Efficacy and Safety of Stereotactic Radiosurgery for Brainstem Metastases: A Systematic Review and Comparative Meta-Analysis

Abstract

Unchecked growth of brainstem metastases (BSM) can lead to acute morbidity and death. Stereotactic radiosurgery (SRS) remains the only local therapy for BSM, but the safety and efficacy of this approach are not fully understood, partly because BSM patients are excluded from many clinical trials. The aim of this study was to perform a systematic review and comparative meta-analysis of studies of SRS for BSM in the context of prospective trials of SRS or molecular/targeted therapy for non-brainstem brain metastases (BM).A comprehensive search of the PubMed and Embase databases was performed on 12/6/19 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to identify relevant studies of SRS for BSM, and prospective trials of SRS or molecular/targeted therapy for BM. Outcomes included 1-year local control (LC), objective response rate (ORR, defined as partial or complete response), 1-year overall survival (OS), neurologic death rate, and CTCAE 4.0 grade 3-5 adverse events. Pooled binomial proportions were estimated using a random effects model. Study heterogeneity was assessed using I2 and τ using the maximum likelihood method and the Wald test.A total of 32 retrospective studies with a study level median follow up of 8.5 months (interquartile range [IQR] 5.7-11.0) were identified comprising 1446 patients undergoing SRS for 1590 B.M.. Median BSM volume was 0.40cm3 (study level IQR 0.20-1.05cm3), and SRS treatments were delivered using fixed-frame radiosurgery (73.8%, median dose 16 Gy, range 6-30 Gy, median isodose 50%), linear accelerator (17.2%, median dose 13.7 Gy, range 11.1-39.0 Gy in 1-13 fractions, median isodose 85%), or robotic-arm radiosurgery (9%, median 17.5 Gy, range 16-24 in 1-5 fractions, median isodose 80%). Pooled 1-year LC was 86% (95% CI 83-88%, I2 = 38%), 1-year OS was 33% (30-37%, I2 = 35%), and the rate of grade 3-5 toxicity was 2.4% (1.5-3.7%, I2 = 33%). On univariate meta-regression, melanoma histology (coefficient 4.26, QM = 4.15, P = 0.042) and prior or concurrent WBRT (coefficient 1.62, QM = 3.98, P = 0.046) were associated with higher grade 3-5 toxicity from SRS for BSM. Deaths from BSM progression after SRS were rare (2.7%), and the neurologic death rate in BSM patients (24%, 19-31%, I2 = 62%) was not statistically different from the neurologic death rate in BM patients who were treated on prospective SRS trials (21%, 13-32%, I2 = 90%, N = 6 trials, Q = 0.36, P = 0.55). The pooled rate of ORR of 59% (47-71%, I2 = 88%) for SRS of BSM compared favorably to the wide range of intracranial ORR reported for molecular therapies (17-56%).SRS for BSM is safe and effective, and the potential for acute morbidity or death from growth of untreated BSM is significant. The data here suggest SRS for BSM should be considered upon or prior to clinical trial enrollment of molecular/targeted therapy for BM.W.C. Chen: None. U. Baal: None. J.D. Baal: None. J. Pai: None. H. Vasudevan: Research Grant; Children's Tumor Foundation. Patent/License Fees/Copyright; Genentech, Eli Lilly. L. Boreta: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.D. Raleigh: None.