Stereotactic Radiosurgery for Multiple Brain Metastases
Purpose of review
To give an overview on the current evidence for stereotactic radiosurgery of brain metastases with a special focus on multiple brain metastases.
While the use of stereotactic radiosurgery in patients with limited brain metastases has been clearly defined, its role in patients with multiple lesions (> 4) is still a matter of controversy. Whole-brain radiation therapy (WBRT) has been the standard treatment approach for patients with multiple brain lesions and is still the most commonly used treatment approach worldwide. Although distant brain failure is improved by WBRT, the overall survival is not readily impacted. As WBRT is associated with significant neurocognitive decline compared to stereotactic radiosurgery (SRS), SRS has been explored and increasingly utilized for selected patients with multiple brain metastases. Recent clinical data indicated the feasibility of stereotactic radiosurgery to multiple brain metastases with a similar survival in patients with more than 4 brain metastases versus patients with a maximum of 4 brain metastases. Also, neurocognitive function and quality of life was maintained after stereotactic radiosurgery which is essential in a palliative setting.
The application of stereotactic radiosurgery with Gamma Knife, Cyberknife, or LINAC-based equipment has emerged as an effective and widely available treatment option for patients with limited brain metastases. Although not formally proven in prospective studies, SRS may also be considered as a safe and effective treatment option in selected patients with multiple brain metastases. Especially in patients with a favorable prognosis, survival over several years is observed also in the setting of multiple BM. For these patients, avoidance of the neurocognitive damage of WBRT is desirable, and SRS is often a more appropriate treatment in the current multimodality treatment of BM in which systemic treatment is often the cornerstone of the treatment. For patients with an intermediate (3–12 months) and poor prognosis (< 3 months), the application of WBRT becomes more and more controversial, because of its acute side effects, such as hair loss and fatigue and, thereby, detrimental effect on quality of life. For these patients, best supportive care, primary systemic treatment, and even SRS may be preferred over WBRT on an individualized patient basis.
KeywordsBrain metastases Multiple brain metastases Stereotactic radiosurgery
Compliance with Ethical Standards
Conflict of Interest
Johannes Kraft and Matthias Guckenberger each declare no potential conflicts of interest. Nicolaus Andratschke reports grants from Brainlab AG, outside the submitted work. Giuseppe Minniti reports personal fees from BrainLAb, outside the submitted work. Jaap Zindler has no personal conflicts of interest—MAASTRO Clinic has a research agreement with Varian Medical Systems Palo Alto USA.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Hardesty DA, Nakaji P. The current and future treatment of brain metastases. Front Surg. 2016;3(30). https://doi.org/10.3389/fsurg.2016.00030.
- 7.• Brown PD, Ahluwalia MS, Khan OH, Asher AL, Wefel JS, Gondi V. Whole-brain radiotherapy for brain metastases: evolution or revolution? J Clin Oncol. 2018;36(5):483–91 This recently published review critically outlines the treatment of WBRT in patients with brain metastases and gives an overview about toxicity considerations and alternative therapies in the management of brain metastases.PubMedCrossRefPubMedCentralGoogle Scholar
- 8.•• Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, 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. 2016;388(10055):2004–14 This study was a phase 3 randomized non-inferiority trial showing neither overall survival benefit nor improved quality of life in poor non-small cell lung cancer patients with whole brain radiotherapy compared to best supportive care and dexamethasone.PubMedPubMedCentralCrossRefGoogle Scholar
- 9.Halasz LM, Uno H, Hughes M, D’Amico T, Dexter EU, Edge SB, et al. Comparative effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for patients with brain metastases from breast or non-small cell lung cancer. Cancer. 2016;122(13):2091–100.PubMedPubMedCentralCrossRefGoogle Scholar
- 12.Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, et al. Individual patient data (IPD) meta-analysis of randomized controlled trials (RCT) comparing stereotactic radiosurgery alone to SRS plus whole brain radiation therapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys. 2013;87(5):1187.CrossRefGoogle Scholar
- 16.Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, 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. 2016;17(7):976–83.PubMedPubMedCentralCrossRefGoogle Scholar
- 20.•• 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):401–9 This trial showed significant cognitive decline with WBRT added to stereotactic radiosurgery in patients with 1–3 brain metastases compared with patients receiving only stereotactic radiosurgery without added WBRT.PubMedPubMedCentralCrossRefGoogle Scholar
- 21.Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952–26,001 study. J Clin Oncol. 2011;29(2):134–41.PubMedCrossRefPubMedCentralGoogle Scholar
- 23.Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, 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 (London, England). 2004;363(9422):1665–72.CrossRefGoogle Scholar
- 24.Sperduto PW, Shanley R, Luo X, Andrews D, Werner-Wasik M, Valicenti R, et al. Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1–3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int J Radiat Oncol Biol Phys. 2014;90(3):526–31.PubMedPubMedCentralCrossRefGoogle Scholar
- 28.Lester SC, Taksler GB, Kuremsky JG, Lucas JT Jr, Ayala-Peacock DN, Randolph DM 2nd, et al. Clinical and economic outcomes of patients with brain metastases based on symptoms: An argument for routine brain screening of those treated with upfront radiosurgery. Cancer. 2014;120(3):433–41.PubMedCrossRefPubMedCentralGoogle Scholar
