Brain metastases are a very common manifestation of cancer that have historically been approached as a single disease entity given the uniform association with poor clinical outcomes. Fortunately, our understanding of the biology and molecular underpinnings of brain metastases has greatly improved, resulting in more sophisticated prognostic models and multiple patient-related and disease-specific treatment paradigms. In addition, the therapeutic armamentarium has expanded from whole-brain radiotherapy and surgery to include stereotactic radiosurgery, targeted therapies and immunotherapies, which are often used sequentially or in combination. Advances in neuroimaging have provided additional opportunities to accurately screen for intracranial disease at initial cancer diagnosis, target intracranial lesions with precision during treatment and help differentiate the effects of treatment from disease progression by incorporating functional imaging. Given the numerous available treatment options for patients with brain metastases, a multidisciplinary approach is strongly recommended to personalize the treatment of each patient in an effort to improve the therapeutic ratio. Given the ongoing controversies regarding the optimal sequencing of the available and expanding treatment options for patients with brain metastases, enrolment in clinical trials is essential to advance our understanding of this complex and common disease. In this Review, we describe the key features of diagnosis, risk stratification and modern paradigms in the treatment and management of patients with brain metastases and provide speculation on future research directions.
Many patient-related and disease-related prognostic criteria have incorporated molecular profiling into the classification schema and should be considered when estimating a patient’s prognosis following a diagnosis of brain metastases.
Genomic profiling of brain metastases has yielded important information about potentially actionable genomic alterations that may not be detected in the primary tumour or extracranial metastases.
Evolving radiotherapy techniques, such as hippocampal avoidance whole-brain radiotherapy (WBRT), mitigate the risk of neurocognitive decline following treatment.
Stereotactic radiosurgery (SRS) is now the primary treatment for patients with either limited or multiple brain metastases, with potential synergistic effects when combined with certain immunotherapeutic agents or targeted therapies.
Postoperative SRS is an alternative to WBRT for patients who undergo resection of brain metastases, with a reduced risk of neurocognitive decline; however, preoperative SRS might be favoured given the lower risks of radiation necrosis and leptomeningeal disease.
Developments in targeted therapies and immunotherapies for patients with non-small-cell lung cancer, breast cancer and melanoma have dramatically transformed the treatment of patients with brain metastases.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Acta Neuropathologica Communications Open Access 14 January 2023
Medical Oncology Open Access 07 September 2022
Retrospective study of hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy for patients with brain metastases
Radiation Oncology Open Access 26 July 2022
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Suh, J. H., Kotecha, R., Ahluwalia, M. S. & Vogelbaum, M. A. in Devita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology 11th edn 1934–1945 (Wolters Kluwer, 2019).
Suh, J. H. Stereotactic radiosurgery for the management of brain metastases. N. Engl. J. Med. 362, 1119–1127 (2010).
Achrol, A. S. et al. Brain metastases. Nat. Rev. Dis. Primers 5, 5 (2019).
Postmus, P. E. & Smit, E. F. Prophylactic cranial irradiation for stage IV small cell lung cancer, live longer or reduce morbidity of brain metastases? J. Thorac. Dis. 9, 3572–3575 (2017).
Scoccianti, S. & Ricardi, U. Treatment of brain metastases: review of phase III randomized controlled trials. Radiother. Oncol. 102, 168–179 (2012).
Tsukada, Y., Fouad, A., Pickren, J. W. & Lane, W. W. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 52, 2349–2354 (1983).
Sampson, J. H., Carter, J. H. Jr., Friedman, A. H. & Seigler, H. F. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J. Neurosurg. 88, 11–20 (1998).
Nayak, L. et al. Epidemiology of brain metastases. Curr. Oncol. Rep. 14, 48–54 (2012).
Cagney, D. N. et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 19, 1511–1521 (2017).
Suki, D., Khoury Abdulla, R., Ding, M., Khatua, S. & Sawaya, R. Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center. J. Neurosurg. Pediatr. 14, 372–385 (2014).
Goldman, S., Echevarria, M. E. & Fangusaro, J. Pediatric brain metastasis from extraneural malignancies: a review. Cancer Treat. Res. 136, 143–168 (2007).
Mehta, M. P. et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J. Clin. Oncol. 21, 2529–2536 (2003).
Meyers, C. A. et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J. Clin. Oncol. 22, 157–165 (2004).
Schellinger, P. D., Meinck, H. M. & Thron, A. Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J. Neurooncol. 44, 275–281 (1999).
Sze, G. et al. Intraparenchymal brain metastases: MR imaging versus contrast-enhanced CT. Radiology 168, 187–194 (1988).
