A Phase 2 Study of Multiparametric Magnetic Resonance Imaging-Guided High-Dose Response-Adaptive Radiation Therapy with Concurrent Temozolomide in Patients with Newly Diagnosed Glioblastoma: Results from an Interim Analysis

Purpose Biologically-informed radiation therapy (RT) targeting an adversely prognostic hypercellular/hyperperfused imaging phenotype in patients with newly diagnosed glioblastoma (GBM) may improve outcomes by identifying emerging regions of treatment resistance associated with overall survival, and is under investigation in an ongoing phase 2 trial (NCT04574856) of individualized, response-adaptive RT. Methods and Materials In this single-arm phase 2 study, patients with newly diagnosed GBM after resection undergo dose-intensified chemoradiation targeting the residual hypercellular (TVHCV, 2 SD above mean intensity contralateral normal brain) and hyperperfused tumor volume (TVCBV, 1 SD above contralateral normal frontal lobe gray matter) identified using high b-value diffusion-weighted and dynamic contrast-enhanced perfusion magnetic resonance imaging. The combination of TVHCV and TVCBV (TVHCV/TVCBV) is treated to 50 Gy in 20 fractions (2.5 Gy/fraction), and after mid-RT reassessment, the persistent and developing TVHCV/TVCBV is treated to 30 Gy in 10 fractions (3 Gy/fraction). The primary endpoint is improvement in overall survival, with planned interim safety analysis. Results At interim analysis, 16 of 30 patients were enrolled. Median age was 58 years (range, 29-75) and 69% were male. No patient underwent biopsy only, and 50% had gross total resection; 19% had O6-methylguanine-DNA methyltransferase methylated tumors. Median TVHCV/TVCBV was 6.9 cc (range, 1.9-42.8) pre-RT and 30% (range, 1%-72%) was nonenhancing. By mid-RT, TVHCV/TVCBV was reduced to 4.2 cc (range, 0.8-34.3) and 47% (range, 3%-74%) was nonenhancing. The TVHCV/TVCBV persisting from pre-RT to mid-RT was 2.3 cc (range, 0-24.2), with an additional 1.8 cc (range, 0.3-20.6) newly developing outside of the initial region. All patients underwent adaptive replanning for boost without interruption. Planned interim analysis determined an acceptable rate of neurologic toxicity and safety to continue enrollment. Conclusions Individualized, response-adaptive chemoradiation using an advanced imaging biomarker to assess emerging and especially nonenhancing regions of treatment resistance in patients with GBM is feasible, with short-term safety and longer-term efficacy outcomes anticipated with completion of accrual.