Multi -paramEtric Imaging to Assess Treatment REsponse After Stereotactic Radiosurgery of Brain Metastases

Study Overview
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Brief Summary
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After stereotactic radiosurgery (SRS) of brain metastases, patients undergo a standard brain magnetic resonance imaging (MRI) to assess treatment response 12 weeks after completion of treatment. The interpretation of this standard MRI can sometimes be challenging as it can be difficult to differentiate tumour getting bigger/returning (progression/recurrence) from expected radiotherapy treatment-related changes known as radionecrosis. This study is a pilot brain imaging study that is investigating if readily available forms of imaging such as contrast-clearance analysis MRI (also known as TRAMs) and/or 18 Fluoromethyl-choline positron emission tomography/computerised tomography (18F-choline PET/CT) are equivalent to multi-parametric MRI in their ability to differentiate tumour from radionecrosis. Multi-parametric MRI has the most evidence for its ability to discriminate tumour from radionecrosis but is resource intensive and not routinely available in most centres.

Detailed Description
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Differentiating tumour progression/recurrence from radionecrosis post- stereotactic radiosurgery (SRS) of brain metastases can be at times challenging on standard brain MRI. This is because radionecrosis mimics the appearances of tumour progression by appearing as contrast enhancing lesions on standard MRI.The definitive way of differentiating this is surgical excision of the area in question and histopathological evaluation. But this is not always feasible in clinical practice as not all areas of the brain are surgically accessible and an en bloc (complete) resection is needed for the result to be meaningful. The next best option we have is the multi-parametric MRI which typically consists of three components-MR perfusion, MR diffusion and MR spectroscopy. This investigation is resource intensive, requiring considerable input form MR physics, neuroradiology reporting time , is not routinely available in all centres and hence not viable for routine clinical practice. Therefore there is an urgent need for a reliable and viable form of imaging modality that helps differentiate tumour from radionecrosis when assessing treatment response post-SRS. It is important to be able to do this accurately as the management of both conditions are entirely different. Currently the Royal Marsden Hospital is using contrast-clearance analysis MRI (TRAMs) to help differentiate tumour from radionecrosis if the changes seen on standard brain MRI post-SRS are deemed to be unclear. Contrast-clearance analysis MRI (TRAMs) is FDA approved and conforms to European standards (CE marked), yet has sparse evidence on its efficacy. There is some evidence for the use of 18F-choline PET/CT in primary brain tumours (gliomas) but more evidence is needed for its use in brain metastases. Given that surgical excision is not always feasible for reasons explained above, in this study the investigators consider the muti-parametric MRI as the gold standard investigation for discriminating tumour from radionecrosis. This pilot brain imaging study is seeking to determine if contrast-clearance analysis MRI (TRAMs) and/or 18F-choline PET/CT are equivalent to multi-parametric MRI in their ability to reliably differentiate between tumour progression/recurrence and radionecrosis. If contrast clearance analysis MRI (TRAMs) and/or 18F-choline PET/CT are found to be equivalent to multi- parametric MRI then it gives the investigators increased confidence in the findings of these readily available imaging modalities, helping treating clinicians to make rapid and reliable management plans- ultimately improving patient outcomes.

Official Title
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Multi-paramEtric Imaging to Assess Treatment REsponse After Stereotactic Radiosurgery of Brain Metastases

Conditions
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Brain Metastases, Adult

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with brain metastases whose primary cancer originates from the lung and whose histology is that of non-small cell lung cancer (NSCLC) Patient should have had SRS as their primary treatment for their brain metastases Follow-up standard brain MRI post-SRS has been discussed in the SRS multi-disciplinary team meeting (MDT) The changes seen on the post-SRS follow-up standard MRI are deemed unclear by the SRS MDT as to whether they represent tumour progression or radionecrosis. It is >=12 weeks since completion of SRS Exclusion Criteria: Prior SRS or external beam radiotherapy to the same area Children (age < 18) Pregnant women Adults that lack capacity to consent Contraindications to intravenous gadolinium contrast and/or 18F-choline radiotracer Contraindications to MRI scanning (for example pacemaker )

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Imaging to asess treatment response post-SRS<br>There will be only one group. All recruited patients will have 3 scans, the multi-parametric MRI, contrast-clearance analysis MRI (TRAMs) and 18F-choline-PET/CT. This is a non interventional study. Only the results of the contrast-clearance analysis MRI (TRAMs) will be used to make clinical decisions (as this is the current standard of care at the recruiting site). The multi-parametric MRI and 18F-choline PET/CT will be treated as research scans. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Equivalence of the contrast-clearance analysis MRI (TRAMs) and/or 18F-Choline PET/CT to multi-parametric MRI in differentiating tumour progression/recurrence from radionecrosis post stereotactic radiosurgery of brain metastases. | Patients will be classified into two groups according to the result of each scan with either tumour progression/recurrence or radionecrosis (i.e. tumour or no tumour). Patients will have all three scans within two weeks of each other, and then each imaging technique will be reviewed and reported by neuroradiologists as either disease or no disease. All three scans will be assessed once. The sensitivity, specificity, positive and negative predictive values in detecting tumour and prevalence will be calculated for the two scan methods where multi-parametric MRI will be used as the definitive diagnosis as we consider this as the gold standard in this study. The two scan methods are contrast-clearance analysis MRI (TRAMs) and 18F-choline PET/CT classification (tumour or no tumour) which will be compared against multi-parametric MRI. These separate measurements will be aggregated to obtain the primary outcome measurement (equivalence). | Primary outcome will be measured after the last visit of last patient-about 8 months from first recruited patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary endpoints are exploratory and will focus on correlating quantitative imaging derived parameters from contrast-clearance analysis MRI (TRAMs) and 18F-choline PET/CT with quantitative parameters in multi-parametric MRI. | Each imaging technique, multi-parametric MRI (this scan has 3 components), contrast-clearance analysis MRI (TRAMs) and 18F-choline PET, measures different quantitative parameters to assess for the presence of tumour. Examples of quantitative parameters include for multi-parametric MRI: relative cerebral blood volume, apparent diffusion coefficient, choline to n-acetylcysteine ratio; contrast-clearance analysis MRI (TRAMs): volume of red versus blue areas on the treatment assessment maps; 18F-Choline PET: uptake value of the 18F-choline. These separate measurements will be aggregated to measure a single outcome, outcome 2 which is - is there a correlation between quantitative parameters from TRAMs and 18F-choline PET/CT and multi-parametric MRI. | This can be measured after the last visit of last patient-about 8 months from first recruited patient. | 
| Correlation of the three scan results with the actual clinical outcomes for the patients-ie tumour or radionecrosis. | Results from the three imaging modalities contrast-clearance analysis MRI (TRAMs), 18F-choline PET/CT, multi-parametric MRI, will be compared with the actual clinical outcomes for the patients (i.e. tumour progression/recurrence or radionecrosis) which will be known with more certainty after a period of follow-up of 6 months has elapsed following the study imaging investigations. This follow-up involves collecting routine standard brain MRI scan results (reports and/or images) and clinical review letters from the primary team. The sensitivity, specificity, positive and negative predictive values in detecting tumour and prevalence for the three scan methods will be compared against actual clinical outcomes. These separate measurements will be aggregated to measure outcome 3, which is - is there a correlation between the three scans and actual clinical outcomes for the patient. | Analysed only after a follow-up period of at least 6 months for all patients post completion of study investigations-about 14 months from first recruited patient and 6 months from last recruited patient. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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brain metastases, stereotactic radiosurgery, multi-parametric MRI, contrast-clearance analysis MRI, TRAMs, 18F-choline PET/CT, treatment response