Sze, G. et al. Hemorrhagic neoplasms: MR mimics of occult vascular malformations. Am. J. Roentgenol. 149, 1223–1230 (1987).
McGann, G. M. & Platts, A. Computed tomography of cranial metastatic malignant melanoma: features, early detection and unusual cases. Br. J. Radiol. 64, 310–313 (1991).
Albert, F. K., Forsting, M., Sartor, K., Adams, H. P. & Kunze, S. Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34, 45–60 (1994).
Forsyth, P. A. et al. Prospective study of postoperative magnetic resonance imaging in patients with malignant gliomas. J. Clin. Oncol. 15, 2076–2081 (1997).
Patel, T. R. et al. A comprehensive review of MR imaging changes following radiosurgery to 500 brain metastases. Am. J. Neuroradiol. 32, 1885–1892 (2011).
Lin, N. U. et al. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol. 14, e396–e406 (2013).
Lin, N. U. et al. Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group. Lancet Oncol. 14, e407–e416 (2013).
Gaspar, L. et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int. J. Radiat. Oncol. Biol. Phys. 37, 745–751 (1997).
Gaspar, L. E., Scott, C., Murray, K. & Curran, W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 47, 1001–1006 (2000).
Sperduto, P. W. et al. Effect of targeted therapies on prognostic factors, patterns of care, and survival in patients with renal cell carcinoma and brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 101, 845–853 (2018).
Weltman, E. et al. Radiosurgery for brain metastases: a score index for predicting prognosis. Int. J. Radiat. Oncol. Biol. Phys. 46, 1155–1161 (2000).
Lorenzoni, J. et al. Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int. J. Radiat. Oncol. Biol. Phys. 60, 218–224 (2004).
Sperduto, P. W., Berkey, B., Gaspar, L. E., Mehta, M. & Curran, W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int. J. Radiat. Oncol. Biol. Phys. 70, 510–514 (2008).
Sperduto, P. W. et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int. J. Radiat. Oncol. Biol. Phys. 77, 655–661 (2010).
Miller, J. A. et al. Overall survival and the response to radiotherapy among molecular subtypes of breast cancer brain metastases treated with targeted therapies. Cancer 123, 2283–2293 (2017).
Sperduto, P. W. et al. Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 82, 2111–2117 (2012).
Sperduto, P. W. et al. The effect of gene alterations and tyrosine kinase inhibition on survival and cause of death in patients with adenocarcinoma of the lung and brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 96, 406–413 (2016).
Miller, J. A. et al. The impact of tumor biology on survival and response to radiation therapy among patients with non-small cell lung cancer brain metastases. Pract. Radiat. Oncol. 7, e263–e273 (2017).
Sperduto, P. W. et al. Estimating survival in patients with lung cancer and brain metastases: an update of the Graded Prognostic Assessment for Lung Cancer using Molecular Markers (Lung-molGPA). JAMA Oncol. 3, 827–831 (2017).
Sperduto, P. W. et al. The prognostic value of BRAF, C-KIT, and NRAS mutations in melanoma patients with brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 98, 1069–1077 (2017).
Sperduto, P. W. et al. Estimating survival in melanoma patients with brain metastases: an update of the Graded Prognostic Assessment for Melanoma using Molecular Markers (Melanoma-molGPA). Int. J. Radiat. Oncol. Biol. Phys. 99, 812–816 (2017).
Kotecha, R. et al. Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome. J. Neurosurg. 129, 50–59 (2018).
Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010).
Van Allen, E. M. et al. Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine. Nat. Med. 20, 682–688 (2014).
Brastianos, P. K. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 5, 1164–1177 (2015).
Wang, H. et al. Genes associated with increased brain metastasis risk in non-small cell lung cancer: comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036). Cancer 125, 3535–3544 (2019).
Ippen, F. M. et al. Targeting the PI3K/Akt/mTOR-pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro Oncol. 21, 1401–1411 (2019).
Siena, S. et al. Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: integrated analysis from three clinical trials. J. Clin. Oncol. 37, 3017–3017 (2019).
Ryken, T. C. et al. Congress of Neurological Surgeons systematic review and evidence-based guidelines on the role of steroids in the treatment of adults with metastatic brain tumors. Neurosurgery 84, E189–E191 (2019).
Gaspar, L. E. et al. Pre-irradiation evaluation and management of brain metastases. American College of Radiology. ACR Appropriateness Criteria. Radiology 215, 1105–1110 (2000).
Jessurun, C. A. C. et al. Evidence-based dexamethasone dosing in malignant brain tumors: what do we really know? J. Neurooncol. 144, 249–264 (2019).
