Predicting sites of tumour progression in the invasive margin of glioblastomas (PRaM-GBM Study)
The locally invasive nature of glioblastomas ensures that residual disease is inevitable following surgery. Chemoradiotherapy is used to treat this, but as conventional imaging cannot identify this occult tumour, radiotherapy fields are indiscriminately applied around the resection cavity, limiting the dose to avoid normal brain injury. Virtually all patients will progress inside this area within a year. We need an imaging biomarker to identify this residual tumour and predict the site of tumour progression. Such a biomarker would redefine surgical targets and allow personalisation of radiotherapy treatment volumes.
Diffusion tensor imaging (DTI) – an MRI method sensitive to subtle disruption of white matter, is one potential biomarker. DTI can identify a larger abnormality than conventional MRI and biopsies of these abnormalities confirm invasive tumour. Follow up studies show it predicts the site of tumour progression with 89% sensitivity. DTI can be acquired on any MR system at both 1.5 and 3 Tesla – scanner variability is less of a concern as it is being used in a non-quantitative manner. Data suggests good inter- and intra-rater repeatability. Imaging processing will be aided by developing an automated, cloud-based analysis platform.
Aims and Objectives
This study aims to qualify an imaging biomarker that can accurately predict the site of glioblastoma progression, allowing personalisation of both radiotherapy and surgical targets.
Our hypothesis is that at progression, contrast-enhancement will occur in the region of DTI-defined invasion, and this will provide a potential target for both extended surgical resections and personalisation of radiotherapy volumes.
PRIMARY OBJECTIVE: to assess the diagnostic accuracy of DTI at pre-surgery or/and pre-radiotherapy as a biomarker to predict the site of glioblastoma progression.
- To explore the difference in accuracy of DTI as a biomarker performed pre-surgery and/or pre-radiotherapy to predict the site of glioblastoma progression
- Investigate the use of perfusion imaging of the invasive margin to improve the accuracy of the biomarker
- Investigate if the pattern of invasion can predict time to progression
- Determine the effect of resection on the invasive margin as determined by DTI
- Compare dose of RT using the DTI-defined invasive region receives with conventional RT plans
This will be a multicentre, longitudinal observational cohort study of 120 patients from up to 8 centres.
- 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;
- Age 16 – 75;
- Patient suitable for tumour resection where the treating neurosurgeon feels that >90% of the enhancing tumour will be resected;
- 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;
- Allergy to gadolinium contrast agent;
- History of severe renal impairment.
- Patients unable to provide written informed consent
- PET sub-study only: Pregnant women
Patients will be imaged pre-operatively and pre-radiotherapy with a protocol including DTI and perfusion MR (see Imaging Manual), and then according to standard of care until progression (trial schema is shown in Figure 1). Primary endpoint is the diagnostic accuracy of DTI to predict site of progressive tumour. Secondary endpoints will explore time-to-progression, location of DTI/perfusion abnormalities in relation to radiotherapy treatment volumes, potential for extended surgical resection and comparison of central vs. local analysis of data.
There are two planned sub-studies as part of PRaM-GBM:
1. Methodology Development sub-study
This is to investigate if staff at multiple sites can be trained in the DTI-analysis methodology developed in order for it to be implemented successfully in routine clinical practice across many hospitals.
2. Amino Acid PET exploratory sub-study
This is to explore whether there is any additional benefit from Amino Acid PET. More specifically:
- To investigate the relationship between Amino Acid PET, area of surgical resection and the area highlighted by DTI-MRI;
- To investigate the feasibility of taking image-guided biopsies from patients in the region outside of the area with increased amino-acid PET uptake;
- To explore the extent of invasive disease (from DTI/perfusion) that is likely to be left following surgery by assessing potential resected tumour using amino acid PET
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