[Skip to Content]
[Skip to Content Landing]

Efficacy and Safety of Stereotactic Radiosurgery for Brainstem MetastasesA Systematic Review and Meta-analysis

Educational Objective
To learn the role of stereotactic radiosurgery for treatment of brainstem metastases.
1 Credit CME
Key Points

Question  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)?

Findings  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.

Meaning  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.


Importance  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.

Objective  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).

Data Sources  A comprehensive search of Pubmed/MEDLINE and Embase was performed on December 6, 2019.

Study Selection  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.

Results  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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

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.

Article Information

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 (david.raleigh@ucsf.edu), and Steve E. Braunstein, MD, PhD, Department of Radiation Oncology (steve.braunstein@ucsf.edu), 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.

Chason  JL , Walker  FB , Landers  JW .  Metastatic carcinoma in the central nervous system and dorsal root ganglia: a prospective autopsy study.   Cancer. 1963;16:781-787. doi:10.1002/1097-0142(196306)16:6<781::AID-CNCR2820160614>3.0.CO;2-M PubMedGoogle ScholarCrossref
Gavrilovic  IT , Posner  JB .  Brain metastases: epidemiology and pathophysiology.   J Neurooncol. 2005;75(1):5-14. doi:10.1007/s11060-004-8093-6 PubMedGoogle ScholarCrossref
Delattre  JY , Krol  G , Thaler  HT , Posner  JB .  Distribution of brain metastases.   Arch Neurol. 1988;45(7):741-744. doi:10.1001/archneur.1988.00520310047016 PubMedGoogle ScholarCrossref
Ostrom  QT , Wright  CH , Barnholtz-Sloan  JS .  Brain metastases: epidemiology.   Handb Clin Neurol. 2018;149:27-42. doi:10.1016/B978-0-12-811161-1.00002-5PubMedGoogle ScholarCrossref
Chang  EL , Wefel  JS , Hess  KR ,  et al.  Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.   Lancet Oncol. 2009;10(11):1037-1044. doi:10.1016/S1470-2045(09)70263-3 PubMedGoogle ScholarCrossref
Kocher  M , Soffietti  R , Abacioglu  U ,  et al.  Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study.   J Clin Oncol. 2011;29(2):134-141. doi:10.1200/JCO.2010.30.1655 PubMedGoogle ScholarCrossref
Yamamoto  M , Serizawa  T , Shuto  T ,  et al.  Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.   Lancet Oncol. 2014;15(4):387-395. doi:10.1016/S1470-2045(14)70061-0 PubMedGoogle ScholarCrossref
Aoyama  H , Shirato  H , Tago  M ,  et al.  Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.   JAMA. 2006;295(21):2483-2491. doi:10.1001/jama.295.21.2483 PubMedGoogle ScholarCrossref
Brown  PD , Jaeckle  K , Ballman  KV ,  et al.  Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial.   JAMA. 2016;316(4):401-409. doi:10.1001/jama.2016.9839PubMedGoogle ScholarCrossref
Andrews  DW , Scott  CB , Sperduto  PW ,  et al.  Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial.   Lancet. 2004;363(9422):1665-1672. doi:10.1016/S0140-6736(04)16250-8 PubMedGoogle ScholarCrossref
Chen  X , Grimm  J , Baker  BR ,  et al.  Fractionated stereotactic radiosurgery for brainstem metastasis and brainstem tolerance.   Int J Radiat Oncol. 2019;105(1)(suppl):E72-E73. doi:10.1016/j.ijrobp.2019.06.2328Google ScholarCrossref