Hempen, C., Weiss, E. & Hess, C. F. Dexamethasone treatment in patients with brain metastases and primary brain tumors: do the benefits outweigh the side-effects? Support Care Cancer 10, 322–328 (2002).
Soffietti, R. et al. EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. Eur. J. Neurol. 13, 674–681 (2006).
Brainin, M. et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces–revised recommendations 2004. Eur. J. Neurol. 11, 577–581 (2004).
Arbour, K. C. et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J. Clin. Oncol. 36, 2872–2878 (2018).
Chang, S. M. et al. Anticonvulsant prophylaxis and steroid use in adults with metastatic brain tumors: ASCO and SNO endorsement of the Congress of Neurological Surgeons Guidelines. J. Clin. Oncol. 37, 1130–1135 (2019).
Arnold, S. M. & Patchell, R. A. Diagnosis and management of brain metastases. Hematol. Oncol. Clin. North. Am. 15, 1085–1107 (2001).
Mikkelsen, T. et al. The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J. Neurooncol. 96, 97–102 (2010).
Sirven, J. I., Wingerchuk, D. M., Drazkowski, J. F., Lyons, M. K. & Zimmerman, R. S. Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin. Proc. 79, 1489–1494 (2004).
Tremont-Lukats, I. W., Ratilal, B. O., Armstrong, T. & Gilbert, M. R. Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst. Rev. 2, CD004424 (2008).
Kong, X. et al. A meta-analysis: do prophylactic antiepileptic drugs in patients with brain tumors decrease the incidence of seizures? Clin. Neurol. Neurosurg. 134, 98–103 (2015).
Wu, A. S. et al. A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors. J. Neurosurg. 118, 873–883 (2013).
Patchell, R. A. et al. A randomized trial of surgery in the treatment of single metastases to the brain. N. Engl. J. Med. 322, 494–500 (1990).
Noordijk, E. M. et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int. J. Radiat. Oncol. Biol. Phys. 29, 711–717 (1994).
Bindal, R. K., Sawaya, R., Leavens, M. E. & Lee, J. J. Surgical treatment of multiple brain metastases. J. Neurosurg. 79, 210–216 (1993).
Schackert, G., Lindner, C., Petschke, S., Leimert, M. & Kirsch, M. Retrospective study of 127 surgically treated patients with multiple brain metastases: indication, prognostic factors, and outcome. Acta Neurochir. 155, 379–387 (2013).
Schackert, G., Schmiedel, K., Lindner, C., Leimert, M. & Kirsch, M. Surgery of recurrent brain metastases: retrospective analysis of 67 patients. Acta Neurochir. 155, 1823–1832 (2013).
Nahed, B. V. et al. Congress of Neurological Surgeons systematic review and evidence-based guidelines on the role of surgery in the management of adults with metastatic brain tumors. Neurosurgery 84, E152–E155 (2019).
Lee, C. H. et al. The role of surgical resection in the management of brain metastasis: a 17-year longitudinal study. Acta Neurochir. 155, 389–397 (2013).
Patel, A. J. et al. Factors influencing the risk of local recurrence after resection of a single brain metastasis. J. Neurosurg. 113, 181–189 (2010).
Patel, A. J. et al. Impact of surgical methodology on the complication rate and functional outcome of patients with a single brain metastasis. J. Neurosurg. 122, 1132–1143 (2015).
Suki, D. et al. Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. J. Neurosurg. 108, 248–257 (2008).
Suki, D. et al. Comparative risk of leptomeningeal dissemination of cancer after surgery or stereotactic radiosurgery for a single supratentorial solid tumor metastasis. Neurosurgery 64, 664–674 (2009).
Baumert, B. G. et al. A pathology-based substrate for target definition in radiosurgery of brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 66, 187–194 (2006).
Berghoff, A. S. et al. Invasion patterns in brain metastases of solid cancers. Neuro Oncol. 15, 1664–1672 (2013).
Yoo, H. et al. Reduced local recurrence of a single brain metastasis through microscopic total resection. J. Neurosurg. 110, 730–736 (2009).
Kamp, M. A. et al. Proof of principle: supramarginal resection of cerebral metastases in eloquent brain areas. Acta Neurochir. 154, 1981–1986 (2012).
Sanmillan, J. L., Fernandez-Coello, A., Fernandez-Conejero, I., Plans, G. & Gabarros, A. Functional approach using intraoperative brain mapping and neurophysiological monitoring for the surgical treatment of brain metastases in the central region. J. Neurosurg. 126, 698–707 (2017).
Vogelbaum, M. A. & Suh, J. H. Resectable brain metastases. J. Clin. Oncol. 24, 1289–1294 (2006).
