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  • Review Article
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Stereotactic radiosurgery for patients with brain metastases: current principles, expanding indications and opportunities for multidisciplinary care

Nature Reviews Clinical Oncology volume 22, pages 327–347 (2025)Cite this article

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An Author Correction to this article was published on 03 October 2025

This article has been updated

Abstract

The management of brain metastases is challenging and should ideally be coordinated through a multidisciplinary approach. Stereotactic radiosurgery (SRS) has been the cornerstone of management for most patients with oligometastatic central nervous system involvement (one to four brain metastases), and several technological and therapeutic advances over the past decade have broadened the indications for SRS to include polymetastatic central nervous system involvement (>4 brain metastases), preoperative application and fractionated SRS, as well as combinatorial approaches with targeted therapy and immune-checkpoint inhibitors. For example, improved imaging and frameless head-immobilization technologies have facilitated fractionated SRS for large brain metastases or postsurgical cavities, or lesions in proximity to organs at risk. However, these opportunities come with new challenges and questions, including the implications of tumour histology as well as the role and sequencing of concurrent systemic treatments. In this Review, we discuss these advances and associated challenges in the context of ongoing clinical trials, with insights from a global group of experts, including recommendations for current clinical practice and future investigations. The updates provided herein are meaningful for all practitioners in clinical oncology.

Key points

  • Advances in imaging, patient immobilization techniques and radiotherapy-planning software have expanded the scope of stereotactic radiosurgery (SRS) for the treatment of brain metastases.

  • Paradigms for determining suitability for SRS are gradually shifting away from strict thresholds of number and size of brain metastases to total intracranial tumour volume along with increased consideration of the influence of tumour histology.

  • Fractionated SRS can increase efficacy while minimizing the risk of adverse radiation events, particularly for larger brain metastases; however, the optimal fractionation schedule and dosing remains to be established.

  • Reliable detection of adverse radiation events, specifically distinguishing radionecrosis from tumour recurrence, remains challenging, although trials using advanced imaging approaches are under way.

  • Neoadjuvant SRS might minimize the risk of leptomeningeal dissemination and simplify radiation-dose planning. Ongoing trials will better define strategies for patient selection (for example, amenable tumour types) as well as the optimal dosing, schedule and timing of SRS before surgery.

  • Immune-checkpoint inhibitors and brain-penetrant targeted therapies have added to our armamentarium of treatment for brain metastases. However, further research is needed to determine the optimal sequencing of these systemic therapies in relation to SRS — or potentially whether SRS can be omitted altogether.

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Fig. 1: Emerging concepts challenging the current treatment paradigm for brain metastases.
Fig. 2: Emerging approaches and frontiers in SRS for patients with brain metastases.
Fig. 3: SRS and integrated multidisciplinary care for a patient with brain metastases.
Fig. 4: Key immunological effects of radiation and potential synergy with immune-checkpoint inhibitors.

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Acknowledgements

The authors acknowledge the contributions of T. Wang, medical illustrator at the University of Maryland School of Medicine, to the drafting of Figs. 1–4. A.O. acknowledges support through the Bagley Research Fellowship from the Department of Neurosurgery at the University of Maryland School of Medicine.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA

    Alireza Mansouri

  2. Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA

    Alireza Mansouri & Leonardo de Macedo Filho

  3. Department of Neurosurgery, Penn State College of Medicine, Pennsylvania State University, Hershey, PA, USA

    Alireza Mansouri, Hannah Wilding & Leonardo de Macedo Filho

  4. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA

    Ahmad Ozair & Graeme F. Woodworth

  5. Department of Neurological Surgery, NYU Langone Health, New York University, New York, NY, USA

    Debarati Bhanja, Elad Mashiach & Douglas Kondziolka

  6. Division of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA

    Waqas Haque

  7. Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Ontario, Canada

    Nicholas Mikolajewicz

  8. Department of Radiation Oncology, Penn State Cancer Institute, Hershey, PA, USA

    Sean S. Mahase & Mitchell Machtay

  9. Department of Neurosurgery, Ramsay Santé, Hôpital Privé Clairval, Marseille, France

    Philippe Metellus

  10. Radiation Therapy Department, Institut Gustave Roussy, Villejuif, France

    Frédéric Dhermain

  11. Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA

    Jason Sheehan

  12. Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    L. Dade Lunsford & Ajay Niranjan