Yen  CP , Sheehan  J , Patterson  G , Steiner  L .  Gamma knife surgery for metastatic brainstem tumors.   J Neurosurg. 2006;105(2):213-219. doi:10.3171/jns.2006.105.2.213 PubMedGoogle ScholarCrossref
Kelly  PJ , Lin  YB , Yu  AYC ,  et al.  Linear accelerator-based stereotactic radiosurgery for brainstem metastases: the Dana-Farber/Brigham and Women’s Cancer Center experience.   J Neurooncol. 2011;104(2):553-557. doi:10.1007/s11060-010-0514-0 PubMedGoogle ScholarCrossref
Kilburn  JM , Ellis  TL , Lovato  JF ,  et al.  Local control and toxicity outcomes in brainstem metastases treated with single fraction radiosurgery: is there a volume threshold for toxicity?   J Neurooncol. 2014;117(1):167-174. doi:10.1007/s11060-014-1373-xPubMedGoogle ScholarCrossref
Koyfman  SA , Tendulkar  RD , Chao  ST ,  et al.  Stereotactic radiosurgery for single brainstem metastases: the Cleveland Clinic experience.   Int J Radiat Oncol Biol Phys. 2010;78(2):409-414. doi:10.1016/j.ijrobp.2009.07.1750 PubMedGoogle ScholarCrossref
Leeman  JE , Clump  DA , Wegner  RE , Heron  DE , Burton  SA , Mintz  AH .  Prescription dose and fractionation predict improved survival after stereotactic radiotherapy for brainstem metastases.   Radiat Oncol. 2012;7:107. doi:10.1186/1748-717X-7-107 PubMedGoogle ScholarCrossref
Li  Y , Xu  D , Zhang  Z ,  et al.  Gamma Knife surgery for brainstem metastases.   J Neurosurg. 2012;117(suppl):13-16. doi:10.3171/2012.7.GKS121020 PubMedGoogle ScholarCrossref
Lin  CS , Selch  MT , Lee  SP ,  et al.  Accelerator-based stereotactic radiosurgery for brainstem metastases.   Neurosurgery. 2012;70(4):953-958. doi:10.1227/NEU.0b013e31823c40fe PubMedGoogle ScholarCrossref
Liu  SH , Murovic  J , Wallach  J ,  et al.  CyberKnife radiosurgery for brainstem metastases: management and outcomes and a review of the literature.   J Clin Neurosci. 2016;25:105-110. doi:10.1016/j.jocn.2015.10.013 PubMedGoogle ScholarCrossref
Lorenzoni  JG , Devriendt  D , Massager  N ,  et al.  Brain stem metastases treated with radiosurgery: prognostic factors of survival and life expectancy estimation.   Surg Neurol. 2009;71(2):188-195. doi:10.1016/j.surneu.2008.01.029 PubMedGoogle ScholarCrossref
Murray  L , Menard  C , Zadeh  G ,  et al.  Radiosurgery for brainstem metastases with and without whole brain radiotherapy: clinical series and literature review.   J Radiat Oncol. 2017;6(1):21-30. doi:10.1007/s13566-016-0281-4 PubMedGoogle ScholarCrossref
Nakamura  M , Nishimura  H , Mayahara  H ,  et al.  Investigation of the efficacy and safety of CyberKnife hypofractionated stereotactic radiotherapy for brainstem metastases using a new evaluation criterion: ‘symptomatic control’.   J Radiat Res. 2017;58(6):834-839. doi:10.1093/jrr/rrx042 PubMedGoogle ScholarCrossref
Fuentes  S , Delsanti  C , Metellus  P , Peragut  JC , Grisoli  F , Regis  J .  Brainstem metastases: management using gamma knife radiosurgery.   Neurosurgery. 2006;58(1):37-42. doi:10.1227/01.NEU.0000190655.95669.5C PubMedGoogle ScholarCrossref
Patel  A , Mohammadi  H , Dong  T ,  et al.  Brainstem metastases treated with Gamma Knife stereotactic radiosurgery: the Indiana University Health experience.   CNS Oncol. 2018;7(1):15-23. doi:10.2217/cns-2017-0029 PubMedGoogle ScholarCrossref
