A Phase 2 Study of Dose-intensified Chemoradiation Using Biologically Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma

Abstract

Purpose: We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TV_HCV) and hyperperfused (TV_CBV) tumor volumes would improve outcomes in patients with glioblastoma.

Methods and materials: This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TV_HCV/TV_CBV >1 cm³, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TV_HCV/TV_CBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TV_HCV/TV_CBV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative ¹¹C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test-Revised.

Results: Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TV_HCV alone, and 13 patients were boosted to both TV_HCV/TV_CBV. Gross or subtotal resection was performed in 87% of patients; 22% were O⁶-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TV_HCV/TV_CBV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TV_HCV/TV_CBV decreased to less than the median volume (3 cm³) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the ¹¹C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy.

Conclusions: Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy.