The Feasibility of Dose-Escalated Radiation Therapy for Glioblastoma Using Biological Image Guided Adaptive Radiotherapy (BIGART).

PURPOSE/OBJECTIVE(S): Radiotherapy dose escalation (DE) for glioblastoma (GBM) has been an area of active research. We aimed to study the imaging changes within residual gross tumor volumes (GTV) through the course of concurrent chemo-radiotherapy (CCRT) using multiparametric magnetic resonance imaging (mpMRI). Diffusion, perfusion and chemical exchange saturation transfer (CEST) characteristics of the tumor and its microenvironment were investigated to identify a GTV subvolume potentially associated with radio resistance. We used biological image-guided adaptive radiotherapy (BIGART) to study the feasibility of DE to this GTV subvolume using either photon or proton beam therapy (PBT).

MATERIALS/METHODS: We prospectively identified GBM patients with >5cc residual tumor post-resection who were candidates for radical CCRT (60 Gy in 30 daily fractions over 6-weeks with concurrent temozolomide 75mg/m2 daily). We observed the imaging changes with serial mpMRI scans done at baseline, after 2, 4 and 6-weeks of CCRT. Regions of interest (ROIs) within the GTV associated with the following abnormal values at week 2 were identified: apparent diffusion coefficient (ADC): 750-1000 ×10-6 mm2/s; relative cerebral blood volume (rCBV): 1.75-6; and APT-w CEST signal intensity >1.79%. The overlap regions of these ROIs were defined as a novel biological target volume (BTV), identifying the potential area of maximal radioresistance. An in silico study was performed using a technology company's treatment planning system to evaluate the feasibility of planning adaptive treatment to the BTV to total dose of 75 Gy in 30 fractions. This is given in two phases: 30 Gy/15# to the whole PTV as per standard practice, followed by a simultaneous integrated boost (SIB) of 45 Gy/15 fractions while maintaining the dose to the rest of the of the PTV to 60 Gy. Either photons or PBT were used to keep doses to organs at risk (OARs) within standard clinical tolerances.

RESULTS: Nine patients were recruited for this analysis and a total of 27 mpMRI scans were studied. Median BTVs to GTVs ratio was 35% (range 22-47%). Volumetric-modulated arc (VMAT) photon and PBT adaptive plans for dose escalation to BTVs were created in all cases whilst maintaining OAR tolerances. Both VMAT and PBT provided acceptable target coverage with average BTV-PTV D98% of 73 Gy (range 71.5-73.8 Gy) and average D2% of 76 Gy (range 75.4-77 Gy) while effectively sparing OARs. Sharper dose gradient between DE-BTV and PTV was achieved with VMAT. PBT was particularly advantageous in minimizing the low-dose spillage outside the BTV.

CONCLUSION: We hereby propose a platform for adaptive radiotherapy to GBM tumors with biological-image guidance through the utilization of mpMRI to evaluate the tumor and its microenvironment during CCRT. We identified thresholds for tumor sub volumes showing the most resistant imaging features and created precise BTVs that allowed for dose escalation. PBT represents an additional useful tool for BIGART planning that will be investigated further in our ongoing work.