Amino-acid PET Versus MRI Guided Re-irradiation in Patients With Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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This study is designed to evaluate the impact of radiotherapy target volume delineation based on AA-PET compared to target volume delineation based on contrast enhanced T1 weighted MRI (T1Gd-MRI) on the clinical outcome of patients with recurrent glioblastoma (GBM) as well as concerning therapeutic safety of the respective strategy.

Detailed Description
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The higher sensitivity and specificity of amino-acids (L-[methyl-11C]-methionine, MET and O-(2-(1)-Fluoroethyl)-L-tyrosine, FET) positron emission tomography (AA-PET) in the diagnosis of gliomas in comparison to computed tomography (CT) and magnetic resonance imaging (MRI) was demonstrated in many studies and is the rationale for using them in target volume delineation of these tumors. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI in gross tumor volume (GTV) delineation for treatment planning. A small prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET or single photon emission tomography (AA-SPECT) were integrated in target volume delineation, in comparison to patients treated using CT/MRI alone (Grosu et al. 2005). However, there are no randomized studies demonstrating the impact of AA-PET based irradiation treatment on the clinical follow-up in comparison to a traditional MRI/CT based treatment. The goal of this study is to evaluate the impact of radiotherapy target volume delineation based on AA-PET (new strategy) on the clinical outcome of patients with recurrent glioblastoma (GBM) compared to target volume delineation based on contrast enhanced T1 weighted MRI (T1Gd-MRI) (traditional, established strategy). Concerning therapeutic safety, the topography of recurrence outside the primary target volume as well as the localization of necrosis after the re-irradiation will be determined. All side effects will be assessed by CTCAE version 4.0 and the safety analyses will present the worst grade of acute and late side effect by treatment arm for the whole study period (treatment and follow up). Patients will be asked to complete a quality of life (QoL) questionnaire (as assessed by the E-ORTC QLQ-C15 PAL) in regular time intervals. This will be the first phase II randomized study evaluating the impact of molecular imaging on outcome after radiotherapy in brain tumor patients. Another goal of the technical part of this study is the development of a standardized physical-technical methodology for the integration of AA-PET and other imaging biomarkers in tumor volume delineation in radiation therapy.

Official Title
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Amino-acid PET Versus MRI Guided Re-irradiation in Patients With Recurrent Glioblastoma Multiforme - a Randomised Phase II Trial

Conditions
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Recurrent Glioma (Glioblastoma Multiforme)

Intervention / Treatment
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* Radiation: Radiation Therapy
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Local recurrence of GBM (WHO grade IV) and either not eligible for tumor resection or with macroscopic residual tumor after resection of recurrent GBM Recurrent tumor visible on AA-PET and MRI-T1-Gd with the diameter measuring 1 cm to 6 cm by either technique Target volume definition possible according to both study arms Previous radiation therapy of the primary with a maximal total dose 60 Gy At least 9 months since the end of pre-irradiation and randomisation At most 2 prior chemotherapy regimes Start of radiation therapy possible within 2 weeks from AA-PET Karnofsky Performance Score (KPS) ≥ 70% Age ≥ 18 years Written informed consent (IC) obtained Exclusion Criteria: - No histological confirmation of Glioma at initial diagnosis) Recent (≤ 4 weeks before IC) histological result showing no tumor recurrence No recurrent tumor detectable on last AA-PET or MRI-T1-Gd Technical impossibility to use existing AA-PET for RT-planning No prior radiation treatment to the primary tumor less than 9 months between the end of first radiation treatment and randomisation more than 2 previous chemotherapy regimes or previous treatment with Avastin or other molecular targeted therapies less than 2 weeks between application of chemotherapy and randomisation additional chemotherapy or molecular targeted therapy or further surgery planned before diagnosis of further tumor progression after study intervention pregnancy, nursing or patient not willing to prevent pregnancy during treatment

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 |
| --- | --- |
| Experimental: Arm A: AA-PET based target volume delineation<br>Experimental intervention (Arm A): High-precision re-irradiation. Target volume delineation based on AA-PET. | Radiation: Radiation Therapy<br>* Experimental intervention (Arm A): High-precision re-irradiation (stereotactic fractionated radiation therapy (SFRT) and/or image guided radiation therapy, (IGRT), total dose 39 Gy, 3 Gy/d, 5x/ week. Target volume delineation based on AA-PET: GTV = AA uptake on PET, clinical target volume (CTV) = GTV+3mm, PTV = CTV+2mm<br>|
| Active Comparator: Arm B: T1Gd-MRI based target volume delineation<br>Control intervention (Arm B): High-precision re-irradiation. Target volume delineation based on T1Gd-MRI. | Radiation: Radiation Therapy<br>* Control intervention (Arm B): High-precision re-irradiation (SFRT and/or IGRT), total dose 39 Gy, 3 Gy/d, 5x/ week. Target volume delineation based on T1Gd-MRI: GTV = contrast enhancement on T1Gd-MRI, CTV = GTV+3mm, PTV = CTV+2mm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) |  | 6 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Kaplan-Meier: Performed on the per protocol population - all patients who are eligible and have started their allocated treatment | 1 year after randomisation | 
| Volumetrical assessment of GTV and PTV | Volumetrical assessment of delineated gross tumor volume (GTV) and planning target volume (PTV) based on AA-PET vs. delineated GTV/PTV based on T1-Gd-MRI. | Interim analysis | 
| Topography of recurrence | local relationship between recurrence and AA-PEt and MRI-derived TV | Follow up (end of radiotherapy, 6 and 12 weeks after radiotherapy, then every 3 months) | 
| Localisation of necrosis after re-irradiation |  | Follow up (end of radiotherapy, 6 and 12 weeks after radiotherapy, then every 3 months) | 
| Rate of long-term survivors | Rate of long-term survivors = Survivors > 1 year after randomisation | Follow up | 
| Quality of Life (QoL) | QoL assessed by the EORTC QlQ-C 15 PAL questionnaire | During Radiotherapy and Follow Up | 
| Rate of side effects | Assessed according to CTCAE | During Radiotherapy and Follow Up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AA-PET, T1-Gd-MRI, re-irradiation, recurrent glioma