Predicting Sites of Tumour Progression in the Invasive Margin of Glioblastomas (PRaM-GBM Study)

Study Overview
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Brief Summary
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Brain tumours are the leading cause of cancer deaths in children, men under the age of 45 and women under the age of 25. Glioblastoma is the most common and most malignant primary tumour. The predominant treatment is surgical removal of the tumour followed by radiotherapy. Sadly the majority of patients given this treatment develop recurrent and progressive disease. Better understanding of the invasive margin might improve outcomes by facilitating more complete surgical resection beyond the traditional contrast enhancing margins. Diffusion tensor MRI (DTI) is an imaging technique which may be able to predict the site of tumour recurrence. DTI has previously been shown to identify regions, which have been confirmed with biopsies, to be areas of invasive tumours and are present before progression is seen with an MRI. The primary aim of this study is to qualify an imaging biomarker that can be applied at initial presentation, that can accurately predict the site of where glioblastomas will progress after treatment and allow personalisation of both radiotherapy and surgical targets.

Detailed Description
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This is a multicentre, prospective longitudinal observational cohort study in patients with high grade glioma, who have surgery planned to remove >90% of the tumour, and subsequent radical radiotherapy with concomitant tomozolomide. The purpose of this study is to establish a model using DTI that can accurately predict the site of where glioblastomas will progress after treatment. This study aims to validate the use of DTI as a biomarker across multiple centres to develop analysis methods that could be used in the future to personalise radiotherapy treatment volumes, and potentially surgical targets. Patients will be given a DTI-MRI both prior to the operation and prior to radiotherapy. Clinical MRIs will take place according to standard guidelines. Whilst the study is open patients will participate in the study until death. Once a total of 70 patients from the first 90 have shown true progression patients will participate in the study for a minimum of 6 months from the beginning of radiotherapy. This study will be conducted in 6-10 NHS centres, where 120 patients will be recruited, patients who are withdrawn will be replaced.

Official Title
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Predicting Sites of Tumour Progression in the Invasive Margin of Glioblastomas (PRaM-GBM Study)

Conditions
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High Grade Glioma

Intervention / Treatment
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* Other: Diffusion tensor Imaging (DTI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have given written informed consent to participate Assessed by a neuroscience MDT to have a high grade glioma on imaging, OR if in the opinion of the CI, with guidance from the local PI that all relevant and appropriate members of a multidisciplinary team agree a high grade glioma diagnosis; Considered suitable for radical radiotherapy (60 Gy) with concomitant chemotherapy (Stupp Regime); WHO PS 0 or 1 (see Appendix 3); Age ≥16; Patient suitable for tumour resection where the treating neurosurgeon feels that >90% of the enhancing tumour will be resected; Exclusion Criteria: Patients who are participating in trials involving investigational treatments Patients who are unsuitable for a contrast-enhanced MRI will be excluded. Such clinical problems include, but are not limited to: MR unsafe metallic implants; Claustrophobia; Allergy to gadolinium contrast agent; History of severe renal impairment. Patients unable to provide written informed consent PET sub-study only: Pregnant women

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| High Grade Glioma<br>Diffusion tensor Imaging (DTI-MRI) scan to be performed pre-operatively and pre-radiotherapy | Other: Diffusion tensor Imaging (DTI)<br>* Diffusion tensor Imaging (DTI) is a technique sensitive to the ordered diffusion of water along white matter tracts and can detect subtle disruption. A diffusion tensor signature method was developed that splits the tensor information into isotropic and anisotropic diffusion components. This can differentiate regions of pure tumour from invaded white matter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Site of glioblastoma true progression correctly predicted by DTI scan | Assess the diagnostic accuracy of DTI at pre-surgery or/and pre-radiotherapy as a biomarker to predict site of glioblastoma progression | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accuracy of DTI as a biomarker | Explore difference of DTI performed pre-surgery and pre-radiotherapy to predict the site of glioblastoma progression | 18 months | 
| Perfusion imaging | Investigate dynamic susceptibility imaging to measure rCBV of the invasive margin to improve the accuracy of the DTI biomarker. | 18 months | 
| Time to progression | Investigate if pattern of invasion can predict time to progression | 18 months | 
| Extent of resection and volume of tumour that remains post-surgery by standard imaging and DTI | Determine the effect of resection on the invasive margin as determined by DTI | 18 months | 
| Radiotherapy dose according to DTI-defined invasive region | Retrospectively compare dose of radiotherapy using the DTI-defined invasive region receives with conventional radiotherapy plans | 18 months |