include chemotherapy, radiotherapy or best supportive care. The focus should be on maintaining a good quality of life for as long as possible.
Radiotherapy to the brain is an effective treatment, however it can produce side effects. The degree of side effects different patients experience can vary widely. It has been thought that if the patient's underlying normal brain is fragile due to an underlying mild dementia or problems associated with high blood pressure or cholesterol then this might make them more vulnerable to radiotherapy.
MRI scans can be used to assess whether there are changes in the normal brain. The BRITER study aims to use MRI scans to see whether the investigators can predict those patients who might be more at risk of side effects from radiotherapy. The trial is aimed at patients aged > 65 who have been newly diagnosed with a GBM and are going to receive radiotherapy. Patients who agree to take part in the trial will have had an MRI scan as part of their normal diagnosis. Participants will undertake some questionnaires before starting their radiotherapy which will aim to assess their quality of life and their mental processes of perception, memory, judgment, and reasoning (called cognitive function). Participants may also need an extra MRI scan.
Participants will repeat these questionnaires 4 and 8 weeks after treatment when they come for their follow up appointments. The investigators will compare them to measurements made on the pre-treatment MRI scan.
Participation in the study does not change the treatment the patient receives.
The investigators hope that the BRITER study will enable them to predict the degree of side effects a patient is likely to experience before embarking on radiotherapy treatment. This will enable more informative, individualised discussions surrounding the best treatment path for older patients with a GBM.
Glioblastoma (GBM) is the commonest primary malignant brain tumour among the adult population with approximately 2,000 new cases diagnosed in the UK per year. Incidence peaks in the 7th and 8th decades of life and as the global population ages, rates are increasing. Outcomes from this disease remain poor with median life expectancy in the range of 12-18 months, dropping to 3-6 months in the older population. The reasons for this are multifactorial, including more aggressive tumour biology in the older age group, decreased tolerance to treatment related side effects and the potential of under treatment by doctors within the older age group.
Given the poor prognosis in this group, treatment must be balanced against side effects and worsening quality of life. In patients aged 65 or over there is a lack of consensus on standard of care. Radiotherapy has a survival advantage over best supportive care however the optimal dose of radiotherapy is yet to be established. A recent Phase III trial randomised elderly GBM patients to standard radiotherapy with 60Gy in 30#, hypofractionated radiotherapy of 34Gy in 10# or temozolomide (TMZ) chemotherapy alone. For patients older than 65, survival was significantly longer with TMZ or hypofractionated radiotherapy than with standard radiotherapy . Those with defects in the DNA repair protein MGMT did significantly better in the chemotherapy arm than those with intact MGMT, a result which was replicated in the NOA-08 trial which randomised elderly GBM patients to standard radiotherapy with 60Gy in 30# or TMZ alone. This non-inferiority trial showed TMZ to be a suitable monotherapy option, with greater effect seen in those with MGMT promoter methylation . Recently published evidence has shown a survival benefit from adding concomitant and adjuvant TMZ to a hypofractionated radiotherapy regime of 40Gy in 15# in patients aged over 65, again with greater effect seen in those with MGMT promoter methylation . There is therefore now evidence to support the use of concomitant chemoradiotherapy or chemotherapy or radiotherapy as single agents amongst elderly GBM patients and an increasing interest in using MGMT promoter methylation status as a biomarker. However there remains a paucity of data surrounding the clinical and radiological basis by which individual patients are assessed for treatment.
The majority of GBM patients over 65 who are actively treated by oncologists receive some form of radiotherapy to the brain. Short term side effects from radiotherapy include fatigue, headache, cognitive defects, nausea, weakness and a need for increased steroid doses. Longer term side effects include persistent cognitive defects, long term fatigue and hormonal imbalances . Radiation causes an inflammatory response within the brain tissue as well as disrupting the blood brain barrier. It affects the vasculature of the brain with endothelial cell damage leading to microvascular dilatation, thickening of the vessel wall and increased risk of microbleeds and ischemic strokes in the months to follow . There is a risk of inducing tissue necrosis from occlusion of small blood vessels within the brain parenchyma, leading to coagulation, focal necrosis and demyelination. Animal models have suggested radiation is cytotoxic to developing neuroglial progenitor cells with areas of stem cells such as the hippocampus and periventricular zones, particularly vulnerable to damage, leading to longer term neurocognitive decline . There is evidence to suggest that radiotherapy can stabilise or improve functional ability for some older patients with GBM as well as providing a survival advantage however clinical experience shows that the degree of side effects experienced and their impact on quality of life varies widely within this patient cohort.