Peterson  HE , Larson  EW , Fairbanks  RK ,  et al.  Gamma knife treatment of brainstem metastases.   Int J Mol Sci. 2014;15(6):9748-9761. doi:10.3390/ijms15069748 PubMedGoogle ScholarCrossref
Samblás  JM , Sallabanda  K , Bustos  JC ,  et al.  Radiosurgery and whole brain therapy in the treatment of brainstem metastases.   Clin Transl Oncol. 2009;11(10):677-680. doi:10.1007/s12094-009-0423-xPubMedGoogle ScholarCrossref
Sengöz  M , Kabalay  IA , Tezcanlı  E , Peker  S , Pamir  N .  Treatment of brainstem metastases with gamma-knife radiosurgery.   J Neurooncol. 2013;113(1):33-38. doi:10.1007/s11060-013-1086-6 PubMedGoogle ScholarCrossref
Shuto  T , Fujino  H , Asada  H , Inomori  S , Nagano  H .  Gamma knife radiosurgery for metastatic tumours in the brain stem.   Acta Neurochir (Wien). 2003;145(9):755-760. doi:10.1007/s00701-003-0034-1 PubMedGoogle ScholarCrossref
Sugimoto  T , Matsuda  R , Tamamoto  T ,  et al.  Linac-based fractionated stereotactic radiotherapy with a micro-multileaf collimator for brainstem metastasis.   World Neurosurg. 2019;132:e680-e686. doi:10.1016/j.wneu.2019.08.049 PubMedGoogle ScholarCrossref
Trifiletti  DM , Lee  CC , Kano  H ,  et al.  Stereotactic radiosurgery for brainstem metastases: an international cooperative study to define response and toxicity.   Int J Radiat Oncol Biol Phys. 2016;96(2):280-288. doi:10.1016/j.ijrobp.2016.06.009 PubMedGoogle ScholarCrossref
Trifiletti  DM , Lee  CC , Winardi  W ,  et al.  Brainstem metastases treated with stereotactic radiosurgery: safety, efficacy, and dose response.   J Neurooncol. 2015;125(2):385-392. doi:10.1007/s11060-015-1927-6 PubMedGoogle ScholarCrossref
Valery  CA , Boskos  C , Boisserie  G ,  et al.  Minimized doses for linear accelerator radiosurgery of brainstem metastasis.   Int J Radiat Oncol Biol Phys. 2011;80(2):362-368. doi:10.1016/j.ijrobp.2010.02.028 PubMedGoogle ScholarCrossref
Voong  KR , Farnia  B , Wang  Q ,  et al.  Gamma knife stereotactic radiosurgery in the treatment of brainstem metastases: the MD Anderson experience.   Neurooncol Pract. 2015;2(1):40-47. doi:10.1093/nop/npu032PubMedGoogle Scholar
Hatiboglu  MA , Chang  EL , Suki  D , Sawaya  R , Wildrick  DM , Weinberg  JS .  Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery.   Neurosurgery. 2011;69(4):796-806. doi:10.1227/NEU.0b013e31821d31de PubMedGoogle ScholarCrossref
Winograd  E , Rivers  CI , Fenstermaker  R , Fabiano  A , Plunkett  R , Prasad  D .  The case for radiosurgery for brainstem metastases.   J Neurooncol. 2019;143(3):585-595. doi:10.1007/s11060-019-03195-y PubMedGoogle ScholarCrossref
Yoo  TW , Park  ES , Kwon  DH , Kim  CJ .  Gamma knife radiosurgery for brainstem metastasis.   J Korean Neurosurg Soc. 2011;50(4):299-303. doi:10.3340/jkns.2011.50.4.299 PubMedGoogle ScholarCrossref
Yükselen Güney  Y , Işik Özşeker  N , Altinişik Inan  G ,  et al.  Cyberknife radiosurgery and fractionated stereotactic radiotherapy for brainstem or adjacent-to-brainstem metastases.   Turkiye Klin J Med Sci. 2013;33(6):1354-1359. doi:10.5336/medsci.2012-32233Google ScholarCrossref
Huang  CF , Kondziolka  D , Flickinger  JC , Lunsford  LD .  Stereotactic radiosurgery for brainstem metastases.   J Neurosurg. 1999;91(4):563-568. doi:10.3171/jns.1999.91.4.0563 PubMedGoogle ScholarCrossref
Hussain  A , Brown  PD , Stafford  SL , Pollock  BE .  Stereotactic radiosurgery for brainstem metastases: survival, tumor control, and patient outcomes.   Int J Radiat Oncol Biol Phys. 2007;67(2):521-524. doi:10.1016/j.ijrobp.2006.08.081 PubMedGoogle ScholarCrossref
