Two-stage radiosurgery for large brain metastases: a systematic review and meta-analysis of clinical outcomes.

Objective: Brain metastases (BMs) are the most common intracranial tumors. In several cases, they present as large masses, which are related to a worse prognosis and more complex therapeutic alternatives. Staged radiosurgery is reported to achieve local control with minimal radiation-related adverse events in BMs. However, no methodological consensus has been achieved in its use for large brain metastases (LBMs; > 2 cm). Therefore, the authors aimed to determine the effectiveness and safety of 2-stage Gamma Knife radiosurgery (GKRS) for LBMs, in order to optimize patients' postoperative course.

Methods: A systematic review of available literature was run in PubMed/MEDLINE, Scopus, Web of Science, Cochrane (OvidSP), and Google Scholar for works published up to December 14, 2022. Nonrandomized clinical trials, case series, and cohort studies were included. The risk of bias was assessed using the Risk of Bias in Nonrandomized Studies-of Interventions (ROBINS-I) and Joanna Briggs Institute tools. Pooled mean difference and rates estimates were calculated by a random-effects model meta-analysis. The degree of heterogeneity was expressed using the I2 statistic. A subgroup analysis was performed. Ultimately, the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment.

Results: Fourteen studies met the eligibility criteria (cohorts, case series, and nonrandomized clinical trials), including 958 patients. A total pooled mean volume reduction of 6.27 cm3 (95% CI 5.67-6.88 cm3) and 54.36% (95% CI 39.92%-68.79%) after 2-stage GKRS was reported. Pooled rates of complete response (44.63%; 95% CI 26.50%-64.31%), neurological mortality (16.19%; 95% CI 7.68%-30.98%), and all-cause mortality (47.92%; 95% CI 28.04%-68.49%) were calculated. Overall certainty of evidence ranged from very low to moderate.

Conclusions: Two-stage GKRS is an effective and safe approach for the treatment of LBMs. Nevertheless, the lack of available literature and the weak methodological approaches used determine a low to very low certainty of evidence and cannot provide robust evidence to recommend this intervention. Therefore, it is necessary to conduct higher-quality primary studies.