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Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and survival[1].

In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 180 patients having undergone biopsy or surgery were randomized to 2 arms. Arm A was the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and six months of TMZ maintenance).  Arm B was the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA>2 and contrast-enhancing lesions or resection cavity. Stratification was performed on surgical (biopsy versus surgery) and MGMT status. An online prospective quality control (QC) of volumes and dose was performed in the experimental arm. The main objective was overall survival, estimated by the Kaplan-Meier method in each randomization arm and compared by the Logrank test, as well as by the Cox model adjusted on the stratification factors and on the already known prognostic factors.

There was no significant difference between the 2 groups regarding characteristics: gender; age median age, weight, PS, 46% were MGMT unmethylated, 85% were surgically resected.

Initial tumors were more frequently <30mm diameter in arm A (36% vs 27%) (p=0.0316).

General, neurological and hematological secondary effects were comparable between the 2 arms, except more frequent grade 1-2 cephalalgia in arm A(59.1% vs 42.9%,p= 0.0075) and more frequent grade 1-2 neurological deficit in Arm B ( 45.7% vs 35.4%,p=0.0043). After a median follow-up of 43.7 Months (95% IC [35.8; 45.8]), no statistical difference between arms were observed for OS  (HR=0.90 [0.64;1.27], p=0.5526)) and PFS (HR=1.09 [0.80;1.48], p = 0.6027). Overall survival (OS) and Progression Free Survival ( PFS)  were comparable between arm A and B, respectively  OS 22.6 months versus 22.2 months (p=0.55) and PFS  8.6 vs 7.8 months (p=0.6) 

In this dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging, dose increase was well tolerated. Overall survival was not improved. This study yields a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging to participate in the efforts in deciphering the pathways of pseudoprogression and radioresistance of glioblastoma.

Trial registration: NCT01507506

[1] : Laprie et al, BMC Cancer 2019 Feb 21;19(1):167.