Phase III Study Comparing 2 Brain Conformational Radiotherapy in Combination With Chemotherapy in the Treatment of Glioblastoma

Study Overview
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Brief Summary
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This is a multi-institutional phase III clinical study of interventional type. The trial will include 220 patients with confirmed unifocal glioblastoma over a period of 3 years + 3 years of follow up. Patients with unifocal glioblastoma (diagnosis confirmed by histology on tumoral biopsy or surgical specimen) and who meet all eligibility criteria will be randomized in one chemoradiotherapy arm : Conventional arm: 3-dimensional conformational radiotherapy + Temozolomide Experimental arm : simultaneous-integrated boost with intensity-modulated radiotherapy guided by magnetic resonance spectroscopic imaging + Temozolomide The patient monitoring will be regular and standardized. The main objective of this study is to improve overall survival of patients treated in experimental group (with simultaneous integrated boost).

Official Title
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Phase III Randomized Study Comparing 2 Brain Conformational Radiotherapy in Combination With Chemotherapy in the Treatment of Glioblastoma : Standard 3D Conformational Radiotherapy Versus Intensity-modulated Radiotherapy With Simultaneous-integrated Boost Guided by Magnetic Resonance Spectroscopic Imaging

Conditions
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Glioblastoma

Intervention / Treatment
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* Radiation: Radiotherapy
* Radiation: Experimental arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have unifocal glioblastoma (grade IV astrocytoma, WHO classification). The GBM can be: Or resectable and the patient has received curative surgery Or unresectable, and the largest tumor diameter (contrast enhancement) must be less than 5 cm on MRI In all cases, the diagnosis must be confirmed by a pathologist. In patients for whom surgery is not possible, the diagnosis is confirmed by a biopsy of tumor tissue. Methylation status of MGMT gene promoter is known Patients who have undergone resection should have received an MRI or a scan after surgery in order to visualize residual tumor. If not, the operative report must be available. Surgery or biopsy must have occurred 45 days before the start of radiotherapy. WHO ≤ 2 Age ≥ 18 years Signed Consent collected before any specific procedure in the study Patient member in a national insurance scheme Exclusion Criteria: Signs of hemorrhage on pre-radiotherapy MRI preventing a good spectrometric analysis Patient with multifocal glioblastoma Tumor located within 2 cm of the optic chiasm Patient with leptomeningeal metastases, patients prone to epileptic seizures despite treatment with anticonvulsant Patients who received other previous treatment for glioblastoma multiforme Abnormal haematological results at inclusion with: Neutrophils < 1500/mm3 Blood-platelets < 100000/mm3 Severe or chronic renal insufficiency (creatinin clearance ≤ 30 ml/min calculated using Cockroft-Gault's formula Patient unable to follow procedures, visits, examinations described in the study Any usual formal indication against imaging examinations (important claustrophobia, pace maker ...) Pregnant women or nursing mothers can not participate in the study. Women of childbearing age must have a negative pregnancy test within 72 hours prior to study entry Men and women of childbearing age must use effective contraception at study entry and throughout the study Any concomitant or previous malignant disease within 5 years prior to study entry Any prior systemic chemotherapy within 5 years prior to inclusion (for malignant disease in medical history) Any other medical conditions making the inclusion of the patient in the study inappropriate in the opinion of the investigator Patient under legal guardianship

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional arm<br>3-dimensional conformal radiotherapy + Temozolomide | Radiation: Radiotherapy<br>* Conventional arm: 3D conformational radiotherapy (arm A): 60 Gy per fractions of 2 Gy in 30 sessions on the PTV1 (contrast enhancement + 2 cm) with a linear accelerator equipped with a portal imaging. + Chemotherapy (Drug) :treatment should be combined with temozolomide during and after radiotherapy in a conventional treatment Stupp (Stupp et al. 2005), ie : during radiotherapy : Temozolomide 75 mg/m2/day by oral route every day, post radiotherapy : 6 cycles of Temozolomide oral route : 150 mg/m2/day from D1 to D5 for the 1st cycle followed by 200 mg/m2/day from D28 to D32.<br>|
| Experimental: Experimental arm<br>simultaneous-integrated boost with intensity-modulated radiotherapy guided by magnetic resonance spectroscopic imaging + Temozolomide | Radiation: Experimental arm<br>* Conformational radiotherapy with simultaneous integrated boost by intensity modulation (Arm B): 60 Gy per fraction of 2 Gy in 30 sessions on the PTV1 (contrast enhancement + 2 cm) with concomitant daily superimposed boost on spectroscopic active region (PTV2) corresponding to the ratio Cho / NAA> 2 + 0.7 mm + contrast enhancement + 3mm. The PTV2 will receive a daily dose of 2.4 Gy for a cumulative dose of 72 Gy Only irradiation with simultaneous integrated boost are allowed + Chemotherapy (Drug) :treatment should be combined with temozolomide during and after radiotherapy in a conventional treatment Stupp (Stupp et al. 2005), ie : during radiotherapy : Temozolomide 75 mg/m2/day by oral route every day, post radiotherapy : 6 cycles of Temozolomide oral route : 150 mg/m2/day from D1 to D5 for the 1st cycle followed by 200 mg/m2/day from D28 to D32.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival defined as the time from randomization to the date of death or date of last follow-up news (censured data) |  | 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival, defined as the time from randomization to the date of progression or death |  | 8 years | 
| Safety evaluated according to the classification of NCI CTCAE (Common Terminology Criteria for Adverse Events)V3.0 |  | 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, Radiotherapy, Intensity modulated radiation therapy (IMRT), Magnetic resonance spectroscopic imaging (MRSI)