Carpentier, A. et al. Laser thermal therapy: real-time MRI-guided and computer-controlled procedures for metastatic brain tumors. Lasers Surg. Med. 43, 943–950 (2011).
Mehta, A. M., Sonabend, A. M. & Bruce, J. N. Convection-enhanced delivery. Neurotherapeutics 14, 358–371 (2017).
Arvanitis, C. D. et al. Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc. Natl Acad. Sci. USA 115, E8717–E8726 (2018).
Ahluwalia, M. et al. Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis. J. Neurosurg. 130, 804–811 (2018).
Tsao, M. N. et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst. Rev. 1, CD003869 (2018).
Kim, J. M. et al. The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies. J. Neurooncol. 133, 357–368 (2017).
Mulvenna, P. et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 388, 2004–2014 (2016).
Trifiletti, D. M., Larner, J. M. & Sheehan, J. P. When should patients with brain metastases receive whole brain irradiation? J. Radiosurg. SBRT 4, 1–3 (2016).
Farris, M. et al. Brain metastasis velocity: a novel prognostic metric predictive of overall survival and freedom from whole-brain radiation therapy after distant brain failure following upfront radiosurgery alone. Int. J. Radiat. Oncol. Biol. Phys. 98, 131–141 (2017).
Patchell, R. A. et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280, 1485–1489 (1998).
Brown, P. D. 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 316, 401–409 (2016).
Nabors, L. B., et al. NCCN Guidelines Version 1.2019 Central Nervous System Cancers. NCCN https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf (2019).
Soffietti, R. et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol. 19, 162–174 (2017).
Brown, P. D. et al. Whole-brain radiotherapy for brain metastases: evolution or revolution? J. Clin. Oncol. 36, 483–491 (2018).
Li, J., Bentzen, S. M., Renschler, M. & Mehta, M. P. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J. Clin. Oncol. 25, 1260–1266 (2007).
Gondi, V. et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J. Clin. Oncol. 32, 3810–3816 (2014).
Rapp, S. R. et al. Donepezil for irradiated brain tumor survivors: a phase III randomized placebo-controlled clinical trial. J. Clin. Oncol. 33, 1653–1659 (2015).
Dye, N. B., Gondi, V. & Mehta, M. P. Strategies for preservation of memory function in patients with brain metastases. Chin. Clin. Oncol. 4, 24 (2015).
Brown, P. D. et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 15, 1429–1437 (2013).
Gondi, V. et al. Preservation of neurocognitive function (NCF) with conformal avoidance of the hippocampus during whole-brain radiotherapy (HA-WBRT) for brain metastases: preliminary results of phase III trial NRG Oncology CC001. Int. J. Radiat. Oncol. Biol. Phys. 102, 1607 (2018).
Redmond, K. J. et al. Prospective study of hippocampal-sparing prophylactic cranial irradiation in limited-stage small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 98, 603–611 (2017).
Nguyen, T. K. et al. Single-fraction stereotactic radiosurgery versus hippocampal-avoidance whole brain radiation therapy for patients with 10 to 30 brain metastases: a dosimetric analysis. Int. J. Radiat. Oncol. Biol. Phys. 105, 394–399 (2019).
Auperin, A. et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N. Engl. J. Med. 341, 476–484 (1999).
Lee, J. J. et al. Decision analysis for prophylactic cranial irradiation for patients with small-cell lung cancer. J. Clin. Oncol. 24, 3597–3603 (2006).
Slotman, B. J. et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J. Clin. Oncol. 27, 78–84 (2009).
Takahashi, T. et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 18, 663–671 (2017).
Gore, E. M. et al. Randomized phase II study comparing prophylactic cranial irradiation alone to prophylactic cranial irradiation and consolidative extracranial irradiation for extensive-disease small cell lung cancer (ED SCLC): NRG Oncology RTOG 0937. J. Thorac. Oncol. 12, 1561–1570 (2017).
Manapov, F. et al. Prophylactic cranial irradiation in small-cell lung cancer: update on patient selection, efficacy and outcomes. Lung Cancer 9, 49–55 (2018).
Le Pechoux, C. et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 10, 467–474 (2009).
Li, N. et al. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann. Oncol. 26, 504–509 (2015).
Pottgen, C. et al. Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J. Clin. Oncol. 25, 4987–4992 (2007).
Sun, A. et al. Prophylactic cranial irradiation vs observation in patients with locally advanced non-small cell lung cancer: a long-term update of the NRG Oncology/RTOG 0214 phase 3 randomized clinical trial. JAMA Oncol. 5, 847–855 (2019).
