Impact of MGMT Promoter Methylation Status on Tumor Dynamics during Weekly Adaptive Radiotherapy for Glioblastoma

Abstract

<h3>Purpose/Objective(s)</h3> Adaptive MRI-guided radiotherapy (RT) on a 1.5T MR-Linac using a reduced clinical target volume (CTV) of 5mm instead of the 15mm standard for glioblastoma (GBM) is currently being evaluated on the UNITED clinical trial (NCT04726397). We present a preliminary comparison of morphological changes during a course of adaptive RT with concurrent temozolomide between tumors with MGMT promotor methylation (MGMT-m) and those that are MGMT promoter unmethylated (MGMT-um). <h3>Materials/Methods</h3> The first 30 patients with GBM (all IDH wildtype) enrolled on the UNITED trial were analyzed. RT consisted of 60 Gy in 30 fractions (n=12) or 40 Gy in 15 fractions (n=18) (Fx). Expansions on the gross tumor volume (GTV) consisted of a 5 mm CTV with the provision to include FLAIR hyperintense areas at-risk and a 3 mm planning target volume (PTV). A pre-treatment reference plan was developed from a standard planning MRI (FxRef) followed by weekly on-line fully adaptive re-planning at Fx1, Fx6, Fx11, etc., based on a gadolinium contrast-enhanced MRI acquired on the MR-Linac. Remaining fractions were image-guided by pre-beam-on onboard non-contrast MRI, to ensure stability of the treatment volumes. The GTV and CTV were quantified by their absolute volumes, volumes relative to the FxRef and the maximum linear distance from the edges of the reference contour at FxRef to the weekly adapted contours (migration distance, d_mig). MGMT promoter methylation status was explored as a fixed effect in a linear mixed statistical model. <h3>Results</h3> The median changes in GTV relative to FxRef at Fx1, Fx6, Fx11, Fx16, Fx21, and Fx25 in MGMT-um tumors (n=12) were 10.3%, 9.2%, 10.6%, 14.5%, 18.0% and 17.3%, respectively, while for MGMT-m (n=18) were 3.4%, 0.0%, -8.6%, -11.3%, -11.3% and -5.6% (p=0.021). A similar significant trend was observed with the CTV. With a median time interval of 6 days (range, 1-18 days) between FxRef and Fx1, the GTV increased by over 10% in 58% of MGMT-um tumors compared to only 33% of MGMT-m tumors. MGMT-um tumors had significantly larger maximum d_mig compared to tumors with MGMT-m, with a median d_mig of 9.6 mm vs. 5.8 mm, respectively (p=0.018). The maximum GTV migration distance was greater than 5, 10 and 15 mm in 83%, 50% and 17% of MGMT-um tumors but only 56%, 11% and 0% for MGMT-m tumors, respectively. <h3>Conclusion</h3> MGMT-um GBM exhibited significant changes in morphology and migration distance between the time of treatment planning to the first treatment fraction, as well as throughout a course of RT. In this population, our results support a greater frequency of imaging and plan adaptation when applying personalized reduced CTV margins.