The clinical relevance of margins in frameless stereotactic radiosurgery for intact brain metastases: A randomized trial of 0 vs 2 mm margins.
Authors: Juloori Aditya , Arshad Muzamil , Wong Anthony C. , Farrey Karl , Yenice Kamil , Collins John , Aydogan Bulent , Usuki Kenneth , Pitroda Sean P. , Milano Michael T. , Chmura Steven J. 
Published: June 2023

TPS2080 Background: Stereotactic radiosurgery (SRS) is a commonly utilized treatment strategy for brain metastases which offers a relatively low rate of morbidity and high rate of local control. SRS delivers an ablative dose of radiation in a single session to a limited target volume while minimizing dose to surrounding normal tissue. Image-guided linear accelerator (LINAC)-based frameless SRS has enabled effective, safe delivery of high dose radiation without the discomfort and logistical complications associated with use of a rigid frame. Localization errors during frameless SRS vary depending on the specific LINAC configuration and immobilization technique. The clinical relevance of potential inaccuracies in localization with frameless SRS remains controversial. When employing frameless systems, many centers will account for set-up uncertainties by adding a circumferential margin of 1-3 mm around the GTV to create a planning target volume (PTV). This PTV expansion ensures adequate tumor coverage if target motion occurs, but exposes more normal brain tissue to radiation and may increase the risk of adverse events, chiefly radionecrosis. There is limited literature available to guide radiation oncologists on the appropriate choice of margin size, if any, for frameless SRS. There are no randomized data evaluating the safety and efficacy of omitting the margin entirely. Given the paucity of data examining margin extent and the potentially significant consequences for treatment efficacy and morbidity, we propose a phase II randomized prospective clinical trial evaluating 0 vs 2 mm marginal GTV to PTV expansions for treating patients with intact brain metastases with frameless SRS. Methods: Eligible patients will have brain metastases from solid tumors with ECOG performance status of 0-2 and life expectancy of >3 months. Patients must have 1 - 5 newly diagnosed well-circumscribed, measurable intraparenchymal brain metastases with maximum tumor diameter ≤3.0 cm. At least one lesion must be ≥ 0.5 cm in maximum diameter to be considered measurable. SRS will be delivered in a single fraction to either 20 Gy or 18 Gy dependent on tumor size. Importantly, PTV margin randomization is blinded and occurs after delineation of tumor volume by radiation oncologist to not bias contouring based on knowledge of margin randomization. This is two-armed multi-center phase II randomized controlled trial. The trial is powered to demonstrate non- inferiority of the experimental arm with regard to the primary endpoint of local PFS at 6 months and the superiority of the experimental arm with regard to the secondary endpoint of radionecrosis or pseudoprogression. We expect the total study duration, from the start of screening for the first participant until the end of follow-up for the last one, to be approximately six years. We plan to accrue 166 patients to this trial at all sites. Clinical trial information: NCT02747303 .