De Ruysscher, D. et al. Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: a randomized phase III NVALT-11/DLCRG-02 study. J. Clin. Oncol. 36, 2366–2377 (2018).
Chang, E. L. et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 10, 1037–1044 (2009).
Aoyama, H. et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295, 2483–2491 (2006).
Hong, A. M. et al. Adjuvant whole-brain radiation therapy compared with observation after local treatment of melanoma brain metastases: a multicenter, randomized phase III trial. J. Clin. Oncol. 37, 3132–3141 (2019).
Tsao, M. N. et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Practical Radiat. Oncol. 2, 210–225 (2012).
Chao, S. T. et al. Stereotactic radiosurgery in the management of limited (1-4) brain metasteses: systematic review and international stereotactic radiosurgery society practice guideline. Neurosurgery 83, 345–353 (2018).
Lal, L. S. et al. Cost-effectiveness analysis of a randomized study comparing radiosurgery with radiosurgery and whole brain radiation therapy in patients with 1 to 3 brain metastases. Am. J. Clin. Oncol. 35, 45–50 (2012).
Lester-Coll, N. H. et al. Cost-effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for up to 10 brain metastases. J. Neurosurg. 125, 18–25 (2016).
Savitz, S. T., Chen, R. C. & Sher, D. J. Cost-effectiveness analysis of neurocognitive-sparing treatments for brain metastases. Cancer 121, 4231–4239 (2015).
Abel, R. J. et al. Stereotactic radiosurgery to the resection cavity for brain metastases: prognostic factors and outcomes. J. Radiosurg. SBRT 3, 179–186 (2015).
Zhang, Y. & Chang, E. L. Resection cavity radiosurgery for intracranial metastases: a review of the literature. J. Radiosurg. SBRT 3, 91–102 (2014).
Brown, P. D. et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 18, 1049–1060 (2017).
Mahajan, A. et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 18, 1040–1048 (2017).
Kocher, M. 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. 29, 134–141 (2011).
Kayama, T. et al. Effects of surgery with salvage stereotactic radiosurgery versus surgery with whole-brain radiation therapy in patients with one to four brain metastases (JCOG0504): a phase III, noninferiority, randomized controlled trial. J. Clin. Oncol. 36, 3282–3289 (2018).
Atalar, B. et al. Cavity volume dynamics after resection of brain metastases and timing of postresection cavity stereotactic radiosurgery. Neurosurgery 72, 180–185 (2013).
Soliman, H. et al. Consensus contouring guidelines for postoperative completely resected cavity stereotactic radiosurgery for brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 100, 436–442 (2018).
Patel, K. R. et al. Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi-institutional analysis. J. Neurooncol. 131, 611–618 (2017).
Routman, D. M. et al. Preoperative stereotactic radiosurgery for brain metastases. Front. Neurol. 9, 959 (2018).
Yamamoto, M. et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 15, 387–395 (2014).
Hughes, R. T. et al. Initial SRS for patients with 5 to 15 brain metastases: results of a multi-institutional experience. Int. J. Radiat. Oncol. Biol. Phys. 104, 1091–1098 (2019).
Joshi, R. S. et al. Prognostic importance of cumulative intracranial tumor volume in patients with gastrointestinal brain metastasis treated with stereotactic radiosurgery. World Neurosurg. 121, e747–e754 (2019).
Hirshman, B. R. et al. Superior prognostic value of cumulative intracranial tumor volume relative to largest intracranial tumor volume for stereotactic radiosurgery-treated brain metastasis patients. Neurosurgery 82, 473–480 (2018).
Prasad, D. in Adult CNS Radiation Oncology (eds Chang, E., Brown, P., Lo, S., Sahgal, A. & Suh, J.) 665–685 (Springer, 2018).
Thomas, E. M., Popple, R. A., Bredel, M. & Fiveash, J. B. in Adult CNS Radiation Oncology (eds Chang, E., Brown, P., Lo, S., Sahgal, A. & Suh, J.) 639–663 (Springer, 2018).
Wiggenraad, R. et al. Dose-effect relation in stereotactic radiotherapy for brain metastases. A systematic review. Radiother. Oncol. 98, 292–297 (2011).
Vogelbaum, M. A. et al. Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin. J. Neurosurg. 104, 907–912 (2006).
Marcrom, S. R. et al. Fractionated stereotactic radiation therapy for intact brain metastases. Adv. Radiat. Oncol. 2, 564–571 (2017).
Minniti, G. et al. Fractionated stereotactic radiosurgery for patients with brain metastases. J. Neurooncol. 117, 295–301 (2014).
Traylor, J. I. et al. Fractionated stereotactic radiotherapy for local control of resected brain metastases. J. Neuro-oncol. 144, 343–350 (2019).