Risk factors for toxicities from radiotherapy include dose, fractionation and age however there are no more accurate ways of predicting which patients are more likely to suffer side effects. MRI has been shown to accurately pick up microhaemorrhages and other ischemic changes which may correlate with a 'vulnerable' brain pre-treatment . These MRI changes have been examined in Alzheimer and dementia research with correlations shown between MRI markers and disease severity , however they have not yet been used within the neuro oncology setting.
The investigators aim to examine the relationship between MRI markers of a 'vulnerable' brain and degree of acute side effects and change in quality of life amongst a population of older patients being treated with cranial radiotherapy for GBM.
The poor prognosis of older GBM patients leads to an emphasis on the need for focusing on quality of life when deciding on treatment regimes. There are pathological markers which can help them determine the sensitivity of the tumour to chemotherapy however there is no such guidance when it comes to making decisions about radiotherapy. If it were possible to predict the degree of side effects likely to be experienced by a patient from radiotherapy treatment then it would enable clinicians to make more individually tailored, patient centred treatment plans.
The investigators aim to see if analysis of pre-radiotherapy MRI scans including T2 gradient echo and susceptibility weighted imaging sequences can correlate with acute treatment related toxicity and quality of life amongst patients aged 65 or over undergoing partial brain radiotherapy for GBM. As these patients have an average life expectancy of 3-6 months within the UK the investigators are focussing on acute rather than long term side effects of radiotherapy.
MRI sequences will be utilised to determine any markers of background subclinical microvascular or degenerative disease in the normal brain including microhaemorrhage secondary to hypertension or cerebral amyloid angiopathy and atrophy with cortical volume measurement of the contralateral hemisphere. Additional susceptibility weighted sequences will be performed to identify the presence of microhaemorrhages in the contralateral normal-appearing brain parenchyma. These will be semi-quantitatively assessed using a modified established microhaemorrhage scoring methodology. Absolute measures of the contralateral normal-appearing hemisphere cortical volumes will be acquired using FSL freesurfer software and a volumetric T1 weighted acquisition. These techniques will give the investigators a number of quantitative scores that can then assessed for correlation with changes in quality of life and toxicity scoring systems.
Radiotherapy is an effective palliative treatment for GBMs and has been shown in clinical trials to maintain or improve health related quality of life. However outside of a clinical trial population, usual clinical practice reveals some patients in whom the side effect profile from cranial radiotherapy is intolerable and has a significant detrimental effect on patients' quality of life for their remaining short lifespan. The BRITER study aims to examine whether analysis of pre-treatment MRI scans in this cohort could help to predict who is more vulnerable to these side effects and therefore reveal a group of patients in whom single agent chemotherapy or best supportive care would be better treatment options.
The BRITER study is being performed in patients aged 65 or over who have a new diagnosis of GBM. It tests the hypothesis that there is a relationship between 6 scores of a 'vulnerable' brain seen on pre-treatment MRI and a clinically significant change in patient quality of life, as defined by a 10 point change in the EORTC QLQ C30 questionnaire from baseline to 8 weeks post treatment.
2,132 studies on the registry are indexed under Glioblastoma; 464 are open to participants now.
This study's enrollment of 125 is above the median of 60 across 208 observational studies indexed under Glioblastoma.
Browse Glioblastoma studies →Brighton and Sussex University Hospitals NHS Trust is the lead sponsor of 22 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Patients aged 65 or over with newly diagnosed Glioblastoma Multiforme planning to receive radiotherapy to the brain
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Patients aged > 65 years with a new diagnosis of GBM. Diagnosis made via histological confirmation following or debulking surgery or radiologically during a Multidisciplinary meeting (MDM) confirmed by a consultant neuro radiologist. This lower age limit is due to previous clinical trials which have established gold standard treatment regimes for patients under the age of 65. Patients aged 65 or over have less clinical trial data available to them and treatment decisions are more nuanced with a greater emphasis on quality of life given the poorer prognosis of older patients.
Exclusion Criteria:
Patients not fit for radiotherapy treatment or having single agent chemotherapy with no radiotherapy
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients aged 65 or older who have been newly diagnosed with a Glioblastoma (either through histological confirmation or confirmed by a consultant radiologist in a multidisciplinary team meeting setting) who are planned to be treated with radiotherapy. There is only 1 arm in this study, there is no randomisation. All participants will undertake questionnaires (as described in detail elsewhere in the form) and if the required MRI sequences are not available on their diagnostic imaging then they will undertake a trail specific MRI scan.
