Impact of [11C]-Methionine PET/MRI for Individual Tailoring Postoperative Radiochemotherapy for Glioblastoma Multiforme

Overview

Local recurrence is a major problem of clinical treatment of glioblastoma multiforme (GBM). Today a very sensitive imaging method to detect glioblastoma is \[11C\]MET Positron emission tomography (PET), where in some patients also tumour manifestations can be detected that are not visible in MRI investigations. The aim of the study is to investigate the association of high \[11C\]MET tracer uptake before postoperative radiochemotherapy and concurrent temozolomide (TMZ) with time to recurrence in patients with glioblastoma multiforme. Also site of recurrence will be correlated with the \[11C\]MET imaging before and early during radiochemotherapy. All imaging information will be included in treatment planning or treatment decisions. The study provides a basis for later radiation dose escalation trials on the base of \[11C\]MET imaging.

The current study aims to investigate the association of high \[11C\]MET tracer uptake before postoperative radiochemotherapy and concurrent temozolomide (TMZ) with time to recurrence in patients with glioblastoma multiforme (GBM). \[11C\]MET-PET is expected to provide diagnostic (quantitative and spatial information) as well as prognostic information, to monitor treatment, to help stratification of patients for radiotherapeutic interventions such as dose-painting in order to optimize clinical applications and potentially improve the treatment outcome. This study aims to provide the basis (e.g. optimal threshold value, sensitivity, specificity of MET uptake) for later intervention trials for treatment intensification, e.g. proton boost irradiation based on specific biomarkers. The trial is a one-arm single-center, non-randomized observational (biomarker) study. After resection or biopsy, patients with newly diagnosed glioblastoma multiforme will receive a \[11C\]MET-PET/MRI scan before start of concurrent radiochemotherapy (\~1-4 weeks after surgery). A fusion with the planning CT for irradiation treatment planning will be performed. Postoperative radiotherapy will be applied in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total dose of 60 Gy (50 Gy and a boost of 10 Gy), with concomitant administration of daily Temozolomide (75 mg/m2 p.o.) from the 1st day to the last day of radiotherapy. Follow up with \[11C\]MET-PET/MRI will be performed every 3 months until recurrence or until death of the patient. The uptake of \[11C\]MET-PET (as standard uptake value - SUV) in tumour and in normal contralateral grey matter before start of concurrent radiochemotherapy will be determined. For each tumour, the ratio between tracer uptake in the tumor and contralateral gray matter will be calculated (lesion-to-gray matter ratio \[l/g\]). Primary end point will be time to recurrence (TTR) as function of \[11C\]MET uptake before chemoradiotherapy. Secondary endpoints will be overall survival; toxicity; C-Index/ROC curve (sensitivity, specificity, optimal threshold for normal/tumour tissue index), necrosis rate; site of recurrence. The primary analysis will use the Cox proportional hazard model to establish the linear association between \[11C\]-MET and time-to-recurrence using a one-sided alpha = 0.1. Parallel translational studies with orthotopic GBM xenografts (generated from the patients material in the trial) in nude mice will be performed in our laboratory to evaluate \[11C\]MET-PET as a tool for tailoring high precision radiotherapy. Histological, biological and genetic studies are planned to validate the imaging finding and to explore the underlying mechanisms.