Single-Fraction vs. Fractionated Radiosurgery and the Development of Post-Treatment Hemorrhage for Intact Melanoma Brain Metastases

Abstract

<h3>Purpose/Objective(s)</h3> To assess whether intracranial stereotactic radiotherapy fractionation is associated with increased risk of post-treatment lesional hemorrhage in patients with intact melanoma brain metastases (MBM). <h3>Materials/Methods</h3> A single institution retrospective review was performed of patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 to 2021. The presence of lesional hemorrhage was determined by multi-disciplinary neuroradiology review of magnetic resonance imaging (MRI). Dosimetric variables were reported as biologically effective doses using an estimated α/β ratio of 2.5 (BED_2.5) for melanoma to permit comparison across varying fractionation schedules. The effect of fractionation and additional prognostic factors on the rate of post-treatment development of hemorrhage was statistically analyzed using logistic regression with random effects to account for interactions between lesions of the same patient. A Cox model was used for local control (LC) with a frailty term to account for dependence between lesions. <h3>Results</h3> The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Evidence of hemorrhage prior to treatment was demonstrated in 69 of 226 metastases (30.5%). For lesions without signs of prior hemorrhage, 65 of 157 (41.4%) demonstrated evidence of hemorrhage after radiosurgical treatment. 63 of 133 lesions (47.4%) receiving single-fraction SRS demonstrated evidence of post-treatment hemorrhage versus 2 of 24 lesions (8.3%) treated with fSRT (<i>p=0.01</i>). Treatment factors including lesion size, prescription isodose line, as well as receipt of corticosteroids, targeted, or immune therapy were not predictive of hemorrhage occurrence. A larger maximum BED_2.5 was observed in lesions developing hemorrhage compared to no hemorrhage (mean 238.3 Gy vs. 211.4 Gy; <i>p=0.022</i>). LC at twelve-months was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment hemorrhage, respectively, with no local failure events observed in non-hemorrhagic lesions (<i>p=<0.001</i>). <h3>Conclusion</h3> Intact MBM without prior evidence of hemorrhage receiving single-fraction SRS were associated with an increased incidence of post-treatment hemorrhage when compared to those treated with fractionated stereotactic radiotherapy. The presence of lesion hemorrhage, either pre- or post-treatment, was associated with inferior local control. Post-treatment hemorrhage was correlated with a larger maximum BED_2.5. Further investigations of the clinical impact of lesional hemorrhage, factors influencing lesion control, as well as optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.