Original Study|Articles in Press

Upfront and Repeated Stereotactic Radiosurgery in Patients With Brain Metastases From NSCLC

Published:January 20, 2023DOI:



      Approximately 40% of non-small-cell lung cancer (NSCLC) patients develop brain metastases (BM). Stereotactic radiosurgery (SRS) instead of whole-brain radiotherapy (WBRT) is increasingly administered as an upfront treatment to patients with a limited number of BM. We present outcomes and validation of prognostic scores for these patients treated with upfront SRS.


      We retrospectively analyzed 199 patients with a total of 268 SRS courses for 539 brain metastases. Median patient age was 63 years. For larger BM, dose reduction to 18 Gy or hypofractionated SRS in 6 fractions was applied. We analyzed the BMV-, the RPA-, the GPA- and the lung-mol GPA score. Cox proportional hazards models with univariate and multivariate analyses were fitted for overall survival (OS) and intracranial progression-free survival (icPFS).


      Sixty-four patients died, 7 of them of neurological causes. Thirty eight patients (19,3%) required a salvage WBRT. Median OS was 38, 8 months (IQR: 6-NA). In univariate analysis as well as multivariate analysis, the Karnofsky performance scale index (KPI) ≥90% (P = 0, 012 and P = 0, 041) remained as independent prognostic factor for longer OS. All 4 prognostic scoring indices could be validated for OS assessment (BMV P = 0, 007; RPA P = 0, 026; GPA P = 0, 003; lung-mol GPA P = 0, 05).


      In this large cohort of NSCLC patients with BM treated with upfront and repeated SRS, OS was markedly favourable, in comparison to literature. Upfront SRS is an effective treatment approach in those patients and can decidedly reduce the impact of BM on overall prognosis. Furthermore, the analysed scores are useful prognostic tools for OS prediction.


