A phase II study of multiparametric MR-guided high-dose response-adaptive radiotherapy with concurrent temozolomide in patients with newly diagnosed glioblastoma: Results from an interim analysis.

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 (XXX) of individualized, response-adaptive RT.

Methods: In this single-arm phase II study, patients with newly diagnosed GBM following resection undergo dose-intensified chemoradiation (chemoRT) targeting the residual hypercellular (TV, 2 SD above mean intensity contralateral normal brain) and hyperperfused tumor volume (TV, 1 SD above contralateral normal frontal lobe grey matter) identified using high b-value diffusion-weighted and dynamic contrast-enhanced perfusion MRI. The combination of TV and TV (TV/TV) is treated to 50 Gy in 20 fractions (2.5 Gy/fraction), and following mid-RT reassessment, the persistent and developing TV/TV is treated to 30 Gy in 10 fractions (3 Gy/fraction). The primary endpoint is improvement in OS, 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 MGMT methylated tumors. Median TV/TV was 6.9 cc (range, 1.9-42.8) pre-RT and 30% (range, 1-72%) was nonenhancing. By mid-RT, TV/TV was reduced to 4.2 cc (range, 0.8-34.3) and 47% (range, 3-74%) was nonenhancing. The TV/TV 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 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.

Conclusion: Individualized, response-adaptive chemoRT 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 and longer-term efficacy outcomes anticipated with completion of accrual.