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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Device: iMRI-guided surgery; Drug: 5-ALA-guided surgery

• Study Type: Interventional
• Enrollment (Actual): 315
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany
    • Department of Neurosurgery, Universitätsklinikum Bonn, Bonn, Germany
  • Cologne, Germany
    • Department of Neurosurgery, Universität zu Köln, Köln, Germany
  • Dresden, Germany
    • Städtisches Klinikum Dresden Friedrichstadt
  • Düsseldorf, Germany
    • Department of Neurosurgery, Heinrich-Heine-Universität Düsseldorf, Düsseldorf
  • Erlangen, Germany
    • Department of Neurosurgery, Friedrich-Alexander-University Erlangen-Nürnberg
  • Frankfurt a.M., Germany
    • Department of Neurosurgery, Johann Wolfgang Goethe-University Frankfurt am Main
  • Göttingen, Germany
    • Department of Neurosurgery, Georg-August-Universität Göttingen, Göttingen,
  • Günzburg, Germany
    • Department of Neurosurgery, University of Ulm, Hospital Günzburg,
  • Hamburg, Germany
    • Asklepios Klinik Hamburg, Klinik für Neurochirurgie
  • Hannover, Germany
    • International Neuroscience Institute Hannover, Hannover, Germany
  • Heidelberg, Germany
    • Department of Neurosurgery, Ruprecht-Karls-University Heidelberg
  • Kiel, Germany
    • Department of Neurosurgery, University of Schleswig-Holstein, Kiel, Germany
  • Münster, Germany
    • Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Münster, Germany
  • Tübingen, Germany
    • Department of Neurosurgery, Eberhard Karls University, Tübingen,
  • Würzburg, Germany
    • Department of Neurosurgery, Julius-Maximilians-Universität Würzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. In MRI suspected primary singular untreated GBM
2. Planned total resection of the tumor according to the surgeon
3. Patient ≥18 years, ≤80 years
4. Preoperative KPS ≥ 60%, American Society of Anesthesiologists (ASA) score 1 and 2
5. Patients' informed consent

Exclusion Criteria:

1. Tumors of the midline, basal ganglia, cerebellum, brain stem, eloquent areas
2. Multifocal glioblastoma
3. Substantial (>50%), non-contrast enhancing tumor areas suggesting low-grade glioma with malignant transformation
4. Contraindications to MRI
5. Inability to give consent because of language barrier or dysphasia
6. Histological diagnosis other than Glioblastoma multiforme WHO °IV
7. Increased risk of thrombosis (e.g. Factor V Leiden)
8. Pregnancy or breast feeding
9. Hypersensibility for 5-ALA oder porphyrins
10. Acute or chronic Porphyria
11. Renal insufficiency
12. Hepatic insufficiency
13. High likelihood of inability to receive adjuvant therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: iMRI-guided surgery; Resection of Glioblastomas with iMRI-guidance	Device: iMRI-guided surgery; 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.
Active Comparator: 5-ALA-guided surgery; Resection of Glioblastomas with 5-ALA-fluorescence-guidance	Drug: 5-ALA-guided surgery; 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.

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preoperative tumor localization and resectability concerning eloquent regions	Independent blinded analysis of the preoperative imaging data by a blinded neurosurgeon with extensive experience in the resection of gliomas. Analysis will be done before the final evaluation of results. (Within 12 months)	Blinded analysis of preoperative imaging (not older than 3 days prior to surgery)

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Investigators: Principal Investigator: Constantin Roder, Dr., University Hospital Tuebingen, Department of Neurosurgery

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: February 18, 2015
• First Submitted That Met QC Criteria: February 26, 2015
• First Posted (Estimate): March 5, 2015

Study Record Updates

• Last Update Posted (Actual): October 22, 2021
• Last Update Submitted That Met QC Criteria: October 21, 2021
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: 5-ALA; Extent of resection; Intraoperative MRI
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: Nch1