18F-DOPA-PET-Guided Re-Irradiation for Recurrent High-Grade Glioma: Initial Results of a Phase II Trial

Abstract

In-field high-grade glioma (HGG) recurrence is a common challenge with limited treatment options, including re-irradiation (re-RT). Delineating re-RT target volumes is especially challenging in the setting of the VEGF-inhibitor bevacizumab, which can produce an MRI pseudo response. The radiotracer 18F-DOPA crosses the blood brain barrier and demonstrates high uptake in tumor but low uptake in normal tissue. We hypothesized that utilizing 18F-DOPA-PET with MRI for target delineation of recurrent HGG would improve progression free survival at 3 months (PFS3) compared to historical controls treated with systemic therapy only.Adults with recurrent or progressive HGG previously treated with radiation were eligible for this single-arm, phase II prospective trial. A sample size of 20 was calculated to detect a 20% improvement from the historical control PFS3 of 20%, with a power of 85.9% (alpha 0.186). Re-RT dose was 35 Gy in 10 fractions. The target volume was MRI T1 contrast-enhancement defined tumor plus 18F-DOPA-PET defined tumor (tumor/normal ratio > 1.5). Concurrent treatment with bevacizumab was encouraged but not required. Patients were followed at 1 and 3 months (primary endpoint), then every 2 months until 2 years or progression, defined by RANO criteria.Twenty patients completed treatment per protocol. Fifteen (75%) were male. Median age was 53 (range 38-69). Diagnosis was most commonly glioblastoma, IDH-wildtype (60%) or glioblastoma, IDH-mutant (20%). Prior to re-RT, 19 (95%) received previous salvage treatments including surgery (35%) and systemic therapy (90%). Bevacizumab was used prior to, during, and immediately following re-RT in 12 (60%), 14 (70%), and 16 (80%) patients, respectively. Median interval between RT courses was 21.5 months (range 5-167), with an interval > 12 months in 85%. Median MRI-defined, PET-defined, and combined tumor volumes were 17 cc (range 0-198), 14 cc (0.2-209), and 23.2 cc (4-258), respectively. MRI-defined volumes were expanded by a median 43% (0-436%) by utilizing 18F-DOPA-PET. PFS3 was 85% (95% CI: 63.2-95.8%), meeting the primary endpoint of PFS3≥40%. At data lock in January 2021 with 9.7 months median follow-up, 17 (85%) had progressed and 13 (65%) had died. Median OS from re-RT was 8.5 months, with 1- and 2-year OS estimates of 31% and 15%, respectively. Median OS from initial diagnosis was 3.7 years. Failure following re-RT was within both the MRI and PET tumor volumes in 75%, MRI only in 13%, PET only in 0%, and neither in 13%. Four (20%) patients experienced grade 3 toxicity, including CNS necrosis (n = 2, both asymptomatic with bevacizumab initiation for radiographic findings), seizures (n = 1), fatigue (n = 1), and nausea (n = 1). No grade 4-5 toxicities were observed.The 18F-DOPA-PET guided re-irradiation for progressive high-grade glioma appears safe and promising for further investigation.