Procedure: MRI scans and questionnaires
Extra baseline MRI scan performed and questionnaires (EORTC validated questionnaires involving EORTC QLQ C-30, EORTC BN20 and EORTC ELD14) to assess quality of life at baseline, 4 weeks and 8 weeks after treatment
Change in Quality of Life at 8 weeks post treatment.
Participants will complete validated quality of life questionnaires at baseline and at 8 weeks after treatment. The main outcome measure is the EORTC QLQ-C30 questionnaire. This will be scored and then assessed for differences between baseline and the 8 week score to assess for a clinically significant (10 point change) in score. The scores shall be calculated using the EORTC scoring manual which involves reverse scoring some domains. A higher overall score indicates a better quality of life.
Time frame: 8 weeks (+/- 1 week) after completing radiotherapy to the brain
Overall survival
As calculated below
Time frame: This will be calculated from the date of diagnosis of a Glioblastoma to the date of death or the date the study is censored (set at 31/12/2021, 16 months after the final patient is recruited) whichever is first
Change in score on MOCA cognitive screening questionnaire
The Montreal Cognitive Assessment is a cognitive screening test which is scored out of 30. A higher test score indicates better cognitive functioning. A score of 26 or below indicates impaired functioning. We will assess scores at baseline and at 8 weeks after treatment to check for changes in cognitive functioning
Time frame: at 8 weeks (+/- 1 week) after treatment complete
Change in score in EORTC BN20 questionnaire
The EORTC BN20 is a quality of life score specifically focussing on Brain related symptoms. It will be scored (higher score indicating better QoL) using the EORTC scoring manual. A linear model will be used
Time frame: Between baseline and 8 weeks
Change in score in EORTC ELD-14 questionnaire
Quality of life questionnaire focusing on elderly symptoms. A higher score indicates better quality of life. This will be scored using the EORTC scoring manual. A linear model will be used
Time frame: Between baseline and 8 weeks
Total brain volume (as a ratio of total intracranial volume to CSF) (mm3)
This is one of six MRI based imaging variables that will be calculated on the participants' baseline MRI scan. These six measures represent a numerical way to score a 'vulnerable' brain parenchyma and will be modelled against the change in quality of life scores
Time frame: Baseline
Contralateral medial temporal lobe volume (mm3)
This is one of six MRI based imaging variables that will be calculated on the participants' baseline MRI scan. These six measures represent a numerical way to score a 'vulnerable' brain parenchyma and will be modelled against the change in quality of life scores
Time frame: Baseline
Volume of T1 white matter hyperintensities in contralateral hemisphere (mm3)
This is one of six MRI based imaging variables that will be calculated on the participants' baseline MRI scan. These six measures represent a numerical way to score a 'vulnerable' brain parenchyma and will be modelled against the change in quality of life scores
Time frame: Baseline
Number of white matter microhaemorrhages seen on T2* or SWI in contralateral hemisphere (range 0 to 7)
This is one of six MRI based imaging variables that will be calculated on the participants' baseline MRI scan. These six measures represent a numerical way to score a 'vulnerable' brain parenchyma and will be modelled against the change in quality of life scores
Time frame: Baseline
Fazakas scale assessing white matter changes on T2 weighted imaging calculated in contralateral hemisphere (range 0-3)
This is one of six MRI based imaging variables that will be calculated on the participants' baseline MRI scan. These six measures represent a numerical way to score a 'vulnerable' brain parenchyma and will be modelled against the change in quality of life scores
Time frame: Baseline
Radiotherapy planning target volume (cc)
This is one of six MRI based imaging variables that will be calculated on the participants' baseline MRI scan. These six measures represent a numerical way to score a 'vulnerable' brain parenchyma and will be modelled against the change in quality of life scores
Time frame: Baseline
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Aug 2018 to primary completion in Sep 2021, 37 months.
Of 84 non-industry observational studies under Glioblastoma, half reached primary completion within 55 months of starting (the median), counting those still running; a quarter within 33 and three quarters within 96. This study's 37 months is below that.
Counting every sponsor, half of 99 studies reached it within 52 months; a quarter within 33 and three quarters within 96.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Dec 2022. You cannot join it, but the record below documents what was studied.
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Brighton and Sussex University Hospitals NHS Trust