Angelov, L. et al. Impact of 2-staged stereotactic radiosurgery for treatment of brain metastases ≥2 cm. J. Neurosurg. 129, 366–382 (2018).
Yomo, S., Hayashi, M. & Nicholson, C. A prospective pilot study of two-session Gamma Knife surgery for large metastatic brain tumors. J. Neurooncol. 109, 159–165 (2012).
Higuchi, Y. et al. Three-staged stereotactic radiotherapy without whole brain irradiation for large metastatic brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 74, 1543–1548 (2009).
Minniti, G. et al. Single-fraction versus multifraction (3×9 Gy) stereotactic radiosurgery for large (>2 cm) brain metastases: a comparative analysis of local control and risk of radiation-induced brain necrosis. Int. J. Radiat. Oncol. Biol. Phys. 95, 1142–1148 (2016).
Kim, K. H. et al. Outcome evaluation of patients treated with fractionated Gamma Knife radiosurgery for large (>3 cm) brain metastases: a dose-escalation study. J. Neurosurg. https://doi.org/10.3171/2019.5.jns19222 (2019).
Choi, C. Y. et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases: prospective evaluation of target margin on tumor control. Int. J. Radiat. Oncol. Biol. Phys. 84, 336–342 (2012).
Shen, C. J. et al. The strategy of repeat stereotactic radiosurgery without whole brain radiation treatment for new brain metastases: outcomes and implications for follow-up monitoring. Pract. Radiat. Oncol. 6, 409–416 (2016).
Kotecha, R. et al. Three or more courses of stereotactic radiosurgery for patients with multiply recurrent brain metastases. Neurosurgery 80, 871–879 (2017).
Shultz, D. B. et al. Repeat courses of stereotactic radiosurgery (SRS), deferring whole-brain irradiation, for new brain metastases after initial SRS. Int. J. Radiat. Oncol. Biol. Phys. 92, 993–999 (2015).
McTyre, E. et al. Multi-institutional competing risks analysis of distant brain failure and salvage patterns after upfront radiosurgery without whole brain radiotherapy for brain metastasis. Ann. Oncol. 29, 497–503 (2018).
Eichler, A. F. et al. The biology of brain metastases — translation to new therapies. Nat. Rev. Clin. Oncol. 8, 344–356 (2011).
Fortin, D. The blood-brain barrier: its influence in the treatment of brain tumors metastases. Curr. Cancer Drug Targets 12, 247–259 (2012).
Lockman, P. R. et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin. Cancer Res. 16, 5664–5678 (2010).
Barlesi, F. et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann. Oncol. 22, 2466–2470 (2011).
Robinet, G. et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95-1. Ann. Oncol. 12, 59–67 (2001).
Cortes, J. et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology 64, 28–35 (2003).
Dinglin, X. X. et al. Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial. J. Neurooncol. 112, 461–466 (2013).
Antonadou, D. et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J. Clin. Oncol. 20, 3644–3650 (2002).
Verger, E. et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 61, 185–191 (2005).
Tomasini, P., Walia, P., Labbe, C., Jao, K. & Leighl, N. B. Targeting the KRAS pathway in non-small cell lung cancer. Oncologist 21, 1450–1460 (2016).
da Cunha Santos, G., Shepherd, F. A. & Tsao, M. S. EGFR mutations and lung cancer. Annu. Rev. Pathol. 6, 49–69 (2011).
Pao, W. et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004).
Cappuzzo, F. et al. Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC). Lung Cancer 41, 227–231 (2003).
Ishida, A. et al. Gefitinib as a first line of therapy in non-small cell lung cancer with brain metastases. Intern. Med. 43, 718–720 (2004).
Fekrazad, M. H., Ravindranathan, M. & Jones, D. V. Jr. Response of intracranial metastases to erlotinib therapy. J. Clin. Oncol. 25, 5024–5026 (2007).
Ceresoli, G. L. et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann. Oncol. 15, 1042–1047 (2004).
Kim, J. E. et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer 65, 351–354 (2009).
Porta, R. et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur. Respir. J. 37, 624–631 (2011).
Grommes, C. et al. "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 13, 1364–1369 (2011).
How, J., Mann, J., Laczniak, A. N. & Baggstrom, M. Q. Pulsatile erlotinib in EGFR-positive non-small-cell lung cancer patients with leptomeningeal and brain metastases: review of the literature. Clin. Lung Cancer 18, 354–363 (2017).
Welsh, J. W. et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J. Clin. Oncol. 31, 895–902 (2013).
Lee, S. M. et al. Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J. Natl Cancer Inst. 106, dju151 (2014).