- 32.•• Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, 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. 2017;18(8):1049–60 This randomized, controlled, phase 3 trial reports on radiotherapy in the postoperative setting of brain metastases and favors stereotactic radiosurgery to the resection cavity compared to whole brain radiotherapy with less toxic effects to the brain and same overall survival.PubMedPubMedCentralCrossRefGoogle Scholar
- 33.•• Mahajan A, Ahmed S, McAleer MF, Weinberg JS, Li J, Brown P, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1040–8 This study highlights the use of post-operative stereotactic radiosurgery to the resection cavity in brain metastases with significantly improved local control rates compared to observation.PubMedPubMedCentralCrossRefGoogle Scholar
- 34.• Soffietti R, Abacioglu U, Baumert B, Combs SE, Kinhult S, Kros JM, et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro-oncology. 2017;19(2):162–74 Amongst others, this guideline recommends stereotactic radiosurgery as the favored treatment for patients with limited brain metastases in good clinical performance status and favorable prognostic factors.PubMedPubMedCentralCrossRefGoogle Scholar
- 37.• Levy A, Faivre-Finn C, Hasan B, De Maio E, Berghoff AS, Girard N, et al. Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey. Eur J Cancer (Oxford, England: 1990). 2018;93:37–46 This online survey-based report gives an overview about the diversity in screening and management of brain metastases of non-small cell lung cancer patients in Europe.CrossRefGoogle Scholar
- 39.Moriarty TMLJ, PMCL B, Shrieve DS, Wen PY, Fine HA, Kooy HM, et al. Long-term follow-up of patients treated with stereotactic radiosurgery for single or multiple brain metastases. In: Kondziolka D, editor. Radiosurgery. Basel: Karger; 1995. p. 83–91.Google Scholar
- 40.Young REJD, Duma C, Rand RW, Henderson J, Vermeulen SS, Grimm P, et al. Gamma Knife radio-surgery for treatment of multiple brain metastases. In: Kondziolka D, editor. Radiosurgery. Basel: Karger; 1995. p. 92–101.Google Scholar
- 41.Yamamoto M, Ide M, Jimbo M, Aiba M, Ito M, Hirai T, et al. Gamma Knife radiosurgery with numerous target points for intracranially disseminated metastases. Radiosurgery 1997. 2: Karger Publishers; 1998. p. 94–109.Google Scholar
- 47.• Nichol A, Ma R, Hsu F, Gondara L, Carolan H, Olson R, et al. Volumetric radiosurgery for 1 to 10 brain metastases: a multicenter, single-arm, phase 2 study. Int J Radiat Oncol Biol Phys. 2016;94(2):312–21 This phase II study reports on feasibility, tolerability, and toxicity of hypo-fractionated radiosurgery in five fractions for up to 10 BMs.PubMedCrossRefPubMedCentralGoogle Scholar
- 50.Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Barfod BE, et al. A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1–4 vs >/= 5 tumors: clinical article. J Neurosurg. 2013;118(6):1258–68.PubMedCrossRefPubMedCentralGoogle Scholar
- 51.Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Watanabe S, et al. Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2–9 versus 10 or more tumors. J Neurosurg. 2014;121(Suppl):16–25.PubMedCrossRefPubMedCentralGoogle Scholar
- 63.Likhacheva A, Pinnix CC, Parikh N, Allen PK, Guha-Thakurta N, McAleer M, et al. Validation of recursive partitioning analysis and diagnosis-specific graded prognostic assessment in patients treated initially with radiosurgery alone. J Neurosurg. 2012;117(0):38–44.PubMedPubMedCentralCrossRefGoogle Scholar
- 64.Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655–61.PubMedCrossRefPubMedCentralGoogle Scholar
- 65.•• Sperduto PW, Yang TJ, Beal K, Pan H, Brown PD, Bangdiwala A, 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. 2017;3(6):827–31 This paper reports on the Lung-molGPA, an updated prognostic tool of the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with non-small-cell lung cancer (NSCLC) and brain metastases, which incorporates gene alteration data into the DS-GPA.PubMedCrossRefPubMedCentralGoogle Scholar
- 68.Ayala-Peacock DN, Peiffer AM, Lucas JT, Isom S, Kuremsky JG, Urbanic JJ, et al. A nomogram for predicting distant brain failure in patients treated with gamma knife stereotactic radiosurgery without whole brain radiotherapy. Neuro-Oncology. 2014;16(9):1283–8.PubMedPubMedCentralCrossRefGoogle Scholar
- 70.Press RH, Prabhu RS, Nickleach DC, Liu Y, Shu HK, Kandula S, et al. Novel risk stratification score for predicting early distant brain failure and salvage whole-brain radiotherapy after stereotactic radiosurgery for brain metastases. Cancer. 2015;121(21):3836–43.PubMedPubMedCentralCrossRefGoogle Scholar
- 71.Farris M, McTyre ER, Cramer CK, Hughes R, Randolph DM 2nd, Ayala-Peacock DN, 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. 2017;98(1):131–41.PubMedCrossRefPubMedCentralGoogle Scholar
- 75.Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, 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. 2014;32(34):3810.PubMedPubMedCentralCrossRefGoogle Scholar
- 80.•• Mok T, Ahn M-J, Han J-Y, Kang JH, Katakami N, Kim H, et al. CNS response to osimertinib in patients (pts) with T790 M-positive advanced NSCLC: data from a randomized phase III trial (AURA3). J Clin Oncol. 2017;35(15_suppl):9005 This study highlights the effectivity of osimertinib in brain metastases in driver-mutated non-small cell lung cancer.CrossRefGoogle Scholar
- 81.•• Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829–38 This study highlights the superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC with alectinib compared to crizotinib.PubMedCrossRefPubMedCentralGoogle Scholar
- 83.Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590–9.PubMedPubMedCentralCrossRefGoogle Scholar
- 85.•• Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, et al. Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis. J Clin Oncol. 2017;35(10):1070–7 This large retrospective multi-institutional study analyzed NSCLC patients with EGFR mutation and brain metastases and showed a significant OS benefit in patients with newly diagnosed BMs receiving upfront radiotherapy plus EGFR-TKI treatment.PubMedCrossRefPubMedCentralGoogle Scholar