Abstract
We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012–2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7 %, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.
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Kelly K, Bunn PA (1998) Is it time to reevaluate our approach to the treatment of brain metastases in patients with non-small cell lung cancer? Lung Cancer (Amst Neth) 20(2):85–91
Schuette W (2004) Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer (Amst Neth) 45(Suppl 2):S253–257
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM et al (2012) 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 13(3):239–246
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362(25):2380–2388
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T et al (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11(2):121–128
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957
Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F et al (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368(25):2385–2394
Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB et al (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371(21):1963–1971
Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, Ross J, Miller V, Ginsberg M, Zakowski MF et al (2013) Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer discov 3(6):630–635
Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, Smith P et al (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14(1):38–47
Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503(7477):548–551
Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, Lee JS (2012) Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer (Amst Neth) 77(3):556–560
Welsh JW, Komaki R, Amini A, Munsell MF, Unger W, Allen PK, Chang JY, Wefel JS, McGovern SL, Garland LL et al (2013) 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(7):895–902
Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu Y et al (2013) Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol 24(4):993–999
Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, Souhami L, Buyyounouski MK, Khuntia D, Demas W et al (2013) 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(5):1312–1318
Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH et al (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10(11):1037–1044
Kondziolka D, Shin SM, Brunswick A, Kim I, Silverman JS (2015) The biology of radiosurgery and its clinical applications for brain tumors. Neuro-oncology 17(1):29–44
Kondziolka D, Cooper BT, Lunsford LD, Silverman JS (2015) Development, implementation, and use of a local and global clinical registry for neurosurgery. Big Data 3(2):80–89
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 11). Eur J Cancer 45(2):228–247
Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R (1997) Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37(4):745–751
Paddick I (2000) A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg 93(Suppl 3):219–222
Paddick I, Lippitz B (2006) A simple dose gradient measurement tool to complement the conformity index. J Neurosurg 105(Suppl):194–201
Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J et al (2013) Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn JMD 15(4):415–453
Kondziolka D, Kano H, Harrison GL, Yang HC, Liew DN, Niranjan A, Brufsky AM, Flickinger JC, Lunsford LD (2011) Stereotactic radiosurgery as primary and salvage treatment for brain metastases from breast cancer. Clinical article. J Neurosurg 114(3):792–800
Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, Sakamori Y, Nagai H, Kim YH, Katsura T et al (2012) Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70(3):399–405
Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, Yu HA, Chan TA, Zhang Z, Wu AJ (2014) Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 89(2):322–329
Clarke JL, Pao W, Wu N, Miller VA, Lassman AB (2010) High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 99(2):283–286
Hata A, Katakami N (2015) Afatinib for erlotinib refractory brain metastases in a patient with EGFR-mutant non-small-cell lung cancer: can high-affinity TKI substitute for high-dose TKI? J Thorac Oncol 10(7):e65–66
Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M, Serke M, Stohlmacher-Williams J, Marten A, Maria Huber R et al (2015) Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol 10(1):156–163
Wang TJ, Saad S, Qureshi YH, Jani A, Nanda T, Yaeh AM, Rozenblat T, Sisti MB, Bruce JN, McKhann GM et al (2015) Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation? Neuro-oncology 17(7):1022–1028
Mak KS, Gainor JF, Niemierko A, Oh KS, Willers H, Choi NC, Loeffler JS, Sequist LV, Shaw AT, Shih HA (2015) Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases. Neuro-oncology 17(2):296–302
Eichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, Lynch TJ, Sequist LV (2010) EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro-oncology 12(11):1193–1199
Granone P, Margaritora S, D’Andrilli A, Cesario A, Kawamukai K, Meacci E (2001) Non-small cell lung cancer with single brain metastasis: the role of surgical treatment. Eur J Cardio Thorac Surg 20(2):361–366
Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, Yamanaka K, Sato Y, Jokura H, Yomo S et al (2014) Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 15(4):387–395
Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H et al (2010) 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(3):655–661
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This work was supported by internal institutional funding only.
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Samuel M. Shin and Benjamin T. Cooper contributed equally to this article and are considered as co-first authors.
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Shin, S.M., Cooper, B.T., Chachoua, A. et al. Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery. J Neurooncol 126, 483–491 (2016). https://doi.org/10.1007/s11060-015-1986-8
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DOI: https://doi.org/10.1007/s11060-015-1986-8