  13. Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza IRCCS Neuromed, Pozzilli, Italy

    Giuseppe Minniti

  14. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jing Li

  15. Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA

    Steven N. Kalkanis

  16. Center For Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Patrick Y. Wen

  17. Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA

    Rupesh Kotecha

  18. Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

    Rupesh Kotecha, Michael W. McDermott & Manmeet S. Ahluwalia

  19. Department of Neurosurgery, Miami Neuroscience Institute, Baptist Health South Florida, Miami, FL, USA

    Michael W. McDermott

  20. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Chetan Bettegowda

  21. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Chetan Bettegowda

  22. Brain Tumour Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA

    Graeme F. Woodworth

  23. University of Maryland-Medicine Institute for Neuroscience Discovery, Baltimore, MD, USA

    Graeme F. Woodworth

  24. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA

    Paul D. Brown

  25. Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

    Arjun Sahgal

  26. Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA

    Manmeet S. Ahluwalia

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Contributions

A.M., D.B., A.O., H.W. and E.M. researched data for the article. A.M., A.O., P.D.B. and R.K. contributed substantially to discussion of the content. A.M., D.B., A.O., H.W., E.M. and W.H. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Alireza Mansouri or Manmeet S. Ahluwalia.

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Competing interests

D.K. declares institutional grant funding from Neuropoint Alliance; and is named on US Patent 11,253,726: Method to select radiation dosage for tumour treatment based on cellular imaging. L.D.L. has acted as a consultant for Insightec and holds stock in Elekta. G.M. has received honoraria for seminars from Accuray and BrainLAB. J.L. has received funding support for clinical trials from Bristol Myer Squibb. P.Y.W. has received research support from AstraZeneca, Black Diamond, Bristol Myers Squibb, Chimerix, Eli Lily, Erasca, Global Coalition for Adaptive Research, Kazia Therapeutics, MediciNova, Merck, Novartis, Quadriga, Servier and VBI Vaccines; and consultancy fees from Anheart, AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GSK, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix and VBI Vaccines. R.K. has received honoraria from Accuray, BrainLAB, Castle Biosciences, Elekta, Elsevier, Ion Beam Applications, Kazia Therapeutics, Novocure and ViewRay; and institutional research funding from AstraZeneca, Blue Earth Diagnostics, BrainLAB, Cantex Pharmaceuticals, Exelixis, GT Medical Technologies, Ion Beam Applications, Kazia Therapeutics, Medtronic, Novocure and ViewRay. G.F.W. has received funding support for clinical trials from Insightec and the Keep Punching Foundation. P.D.B. has received honoraria from UpToDate. A.S. has acted as a consultant for Abbvie, BrainLAB, Elekta (Gamma Knife Icon), Merck, Roche and Varian; has received honorarium for educational seminars from Accuray, AstraZeneca, BrainLAB, Elekta, Seagen and Varian; research grants from BrainLAB, Elekta, Seagen and Varian; travel accommodations/expenses from BrainLAB, Elekta and Varian; and is also a Clinical Steering Committee Member of the Elekta MR-Linac Research Consortium and chairs the Elekta Oligometastases Group and the Elekta Gamma Knife Icon Group. M.S.A. has received research grants from AstraZeneca, Bayer, Bristol Myers Squibb, Incyte, Merck, Mimivax, Novocure and Pharmacyclics; consultancy fees from Allovir, Anheart Therapeutics, Apollomics, Autem, Bayer, Cairn Therapeutics, Caris Lifesciences, Celularity, GSK, Insightec, Janssen, Kiyatec, Novocure, Nuvation, Prelude Therapeutics, Pyramid Biosciences, SDP Oncology, Theraguix, Tocagen, Varian Medical Systems, Viewray, Voyager Therapeutics and Xoft; is a scientific advisory board member for Cairn Therapeutics, Modifi Biosciences and Pyramid Biosciences; and holds stock in Cytodyn, MedInnovate Advisors and MimiVax. The other authors declare no competing interests.