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        • Erdmann F
        • Spix C
        • Katalinic A
        • et al.
        Krebs in Deutschland für 2017/2018.
        Krebsregister. 2021; 13 (Ausgabe. Accessed January 16 2022)
        • Lin NU
        • Lee EQ
        • Aoyama H
        • 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. 2013; 14: e396-e406
        • Bajard A
        • Westeel V
        • Dubiez A
        • et al.
        Multivariate analysis of factors predictive of brain metastases in localised non-small cell lung carcinoma.
        Lung Cancer. 2004; 45: 317-323
        • Thomas NJ
        • Myall NJ
        • Sun F
        • et al.
        Brain metastases in EGFR- and ALK-positive NSCLC: outcomes of central nervous system-penetrant tyrosine kinase inhibitors alone versus in combination with radiation.
        J Thorac Oncol. 2022; 17: 116-129
        • Rosell R
        • Carcereny E
        • Gervais R
        • et al.
        Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
        Lancet Oncol. 2012; 13: 239-246
        • Borghaei H
        • Paz-Ares L
        • Horn L
        • et al.
        Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
        N Engl J Med. 2015; 373: 1627-1639
        • Baum P
        • Winter H
        • Eichhorn ME
        • et al.
        Trends in age- and sex-specific lung cancer mortality in Europe and Northern America: analysis of vital registration data from the WHO Mortality Database between 2000 and 2017.
        Eur J Cancer. 2022; 171: 269-279
        • 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: 387-395
        • Sheehan JP
        • Sun M-H
        • Kondziolka D
        • Flickinger J
        • Lunsford LD.
        Radiosurgery for non-small cell lung carcinoma metastatic to the brain: long-term outcomes and prognostic factors influencing patient survival time and local tumor control.
        J Neurosurg. 2002; 97: 1276-1281
        • 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: 134-141
        • Soffietti R
        • Kocher M
        • Abacioglu UM
        • et al.
        A European organisation for research and treatment of cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results.
        J Clin Oncol. 2013; 31: 65-72
        • Mulvenna P
        • Nankivell M
        • Barton R
        • 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: 2004-2014
        • 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: 401-409
        • 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: 2483-2491
        • 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: 1037-1044
        • Navarria P
        • Pessina F
        • Cozzi L
        • et al.
        Hypo-fractionated stereotactic radiotherapy alone using volumetric modulated arc therapy for patients with single, large brain metastases unsuitable for surgical resection.
        Radiat Oncol. 2016; 11: 76
        • Wegner RE
        • Leeman JE
        • Kabolizadeh P
        • et al.
        Fractionated stereotactic radiosurgery for large brain metastases.
        Am J Clin Oncol. 2015; 38: 135-139
        • Gaspar L
        • Scott C
        • Rotman M
        • 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. 1997; 37: 745-751
        • Farris M
        • McTyre ER
        • Cramer CK
        • 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: 131-141
        • Sperduto PW
        • Kased N
        • Roberge D
        • et al.
        Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases.
        J Clin Oncol. 2012; 30: 419-425
        • Sperduto PW
        • Yang TJ
        • Beal K
        • 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: 827-831
        • Volckmar A-L
        • Leichsenring J
        • Kirchner M
        • et al.
        Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases.
        Int J Cancer. 2019; 145: 649-661
        • Adler JR
        • Chang SD
        • Murphy MJ
        • Doty J
        • Geis P
        • Hancock SL.
        The Cyberknife: a frameless robotic system for radiosurgery.
        Stereotact Funct Neurosurg. 1997; 69: 124-128
        • Levin VA
        • Bidaut L
        • Hou P
        • 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. 2011; 79: 1487-1495
        • Nabors LB
        • Portnow J
        • Ahluwalia M
        • et al.
        Central nervous system cancers, version 3.2020, NCCN clinical practice guidelines in oncology.
        J Natl Compr Canc Netw. 2020; 18: 1537-1570
        • Mok TS
        • Wu Y-L
        • Ahn M-J
        • et al.
        Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
        N Engl J Med. 2017; 376: 629-640
        • Gandhi L
        • Ou S-HI
        • Shaw AT
        • et al.
        Efficacy of alectinib in central nervous system metastases in crizotinib-resistant ALK-positive non-small-cell lung cancer: comparison of RECIST 1.1 and RANO-HGG criteria.
        Eur J Cancer. 2017; 82: 27-33
        • Gabay MP
        • Wirth SM
        • Stachnik JM
        • et al.
        Oral targeted therapies and central nervous system (CNS) metastases.
        CNS Drugs. 2015; 29: 935-952
        • Magnuson WJ
        • Lester-Coll NH
        • Wu AJ
        • et al.
        Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis.
        J Clin Oncol. 2017; 35: 1070-1077
        • Peters S
        • Camidge DR
        • Shaw AT
        • et al.
        Alectinib versus Crizotinib in untreated ALK-positive non-small-cell lung cancer.
        N Engl J Med. 2017; 377: 829-838
        • Reungwetwattana T
        • Nakagawa K
        • Cho BC
        • et al.
        CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated egfr-mutated advanced non-small-cell lung cancer.
        J Clin Oncol. 2018; JCO2018783118
        • Miyawaki E
        • Kenmotsu H
        • Mori K
        • et al.
        Optimal sequence of local and EGFR-TKI therapy for EGFR-mutant non-small cell lung cancer with brain metastases stratified by number of brain metastases.
        Int J Radiat Oncol Biol Phys. 2019; 104: 604-613
        • Minniti G
        • Clarke E
        • Lanzetta G
        • et al.
        Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis.
        Radiat Oncol. 2011; 6: 48
        • Milano MT
        • Grimm J
        • Niemierko A
        • et al.
        Single- and multifraction stereotactic radiosurgery dose/volume tolerances of the brain.
        Int J Radiat Oncol Biol Phys. 2021; 110: 68-86
        • Miyatake S-I
        • Nonoguchi N
        • Furuse M
        • et al.
        Pathophysiology, diagnosis, and treatment of radiation necrosis in the brain.
        Neurol Med Chir (Tokyo). 2015; 55: 50-59
        • Dohm AE
        • Tang J
        • Mills MN
        • et al.
        Clinical outcomes of non-small cell lung cancer brain metastases treated with stereotactic radiosurgery and immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy and immune checkpoint inhibitors, or chemotherapy alone.
        Int J Radiat Oncol Biol Phys. 2021; 111: e567
        • Yomo S
        • Oda K.
        Impacts of EGFR-mutation status and EGFR-TKI on the efficacy of stereotactic radiosurgery for brain metastases from non-small cell lung adenocarcinoma: A retrospective analysis of 133 consecutive patients.
        Lung Cancer. 2018; 119: 120-126
        • Rubino S
        • Oliver DE
        • Tran ND
        • et al.
        Improving brain metastases outcomes through therapeutic synergy between stereotactic radiosurgery and targeted cancer therapies.
        Front Oncol. 2022; 12854402
        • Fritz C
        • Borsky K
        • Stark LS
        • et al.
        Repeated courses of radiosurgery for new brain metastases to defer whole brain radiotherapy: feasibility and outcome with validation of the new prognostic metric brain metastasis velocity.
        Front Oncol. 2018; 8: 551
        • El Shafie RA
        • Paul A
        • Bernhardt D
        • et al.
        Robotic radiosurgery for brain metastases diagnosed with either SPACE or MPRAGE sequence (CYBER-SPACE)-a single-center prospective randomized trial.
        Neurosurgery. 2019; 84: 253-260
        • Hunter GK
        • Suh JH
        • Reuther AM
        • et al.
        Treatment of five or more brain metastases with stereotactic radiosurgery.
        Int J Radiat Oncol Biol Phys. 2012; 83: 1394-1398
        • Yamamoto M
        • Aiyama H
        • Koiso T
        • et al.
        Validity of a recently proposed prognostic grading index, brain metastasis velocity, for patients with brain metastasis undergoing multiple radiosurgical procedures.
        Int J Radiat Oncol Biol Phys. 2019; 103: 631-637
        • McTyre ER
        • Soike MH
        • Farris M
        • et al.
        Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery.
        Radiother Oncol. 2020; 142: 168-174
        • Farago AF
        • Azzoli CG.
        Beyond ALK and ROS1: RET, NTRK, EGFR and BRAF gene rearrangements in non-small cell lung cancer.
        Transl Lung Cancer Res. 2017; 6: 550-559
        • Sharabi AB
        • Lim M
        • DeWeese TL
        • Drake CG.
        Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy.
        Lancet Oncol. 2015; 16: e498-e509