Hitting the Mark: Introducing State-of-the-art MRI for Precision Radiotherapy of Glioblastoma

Study Overview
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Brief Summary
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The goal of this prospective cohort study is to assess the potential of advanced MRI for improved radiotherapy target delineation in patients diagnosed with glioblastoma. The main questions it aims to answer are: How does the coverage of the recurrence volume by a radiotherapy plan based on advanced MRI compare to the coverage by the clinical radiotherapy plan? How does the distribution of the dose to organs at risk by a radiotherapy plan based on advanced MRI compare to the distribution by the clinical radiotherapy plan? Participants will undergo an extended MRI-protocol prior to radiotherapy. This extended MRI-protocol includes the clinical brain tumor imaging protocol plus additional advanced MRI-sequences. Radiation treatment and patient follow-up will occur according to the clinical standard.

Detailed Description
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Rationale: One of the fundamentals of glioblastoma management is radiotherapy, where ionizing radiation is aimed towards a specific target area in the brain to inhibit further tumor growth. As these brain tumors are notorious for their extensive tumor infiltration, where tumor grows beyond the tumor that is visible on conventional magnetic resonance imaging (MRI), this target area, defined as the clinical target volume (CTV), consists of the visible tumor plus a 1.5-cm isotropic safety margin. In the majority of cases, this unspecific CTV margin adequately covers tumor infiltration, but inevitably also includes considerable amounts of healthy tissue. Radiation-induced side-effects like headaches, nausea, fatigue and cognitive decline can substantially affect the quality of life for these patients. An opportunity arises to indirectly visualize tumor infiltration with state-of-the-art advanced MRI (aMRI) techniques, providing additional information on physiology rather than only showing anatomical information through conventional MRI. A workflow has been developed to create a CTV based on these aMRI scans (CTVaMRI) rather than an isotropic expansion. With the additional information that aMRI provides, it could be possible to more accurately define what needs to be targeted and thus minimize damage to healthy tissue. In this research, the aim is to assess the potential of integrating aMRI into radiotherapy target delineation for patients with a glioblastoma by comparing the pattern of failure (coverage of radiological tumor recurrence by the radiotherapy plan) and the expected radiation dose to organs at risk between the CTVaMRI and the 1.5-cm CTV. It is hypothesized that the CTVaMRI can result in decreased radiation dose to organs at risk, whilst having similar pattern of failure. Primary objective: To demonstrate that the probability for reduced coverage of the recurrence volume by a radiotherapy plan based on a CTVaMRI, compared to the clinical radiotherapy plan (1.5-cm CTV), is lower than 0.20. Secondary objective: To illustrate a reduction in dose to organs at risk with a radiotherapy plan based on a conceptual CTVaMRI compared to the clinical radiotherapy plan (1.5-cm CTV). To evaluate the synergistic information that each individual aMRI-scan provides for the identification of tumor infiltration. To explore the association between pathophysiological changes on aMRI and future tumor recurrence. Study design: In this prospective cohort study, the clinical standard MRI session used for radiotherapy planning of glioblastoma patients will be extended with aMRI techniques that assess altered oxygenation, angiogenesis and increased protein concentration. Radiation treatment (and patient follow-up) will occur according to the clinical standard, i.e. using the 1.5-cm CTV for radiotherapy planning. The aMRI-scans will be used to create a theoretical CTVaMRI and corresponding radiotherapy plan. Pattern-of-failure analysis and assessment of dose to organs at risk will be done to compare the radiotherapy plan based on the 1.5-cm CTV with the (theoretical) radiotherapy plan based on the CTVaMRI. Additionally, various theoretical CTVs based on different combinations of aMRI-scans are generated to explore the added value of the different aMRI techniques. Lastly, the signal intensities on the aMRI-scans at the site of tumor recurrence are compared with contralateral normal-appearing white matter. Study population: Patients (≥ 18 years), diagnosed with IDH-wildtype glioblastoma, as confirmed by molecular or immunohistochemistry analysis post resection/biopsy and referred to outpatient clinic of the Department of Radiotherapy to undergo standard treatment with radiotherapy. The inclusion comes to an end when 53 patients have been included. Intervention: Each patient will have an extension to their standard radiotherapy planning MRI-scan taken for regular clinical care (Brain tumor MRI protocol: ± 25 minutes). The duration of the extended MRI-scan, which includes the brain tumor MRI protocol, is ± 45 minutes. Main study parameters/endpoints: Pattern of failure and dose to organs at risk by the radiotherapy plan based on the 1.5-cm CTV and the theoretical plan created with the CTVaMRI. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The patients have the burden of prolonged scan time (+ 20 minutes, scan will last at maximum 60 minutes in total) during their standard radiotherapy planning MRI-scan. The remainder of their clinical care will not be altered: Radiotherapy will be given to these patients based on standard 1.5-cm CTVs. Follow-up will follow the clinical protocol. There will be no personal benefit for the patients in this research project.

Official Title
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Hitting the Mark: Introducing State-of-the-art MRI for Precision Radiotherapy of Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Diagnostic Test: Extended MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent; Adult (18 years or older); Diagnosed with IDH-wildtype glioblastoma, as confirmed by pathology including molecular analysis post resection/biopsy; Referred to the outpatient clinic of the Dept. of Radiotherapy to undergo standard treatment with radiotherapy (30x2 Gy or 15x2.67Gy) and scheduled for an MRI for radiotherapy planning. Exclusion Criteria: Contraindication for (3 Tesla) MRI; Contraindication for use of gadolinium-based contrast agent (e.g. subject having renal deficiency or known allergy); Referred for treatment of recurrent glioblastoma; Previous radiotherapy to the head-and-neck region; Unable to give informed consent

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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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Extended MRI group<br>In this group, patients with a glioblastoma undergo an extended MRI-scan prior to radiotherapy. | Diagnostic Test: Extended MRI<br>* The MRI-protocol before radiotherapy is extended with 20 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pattern-of-failure analysis | The primary outcome measure is a comparison of the pattern-of-failure by the radiotherapy plan based on CTVaMRI and the clinical radiotherapy plan (1.5-cm CTV). For both the clinical radiotherapy plan and the aMRI radiotherapy plan of each patient, the recurrence volumes will be classified as in-field, marginal, or distant recurrence if more than 80%, 20-80%, or less than 20% of the recurrence volume falls within the 95% isodose line, respectively. | The time frame is until tumor recurrence occurs (follow-up for this study will last 2 years maximum for a participant). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of dose to organs at risk. | The difference in expected dose to important organs at risk between the clinical radiotherapy plan (1.5-cm CTV) and the aMRI radiotherapy plan (CTVaMRI). Important organs at risk include the brainstem, optic nerves, eyes, lenses, cochlea and optic chiasm. | Through study completion (on average 1 year after the extended MRI-scan). | 
| Recurrence coverage by different combinations of CTVaMRI | The differences in tumor recurrence coverage and size between the CTVaMRI (based on all four aMRI-scans) and CTVs based on individual or other combinations of aMRI, i.e. based on three, two or one aMRI-scan(s). | The time frame is until tumor recurrence occurs (follow-up for this study will last 2 years maximum for a participant). | 
| Signal intensity on aMRI at the site of tumor recurrence | The difference in mean and maximum signal intensity on the individual aMRI-scans between the tumor recurrence site and the contralateral normal-appearing white matter. | The time frame is until tumor recurrence occurs (follow-up for this study will last 2 years maximum for a participant). |