Interim analysis of a phase ii study of multiparametric mr-guided high-dose response-adaptive radiotherapy with concurrent temozolomide in patients with newly diagnosed glioblastoma

Abstract BACKGROUND Biologically-informed radiotherapy (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 survival (OS), and is under investigation in an ongoing Phase II trial (NCT04574856) of individualized, response-adaptive RT. METHODS In this single-arm phase II study, patients with newly diagnosed GBM following resection undergo dose-intensified chemoradiation targeting the residual hypercellular (TVHCV, mean contralateral normal brain+2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal grey matter+1SD) identified using high b-value diffusion-weighted and dynamic contrast-enhanced perfusion MRI. The combination of TVHCVCBV (TVHCVCBV) is treated to 50 Gy in 20 fractions (2.5 Gy/fraction), and following mid-RT reassessment, the persistent and developing TVHCVCBV is treated to 30 Gy in 10 fractions (3 Gy/fraction). The primary endpoint is improvement in OS, with planned interim safety analysis. RESULTS Since October 2020, 16 of 30 patients have been enrolled. Median age was 58 years (range, 29-75) and 69% were male. No patient underwent biopsy only, and 50% had gross total resection; 23% had MGMT 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, TVHCVCBV was reduced to 4.2 cc (range, 0.8-34.3) and 47% (range, 3-74%) was nonenhancing. The TVHCVCBV persisting from pre- 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 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. CONCLUSION Individualized, response adaptive RT using an advanced imaging biomarker to assess emerging and especially non-enhancing regions of treatment resistance in patients with GBM is feasible, with short term safety in an early cohort and longer-term efficacy outcomes anticipated with ongoing accrual.