Is Mean Radiation Dose to the Subventricular Zone a Prognostic Indicator?

Abstract

It has been postulated that the capability of glioblastoma (GBM) to withstand multi-modality treatment is driven by a niche of mutated neural progenitor cells (NPCs) called cancer stem cells (CSCs) residing in the subventricular zone (SVZ). Previous studies suggest that increased radiation dose to the SVZ is associated with improved outcomes while others have not found this association and underline the importance of NPC preservation during radiation therapy (RT). Given this conflicting data, we examined the relationship between dose to the SVZ and treatment outcomes in GBM patients treated with surgery followed by RT- Temozolomide (TMZ). Patients with GBM who completed a course of RT-TMZ at single institution between 2010 and 2016 were included. All patients were >18 years old, underwent surgery followed by intensity modulated radiation therapy (IMRT) to 60 Gy in 30 fractions with concomitant TMZ, and had a minimum of 6 month follow-up. Time to tumor recurrence was defined as the date that tumor progression on Magnetic Resonance Imaging (MRI) was documented by both the neuro-radiologist and treating neuro-oncologist. Dates of patients’ deaths were obtained from medical records and the Social Security Death Index. SVZ contours were delineated on the fused computed tomography simulation and post-surgical MRI T1-weighted images and defined as the lateral wall of the lateral ventricles using a 5-mm brush. Mean doses were calculated for ipsilateral, contralateral and bilateral SVZ regions. Log Rank tests, cox regression and backward stepwise model selection were employed for data analyses. 109 patients (median age 62 years) were identified. 45.9% underwent gross total resection, 43.1% subtotal resection, and 11% biopsy. At diagnosis, 18.3% of patients were RPA Class III, 47% RPA Class IV, 16% Class V. 66.1% of patients had tumor in contact with the SVZ. The median ipsilateral, contralateral, and bilateral mean doses were 57.8 Gy, 37.5 Gy, and 47.1 Gy, respectively. At a median follow up of 14.4 months, the 1 and 2-year progression-free survival (PFS) and overall survival (OS) rates were 27.5%, 6.4%, 67.0% and 21.1%, respectively. There was a trend of worse OS with higher mean ipsilateral SVZ dose in patients who received >57.8 Gy (14.5 vs 19.4 months, p=0.06). Lack of SVZ involvement at diagnosis was associated with an OS benefit on univariate analysis (16.8 vs 13.8 months, p=0.03). On multivariate analysis, lower RPA class and greater extent of resection were associated with improved PFS. Younger age, higher performance status, greater extent of resection, and MGMT methylation were associated with improved OS. This study suggests a trend towards worse OS with higher mean ipsilateral SVZ doses and significantly worse OS with SVZ involvement. Additionally, our study continues to underline the importance of RPA class, age, performance status, resection type and MGMT status as the most important prognostic indicators of survival outcomes.