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.

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 biology rather than only showing anatomical information through conventional MRI. A workflow has been developed to create a CTV based on these aMRI scans (CTVbio) 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 first tumor recurrence by the radiotherapy plan) and the expected radiation dose to organs at risk between the CTVbio and the 1.5-cm CTV. It is hypothesized that the CTVbio 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 CTVbio, compared to the clinical radiotherapy plan (1.5-cm CTV), is lower than 0.20.

Secondary objectives:

• To illustrate a reduction in dose to organs at risk with a radiotherapy plan based on a conceptual CTVbio 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. In clinical practice at the Erasmus MC, not all patients get an MRI-scan prior to radiotherapy. Patients who would not have received an MRI-scan prior to radiotherapy, will get an extra MRI-scan when they participate in this study. 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 CTVbio 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 CTVbio. 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: Patients will have an extension to their standard radiotherapy planning MRI-scan taken for regular clinical care (Brain tumor MRI protocol: ± 25 minutes). Patients who would not have received an MRI-scan prior to radiotherapy, will get an extra MRI-scan when they participate in the study. 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 CTVbio.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: For patients who will already undergo an MRI-scan for radiotherapy, the burden will be an extended MRI-scan (+20 minutes; the total scan time will be 45 minutes instead of 25 minutes). There is no benefit for these patients. For patients who would not have received an MRI-scan prior to radiotherapy, the burden of participation will be an extra MRI-scan (total scan time: 45 minutes) with additional contrast injection. The dosage and administration are similar to the standard Brain tumor MRI protocol, which has often already been acquired before in these patients. The radiation oncologist may decide to use the conventional MRI-scan from this study MRI for target delineation if they believe it has an added value. The use of the conventional MRI-scans is recommended in the ESTRO-EANO guidelines, but is not routinely done for all patients at Erasmus MC. The advanced MRI-scans investigated in this research will not be used by the radiation oncologist

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 or 10x3.4Gy).

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 brain;
• Unable to give informed consent

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