Sperduto, P. W. et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: radiation therapy oncology group 0320. Int. J. Radiat. Oncol. Biol. Phys. 85, 1312–1318 (2013).
Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017).
Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).
Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446–454 (2018).
Janne, P. A. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372, 1689–1699 (2015).
Solomon, B. J. et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J. Clin. Oncol. 34, 2858–2865 (2016).
Venur, V. A. & Ahluwalia, M. S. Targeted therapy in brain metastases: ready for primetime? Am. Soc. Clin. Oncol. Educ. Book 35, e123–e130 (2016).
Crino, L. et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J. Clin. Oncol. 34, 2866–2873 (2016).
Gadgeel, S. M. et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 15, 1119–1128 (2014).
Hida, T. et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 390, 29–39 (2017).
Peters, S. et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017).
Camidge, D. R. et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 379, 2027–2039 (2018).
Freedman, R. A. et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J. Clin. Oncol. 37, 1081–1089 (2019).
Venur, V. A. & Leone, J. P. Targeted therapies for brain metastases from breast cancer. Int. J. Mol. Sci. 17, 1543 (2016).
Bachelot, T. et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 14, 64–71 (2013).
Lin, N. U. et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin. Cancer Res. 15, 1452–1459 (2009).
Lin, N. U. et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 26, 1993–1999 (2008).
Freedman, R. A. et al. Translational Breast Cancer Research Consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J. Clin. Oncol. 34, 945–952 (2016).
Freedman, R. et al. TBCRC 022: phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J. Clin. Oncol. 35, 1005 (2017).
Borges, V. F. et al. Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases. J. Clin. Oncol. 34, 513 (2016).
Lin, N. U. et al. Determination of the maximum tolerated dose (MTD) of the CNS penetrant tyrosine kinase inhibitor (TKI) tesevatinib administered in combination with trastuzumab in HER2+ patients with metastatic breast cancer (BC). J. Clin. Oncol. 34, 514 (2016).
Dijkers, E. C. et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin. Pharmacol. Ther. 87, 586–592 (2010).
Lewis Phillips, G. D. et al. Trastuzumab uptake and its relation to efficacy in an animal model of HER2-positive breast cancer brain metastasis. Breast Cancer Res. Treat. 164, 581–591 (2017).
Lin, N. U. et al. Interim analysis of PATRICIA: an open-label, single-arm, phase II study of pertuzumab (P) with high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression post radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC). J. Clin. Oncol. 35, 2074 (2017).
Bartsch, R. et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin. Exp. Metastasis 32, 729–737 (2015).
Kennecke, H. et al. Metastatic behavior of breast cancer subtypes. J. Clin. Oncol. 28, 3271–3277 (2010).
Lin, N. U., Bellon, J. R. & Winer, E. P. CNS metastases in breast cancer. J. Clin. Oncol. 22, 3608–3617 (2004).
Anders, C. K. et al. Phase 2 study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC). J. Clin. Oncol. 37, 1017 (2019).
Cheng, L., Lopez-Beltran, A., Massari, F., MacLennan, G. T. & Montironi, R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod. Pathol. 31, 24–38 (2018).
McArthur, G. A. et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann. Oncol. 28, 634–641 (2017).
Long, G. V. et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 1087–1095 (2012).
Davies, M. A. et al. Dabrafenib plus trametinib in patients with BRAF V600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 18, 863–873 (2017).
Shonka, N., Venur, V. A. & Ahluwalia, M. S. Targeted treatment of brain metastases. Curr. Neurol. Neurosci. Rep. 17, 37 (2017).
Margolin, K. et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13, 459–465 (2012).
Goldberg, S. B. et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 17, 976–983 (2016).
Tawbi, H. et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study checkmate 204. J. Clin. Oncol. 35, 9507 (2017).
Long, G. et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): the anti-PD1 brain collaboration (ABC). J. Clin. Oncol. 35, 9508 (2017).
Tawbi, H. A. et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N. Engl. J. Med. 379, 722–730 (2018).
Flippot, R. et al. Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study. J. Clin. Oncol. 37, 2008–2016 (2019).
Kondziolka, D., Shin, S. M., Brunswick, A., Kim, I. & Silverman, J. S. The biology of radiosurgery and its clinical applications for brain tumors. Neuro Oncol. 17, 29–44 (2015).
Reynders, K., Illidge, T., Siva, S., Chang, J. Y. & De Ruysscher, D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat. Rev. 41, 503–510 (2015).
Kotecha, R. et al. The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis. Neuro Oncol. 21, 1060–1068 (2019).
