Impact of iMRI on the Extent of Resection in Patients With Newly Diagnosed Glioblastomas

Study Overview
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Brief Summary
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Standard treatment of glioblastomas (GBMs) consists of microsurgical resection followed by concomitant chemoradiation. The extent of resection is one of the most important prognostic factors with significant influence on the survival of patients. State of the art technique to achieve the most radical resection possible in conventional surgery is fluorescence-guidance with 5-aminolevulinic acid (5-ALA). If available, intraoperative MRI (iMRI)-guided tumor resection enables an intraoperative resection control and subsequent continuation of surgery if contrast enhancing tumor remnants are found. Therefore a more radical resection and longer survival of patients might be possible. To date no comparison of these two leading technologies for GBM-surgery is available to identify the best surgical therapy of this fatal disease and to justify significant healthcare-economic differences between both technologies. Goal of this study is to assess the value of iMRI guidance in the resection of GBMs in comparison to conventional 5-ALA microsurgery. Primary endpoint is the number of total resections (no residual contrast enhancement) in the postoperative MRI (T1+CM within 48 hours after surgery) in each group. Secondary endpoints are perioperative clinical data, progression free survival, patients' clinical condition and overall survival. The study design was chosen to be a parallel-group approach to compare iMRI and 5-ALA centers (n=13) to exclude possible bias which might be found by randomizing patients within individual iMRI centers and to have surgeons with the most experience possible in use of each respective technology.

Official Title
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Impact of iMRI on the Extent of Resection in Patients With Newly Diagnosed Glioblastomas - A Prospective Multicenter Parallel Group Clinical Trial

Conditions
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Glioblastoma

Intervention / Treatment
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* Device: iMRI-guided surgery
* Drug: 5-ALA-guided surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In MRI suspected primary singular untreated GBM Planned total resection of the tumor according to the surgeon Patient ≥18 years, ≤80 years Preoperative KPS ≥ 60%, American Society of Anesthesiologists (ASA) score 1 and 2 Patients' informed consent Exclusion Criteria: Tumors of the midline, basal ganglia, cerebellum, brain stem, eloquent areas Multifocal glioblastoma Substantial (>50%), non-contrast enhancing tumor areas suggesting low-grade glioma with malignant transformation Contraindications to MRI Inability to give consent because of language barrier or dysphasia Histological diagnosis other than Glioblastoma multiforme WHO °IV Increased risk of thrombosis (e.g. Factor V Leiden) Pregnancy or breast feeding Hypersensibility for 5-ALA oder porphyrins Acute or chronic Porphyria Renal insufficiency Hepatic insufficiency High likelihood of inability to receive adjuvant therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: iMRI-guided surgery<br>Resection of Glioblastomas with iMRI-guidance | Device: iMRI-guided surgery<br>* For iMRI-guided glioma resections the surgery can be paused and a direct intraoperative resection control is possible by performing an intraoperative MRI scan. If residual tumor is found, the resection might be continued.<br>|
| Active Comparator: 5-ALA-guided surgery<br>Resection of Glioblastomas with 5-ALA-fluorescence-guidance | Drug: 5-ALA-guided surgery<br>* For 5-ALA guided glioma resections patients have to drink 100ml of a solution with 5-Aminolevulinic acid 4-6 hours before surgery. Intraoperatively the light source of the surgical microscope can be switched to a certain wave length to enable fluorescence of the glioma cells, which helps resecting the tumor as radical as possible.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete resections in the postoperative MRI (T1+/-CM) within 48 hours after surgery | Completeness of resection in the postoperative MRI within 48h after surgery. Blinded analysis by an independent radiologist. | 48 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients' clinical condition (KPS) | -KPS clinical scoring | preoperative (day before surgery), 1 week, 3Months, 6Months, 9Months, 12Months after surgery | 
| Patients' clinical condition (NIHSS) | -NIHSS stroke score | preoperative (day before surgery), 1 week, 3Months, 6Months, 9Months, 12Months after surgery | 
| Patients' clinical condition (QoL) | -quality of life (EORTC) questionnaire | preoperative (day before surgery), 1 week, 3Months, 6Months, 9Months, 12Months after surgery | 
| ICU and hospital stay after surgery | -ICU and overall hospital stay after surgery | Time of hospital stay (average 7days) | 
| Patients' adjuvant treatment | -adjuvant treatment each patient has received | 3Months, 6Months, 9Months, 12Months after surgery | 
| Recurrent tumor growth (RANO criteria) | -recurrent tumor growth (RANO criteria) according to local tumor boards and independent blinded analysis | 3Months, 6Months, 9Months, 12Months after surgery | 
| Follow-up imaging | -follow-up imaging 3, 6, 9, 12 months postoperative incl. independent blinded analysis | 3Months, 6Months, 9Months, 12Months after surgery | 
| Histology | Histological analysis | 1 week after surgery | 
| MGMT (O6-methylguanine-DNA-methyltransferase) analysis | MGMT promoter analysis (Routine molecular diagnostics) | 1 week after surgery | 
| IDH-1 (isocitrate dehydrogenase) analysis | IDH-1 mutation analysis (Routine molecular diagnostics) | 1 week after surgery | 
| Progression-free survival (PFS) | 6M&12M-PFS | Day of surgery - 6 months - 12 months | 
| Overall survival (OS) | OS of patients | Day of surgery - Death of patient (Max. 10 years follow-up) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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5-ALA, Intraoperative MRI, Extent of resection