Brain Imaging to Predict Toxicity in Elderly Patients After Radiotherapy

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.