Joshi  R , Johnson  MD , Maitz  A , Marvin  KS , Olson  RE , Grills  IS .  Utility of graded prognostic assessment in evaluation of patients with brainstem metastases treated with radiosurgery.   Clin Neurol Neurosurg. 2016;147:30-33. doi:10.1016/j.clineuro.2016.05.001 PubMedGoogle ScholarCrossref
Jung  EW , Rakowski  JT , Delly  F ,  et al.  Gamma Knife radiosurgery in the management of brainstem metastases.   Clin Neurol Neurosurg. 2013;115(10):2023-2028. doi:10.1016/j.clineuro.2013.06.012 PubMedGoogle ScholarCrossref
Kased  N , Huang  K , Nakamura  JL ,  et al.  Gamma knife radiosurgery for brainstem metastases: the UCSF experience.   J Neurooncol. 2008;86(2):195-205. doi:10.1007/s11060-007-9458-4 PubMedGoogle ScholarCrossref
Kawabe  T , Yamamoto  M , Sato  Y ,  et al.  Gamma Knife surgery for patients with brainstem metastases.   J Neurosurg. 2012;117(suppl):23-30. doi:10.3171/2012.7.GKS12977 PubMedGoogle ScholarCrossref
Slim  K , Nini  E , Forestier  D , Kwiatkowski  F , Panis  Y , Chipponi  J .  Methodological index for non-randomized studies (minors): development and validation of a new instrument.   ANZ J Surg. 2003;73(9):712-716. doi:10.1046/j.1445-2197.2003.02748.x PubMedGoogle ScholarCrossref
Shamseer  L , Moher  D , Clarke  M ,  et al; PRISMA-P Group.  Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.   BMJ. 2015;350:g7647. doi:10.1136/bmj.g7647 PubMedGoogle ScholarCrossref
Patchell  RA , Tibbs  PA , Walsh  JW ,  et al.  A randomized trial of surgery in the treatment of single metastases to the brain.   N Engl J Med. 1990;322(8):494-500. doi:10.1056/NEJM199002223220802 PubMedGoogle ScholarCrossref
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. National Cancer Institute. Accessed April 7, 2021. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40.
Higgins  JPT , Thompson  SG , Deeks  JJ , Altman  DG .  Measuring inconsistency in meta-analyses.   BMJ. 2003;327(7414):557-560. doi:10.1136/bmj.327.7414.557 PubMedGoogle ScholarCrossref
Sneed  PK , Mendez  J , Vemer-van den Hoek  JGM ,  et al.  Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors.   J Neurosurg. 2015;123(2):373-386. doi:10.3171/2014.10.JNS141610 PubMedGoogle ScholarCrossref
Liew  DN , Kano  H , Kondziolka  D ,  et al.  Outcome predictors of Gamma Knife surgery for melanoma brain metastases: clinical article.   J Neurosurg. 2011;114(3):769-779. doi:10.3171/2010.5.JNS1014 PubMedGoogle ScholarCrossref
Marquart  J , Chen  EY , Prasad  V .  Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology.   JAMA Oncol. 2018;4(8):1093-1098. doi:10.1001/jamaoncol.2018.1660 PubMedGoogle ScholarCrossref
Haslam  A , Prasad  V .  Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs.   JAMA Netw Open. 2019;2(5):e192535. doi:10.1001/jamanetworkopen.2019.2535 PubMedGoogle Scholar
Erbagci  H , Keser  M , Kervancioglu  S , Kizilkan  N .  Estimation of the brain stem volume by stereological method on magnetic resonance imaging.   Surg Radiol Anat. 2012;34(9):819-824. doi:10.1007/s00276-012-0966-3 PubMedGoogle ScholarCrossref
Guyatt  GH , Oxman  AD , Vist  GE ,  et al; GRADE Working Group.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.   BMJ. 2008;336(7650):924-926. doi:10.1136/bmj.39489.470347.AD PubMedGoogle ScholarCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.


My Saved Courses

You currently have no courses saved.