Schoenfeld, J. D. et al. Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. J. Immunother. Cancer 3, 50 (2015).
Knisely, J. P. et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J. Neurosurg. 117, 227–233 (2012).
Schapira, E. et al. Improved overall survival and locoregional disease control with concurrent PD-1 pathway inhibitors and stereotactic radiosurgery for lung cancer patients with brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 101, 624–629 (2018).
Levin, V. A. et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int. J. Radiat. Oncol. Biol. Phys. 79, 1487–1495 (2011).
Acharya, S. et al. Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents. Adv. Radiat. Oncol. 2, 572–580 (2017).
Colaco, R. J., Martin, P., Kluger, H. M., Yu, J. B. & Chiang, V. L. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J. Neurosurg. 125, 17–23 (2016).
Lehrer, E. J. et al. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother. Oncol. 130, 104–112 (2019).
Lin, N. U. et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 16, e270–e278 (2015).
Shearkhani, O. et al. Detection of volume-changing metastatic brain tumors on longitudinal MRI using a semiautomated algorithm based on the Jacobian operator field. Am. J. Neuroradiol. 38, 2059–2066 (2017).
Jakubovic, R. et al. The predictive capacity of apparent diffusion coefficient (ADC) in response assessment of brain metastases following radiation. Clin. Exp. Metastasis 33, 277–284 (2016).
Detsky, J. S. et al. Differentiating radiation necrosis from tumor progression in brain metastases treated with stereotactic radiotherapy: utility of intravoxel incoherent motion perfusion MRI and correlation with histopathology. J. Neurooncol. 134, 433–441 (2017).
Mehrabian, H. et al. Water exchange rate constant as a biomarker of treatment efficacy in patients with brain metastases undergoing stereotactic radiosurgery. Int. J. Radiat. Oncol. Biol. Phys. 98, 47–55 (2017).
Desmond, K. L. et al. Chemical exchange saturation transfer for predicting response to stereotactic radiosurgery in human brain metastasis. Magn. Reson. Med. 78, 1110–1120 (2017).
Mehrabian, H., Desmond, K. L., Soliman, H., Sahgal, A. & Stanisz, G. J. Differentiation between radiation necrosis and tumor progression using chemical exchange saturation transfer. Clin. Cancer Res. 23, 3667–3675 (2017).
Peng, L. et al. Distinguishing true progression from radionecrosis after stereotactic radiation therapy for brain metastases with machine learning and radiomics. Int. J. Radiat. Oncol. Biol. Phys. 102, 1236–1243 (2018).
Schouten, L. J., Rutten, J., Huveneers, H. A. & Twijnstra, A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94, 2698–2705 (2002).
Barnholtz-Sloan, J. S. et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J. Clin. Oncol. 22, 2865–2872 (2004).
Sperduto, P. W. et al. Estimating survival in patients with gastrointestinal cancers and brain metastases: an update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA). Clin. Transl. Radiat. Oncol. 18, 39–45 (2019).
J.H.S. has acted as a consultant of AbbVie. R.K. has received honoraria from Accuray, Elekta AB, Elsevier and Novocure, and has served on the advisory board of Accuray and Novocure. S.T.C. has received honoraria from Varian Medical Systems. M.S.A. has acted as a consultant of AbbVie, Bayer, Elsevier, Flatiron, Karyopharm, Varian Medical Systems and VBI vaccines, has received royalties from Wiley, fees for contracted research from AbbVie, AstraZeneca, Bayer, BMS, Incyte, Merck, Novocure and Pharmacyclics, and owns stocks in Doctible and Mimivax. A.S. has acted as a consultant of AbbVie, BrainLAB, Elekta (Gamma Knife Icon), Merck, Roche and Varian, has served on the advisory board of VieCure and the International Stereotactic Radiosurgery Society (ISRS), has conducted educational seminars on behalf of Accuray, BrainLAB, Elekta AB and Varian (CNS Teaching Faculty), has received a research grant from Elekta AB, has received travel and accommodation fees from BrainLAB, Elekta and Varian, and is a member of the Elekta MR Linac, Elekta Spine, Oligometastases and Linac-based SRS consortia. E.L.C. declares no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Suh, J.H., Kotecha, R., Chao, S.T. et al. Current approaches to the management of brain metastases. Nat Rev Clin Oncol 17, 279–299 (2020). https://doi.org/10.1038/s41571-019-0320-3
This article is cited by
Acta Neuropathologica Communications (2023)
MRI-based two-stage deep learning model for automatic detection and segmentation of brain metastases
European Radiology (2023)
Retrospective study of hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy for patients with brain metastases
Radiation Oncology (2022)
Nature Medicine (2022)