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Peer review information

Nature Reviews Clinical Oncology thanks F. Moraes, B.S. Skeie and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Review criteria

This review utilizes data from landmark trials reported over the past two decades along with recent published literature (through database searches using appropriate combinations of search terms related to ‘brain metastasis’, ‘brain malignancies’, ‘SRS’, ‘stereotactic radiosurgery’, ‘radiotherapy’, ‘whole brain radiotherapy’, ‘WBRT’, ‘brain radiation’, ‘Gamma Knife’, ‘Cyber Knife’, ‘LINAC’) as well as works presented at the 2022, 2023 and 2024 annual meetings of the Society for Neuro-Oncology (SNO), American Society for Radiation Oncology (ASTRO), American Society for Clinical Oncology (ASCO), and the SNO/ASCO Annual Conferences on CNS Clinical Trials and Brain Metastases. References were also curated from major reviews in the field as well as guideline publications from professional societies. Clinical trials pertaining to brain metastases were also reviewed from ClinicalTrials.gov (accessed 20 September 2024). The final reference list was refined by a multidisciplinary panel with expertise in radiation oncology, medical oncology, neuro-oncology, neurosurgery, neuroradiology and clinical trial design.

Supplementary information

Glossary

Adverse radiation events (AREs)

are any negative adverse effects or complications arising secondary to radiotherapy, which affect non-tumour tissues and organs near the treatment site, can occur during or following treatment and range in severity. AREs reflecting necrosis or leaky blood vessels resulting in oedema are sometimes referred to as radiation necrosis or radionecrosis or radiation-induced contrast enhancement.

Beam modulation

refers to the technique of varying the intensity and shape of radiation beams as they are delivered to the patient. This enables more precise targeting of the tumour while minimizing exposure and thus damage to surrounding non-tumour tissues.

Biologically effective dose (BED)

is a measure that quantifies the biological effect of a given dose of radiation, taking into account the dose per fraction and the total dose delivered, relative to the tissue-specific sensitivity to radiation.

Clinical target volume (CTV)

as defined broadly, is the volume of tissue that contains the gross tumour volume visible on imaging, along with a potential margin of surrounding tissue potentially invaded by malignant cells. For whole-brain radiotherapy, the CTV is typically the entire brain. With stereotactic radiosurgery for small intact lesions, the CTV is the same as gross tumour volume on imaging as microscopic spread is considered minimal.

Co-planar beams

refer to multiple radiation beams that are directed from different angles but lie within the same plane. This technique is used to ensure uniform dose distribution across the target area while sparing surrounding non-tumour tissues.

Gross tumour volume

is the volume of the tumour that is clearly visible on imaging, typically a fine-cut contrast-enhanced T1-weighted MRI for SRS targeting intact lesions.

Isocentres

are crucial in radiotherapy planning as the focal points of radiation beam intersection, around which the gantry, the treatment couch and the collimators all rotate to ensure accurate tumour targeting.

Isodose

refers to lines on a radiation treatment plan that connect points receiving the same dose of radiation. These lines help visualize the distribution of radiation within the target area and surrounding tissues, facilitating treatment planning.

Planning target volume (PTV)

includes the clinical target volume plus a margin of surrounding tissue (such as an added 1–2 mm for stereotactic radiosurgery or 3–5 mm for whole-brain radiotherapy — referred to as the PTV expansion) to account for variations in lesion size, shape and position, relative to the radiotherapy beam.

Simultaneous-integrated boost techniques

involve delivering different doses of radiation to different areas of the tumour simultaneously within a single treatment session. This approach enables higher doses to be targeted at the tumour while sparing surrounding non-tumour tissues, potentially improving treatment efficacy and reducing overall treatment time.

Stereotactic radiosurgery (SRS)

is a highly conformal radiation therapy approach that is predicated on the ability to immobilize the target organ for precise targeting of radiation beams. The skull being a fixed and rigid space is an ideal region for SRS, as there is minimal motion during therapy.

Tumour treating fields (TTFields)

is a novel treatment modality involving non-invasive delivery of low-intensity, intermediate-frequency alternating electrical fields, typically via several electrodes placed on the scalp — ideally near the tumour — for brain metastases, to disrupt the ability of cancer cells to grow and divide.

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Mansouri, A., Ozair, A., Bhanja, D. et al. Stereotactic radiosurgery for patients with brain metastases: current principles, expanding indications and opportunities for multidisciplinary care. Nat Rev Clin Oncol 22, 327–347 (2025). https://doi.org/10.1038/s41571-025-01013-1

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