Is stereotactic radiosurgery (SRS) safe and effective for the treatment of brainstem metastasis (BSM), and how does this approach compare with SRS or targeted therapy for nonbrainstem brain metastasis (BM)?
This systematic review and meta-analysis of 32 studies comprising 1446 patients found associations with high local control (86%), high therapeutic ratio of symptom relief and tumor response (50%-60%) when compared with targeted therapy (17%-56%), rare significant toxic effects (2.4%), and rare death from BSM progression (2.7%). The neurologic death rate in patients with BSM who were treated with SRS was equivalent to that in patients with BM who were treated with SRS on prospective trials.
Given the risks of acute morbidity or death from BSM growth in the context of the efficacy and safety of SRS for BSM, future trials of targeted therapy or immunotherapy for BM should consider including patients with BSM after treatment with SRS.
Owing to the proximity to critical neurologic structures, treatment options for brainstem metastases (BSM) are limited, and BSM growth can cause acute morbidity or death. Stereotactic radiosurgery (SRS) is the only local therapy for BSM, but efficacy and safety of this approach are incompletely understood because patients with BSM are excluded from most clinical trials.
To perform a systematic review and comparative meta-analysis of SRS studies for BSM in the context of prospective trials of SRS or molecular therapy for nonbrainstem brain metastases (BM).
A comprehensive search of Pubmed/MEDLINE and Embase was performed on December 6, 2019.
English-language studies of SRS for BSM with at least 10 patients and reporting 1 or more outcomes of interest were included. Duplicate studies or studies with overlapping data sets were excluded. Studies were independently evaluated by 2 reviewers, and discrepancies were resolved by consensus. A total of 32 retrospective studies published between 1999 and 2019 were included in the analysis.
Data Extraction and Synthesis
Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify studies. Study quality was assessed using Methodological Index for Non-Randomized Studies criteria. Fixed and random-effects meta-analyses and meta-regressions were performed for the outcomes of interest.
Main Outcomes and Measures
Primary study outcomes included 1-year and 2-year local control and overall survival, objective response rate, symptom response rate, neurological death rate, and rate of grade 3 to 5 toxic effects as described in Common Terminology Criteria for Adverse Events, version 4.0.
The 32 retrospective studies included in the analysis comprised 1446 patients with 1590 BSM that were treated with SRS (median [range] dose, 16 [11-39] Gy; median [range] fractions, 1 [1-13]). Local control at 1 year was 86% (95% CI, 83%-88%; I2 = 38%) in 1410 patients across 31 studies, objective response rate was 59% (95% CI, 47%-71%; I2 = 88%) in 642 patients across 17 studies, and symptom improvement was 55% (95% CI, 47%-63%; I2 = 41%) in 323 patients across 13 studies. Deaths from BSM progression after SRS were rare (19 of 703 [2.7%] deaths across 19 studies), and the neurologic death rate in patients with BSM (24%; 95% CI, 19%-31%; I2 = 62%) was equivalent to the neurologic death rate in patients with BM who were treated on prospective trials. The rate of treatment-related grade 3 to 5 toxic effects was 2.4% (95% CI, 1.5%-3.7%; I2 = 33%) in 1421 patients across 31 studies. These results compared favorably to trials of targeted or immunotherapy for BM, which had a wide objective response rate range from 17% to 56%.
Conclusions and Relevance
Results of this systematic review and meta-analysis show that SRS for BSM was associated with effectiveness and safety and was comparable to SRS for nonbrainstem BM, suggesting that patients with BSM should be eligible for clinical trials of SRS. In this analysis, patients treated with SRS for BSM rarely died from BSM progression and often experienced symptomatic improvement. Given the apparent safety and efficacy of SRS for BSM in the context of acute morbidity or death from BSM growth, consideration of SRS at the time of enrollment on emerging trials of targeted therapy for BM should be considered.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: March 24, 2021.
Published Online: May 13, 2021. doi:10.1001/jamaoncol.2021.1262
Correction: This article was corrected on July 15, 2021, to fix a typo in the Conclusions section.
Corresponding Authors: David R. Raleigh, MD, PhD, Departments of Radiation Oncology and Neurological Surgery (email@example.com), and Steve E. Braunstein, MD, PhD, Department of Radiation Oncology (firstname.lastname@example.org), University of California, San Francisco, 1450 Third St, Helen Diller Cancer Research Building, HD481, San Francisco, CA 94158.
Author Contributions: Drs Braunstein and Raleigh had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Braunstein and Raleigh contributed equally to the study.
Concept and design: Chen, Braunstein, Raleigh.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chen, U. Baal, Braunstein, Raleigh.
Critical revision of the manuscript for important intellectual content: Chen, J. Baal, Pai, Boreta, Braunstein, Raleigh.
Statistical analysis: Chen, U. Baal.
Obtained funding: Raleigh.
Administrative, technical, or material support: J. Baal, Pai, Raleigh.
Supervision: U. Baal, Boreta, Braunstein, Raleigh.
Conflict of Interest Disclosures: None reported.
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