Skip to main content
Top
Published in: Current Treatment Options in Oncology 4/2017

Open Access 01-04-2017 | Lung Cancer (HA Wakelee, Section Editor)

A Neuro-oncologist’s Perspective on Management of Brain Metastases in Patients with EGFR Mutant Non-small Cell Lung Cancer

Authors: Tresa McGranahan, MD PhD, Seema Nagpal, MD

Published in: Current Treatment Options in Oncology | Issue 4/2017

Login to get access

Opinion statement

Management of non-small cell lung cancer (NSCLC) with brain metastasis (BrM) has been revolutionized by identification of molecular subsets that have targetable oncogenes. Historically, survival for NSCLC with symptomatic BrM was weeks to months. Now, many patients are surviving years with limited data to guide treatment decisions. Tumors with activating mutations in epidermal growth factor receptor (EGFRact+) have a higher incidence of BrM, but a longer overall survival. The high response rate of both systemic and BrM EGFRact+ NSCLC to tyrosine kinase inhibitors (TKIs) has led to the rapid incorporation of new therapies but is outpacing evidence-based decisions for BrM in NSCLC. While whole brain radiation therapy (WBRT) was the foundation of management of BrM, extended survival raises concerns for the subacute and late effects radiotherapy. We favor the use of TKIs and delaying the use of WBRT when able. At inevitable disease progression, we consider alternative dosing schedules to increase CNS penetration (such as pulse dosing of erlotinib) or advance to next generation TKI if available. We utilize local control options of surgery or stereotactic radiosurgery (SRS) for symptomatic accessible lesions based on size and edema. At progression despite available TKIs, we use pemetrexed-based platinum doublet chemotherapy or immunotherapy if the tumor has high expression of PDL-1. We reserve the use of WBRT for patients with more than 10 BrM and progression despite TKI and conventional chemotherapy, if performance status is appropriate.
Literature
1.
go back to reference •• 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. 2016; doi:10.1001/jamaoncol.2016.3834. Updated prognositc scale for BrM in lung cancer accounting for mutational status.PubMed •• 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. 2016; doi:10.​1001/​jamaoncol.​2016.​3834. Updated prognositc scale for BrM in lung cancer accounting for mutational status.PubMed
5.
go back to reference Di Carlo A, Mariano A, Coppa A, Macchia V, Maiuri F, Iaconetta G, et al. Epidermal growth factor receptor and tissue tumor markers in human intracranial neoplasms. J Neurosurg Sci. 1990;34(3–4):181–5.PubMed Di Carlo A, Mariano A, Coppa A, Macchia V, Maiuri F, Iaconetta G, et al. Epidermal growth factor receptor and tissue tumor markers in human intracranial neoplasms. J Neurosurg Sci. 1990;34(3–4):181–5.PubMed
6.
go back to reference Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39. doi:10.1056/NEJMoa040938.PubMedCrossRef Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39. doi:10.​1056/​NEJMoa040938.PubMedCrossRef
8.
go back to reference • Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5(9):2892–911. EGFRact+ worldwide incidence with maps for mutation frequency as well as reported ranges based on gender and smoking status.PubMedPubMedCentral • Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5(9):2892–911. EGFRact+ worldwide incidence with maps for mutation frequency as well as reported ranges based on gender and smoking status.PubMedPubMedCentral
11.
12.
go back to reference • Peters S, Bexelius C, Munk V, Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev. 2016;45:139–62. doi:10.1016/j.ctrv.2016.03.009. Systematic review of quality of life and survival in patients with NSCLC.PubMedCrossRef • Peters S, Bexelius C, Munk V, Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev. 2016;45:139–62. doi:10.​1016/​j.​ctrv.​2016.​03.​009. Systematic review of quality of life and survival in patients with NSCLC.PubMedCrossRef
15.
go back to reference Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005;103(11):2344–8. doi:10.1002/cncr.21033.PubMedCrossRef Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005;103(11):2344–8. doi:10.​1002/​cncr.​21033.PubMedCrossRef
16.
17.
18.
go back to reference Fang L, Sun X, Song Y, Zhang Y, Li F, Xu Y, et al. Whole-brain radiation fails to boost intracerebral gefitinib concentration in patients with brain metastatic non-small cell lung cancer: a self-controlled, pilot study. Cancer Chemother Pharmacol. 2015;76(4):873–7. doi:10.1007/s00280-015-2847-z.PubMedCrossRef Fang L, Sun X, Song Y, Zhang Y, Li F, Xu Y, et al. Whole-brain radiation fails to boost intracerebral gefitinib concentration in patients with brain metastatic non-small cell lung cancer: a self-controlled, pilot study. Cancer Chemother Pharmacol. 2015;76(4):873–7. doi:10.​1007/​s00280-015-2847-z.PubMedCrossRef
19.
go back to reference Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crino L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15(7):1042–7. doi:10.1093/annonc/mdh276.PubMedCrossRef Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crino L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15(7):1042–7. doi:10.​1093/​annonc/​mdh276.PubMedCrossRef
20.
go back to reference Pesce GA, Klingbiel D, Ribi K, Zouhair A, von Moos R, Schlaeppi M, et al. Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03). Eur J Cancer. 2012;48(3):377–84. doi:10.1016/j.ejca.2011.10.016.PubMedCrossRef Pesce GA, Klingbiel D, Ribi K, Zouhair A, von Moos R, Schlaeppi M, et al. Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03). Eur J Cancer. 2012;48(3):377–84. doi:10.​1016/​j.​ejca.​2011.​10.​016.PubMedCrossRef
21.
go back to reference Namba Y, Kijima T, Yokota S, Niinaka M, Kawamura S, Iwasaki T, et al. Gefitinib in patients with brain metastases from non–small-cell lung cancer: review of 15 clinical cases. Clinical Lung Cancer. 2004;6(2):123–8. doi:10.3816/CLC.2004.n.026.PubMedCrossRef Namba Y, Kijima T, Yokota S, Niinaka M, Kawamura S, Iwasaki T, et al. Gefitinib in patients with brain metastases from non–small-cell lung cancer: review of 15 clinical cases. Clinical Lung Cancer. 2004;6(2):123–8. doi:10.​3816/​CLC.​2004.​n.​026.PubMedCrossRef
23.
go back to reference •• Iuchi T, Shingyoji M, Sakaida T, Hatano K, Nagano O, Itakura M, et al. Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013;82(2):282–7. doi:10.1016/j.lungcan.2013.08.016. Trial design of advancing from gefitinib to erlotinib prior to salvage XRT that resulted in delayed XRT 17.9m.PubMedCrossRef •• Iuchi T, Shingyoji M, Sakaida T, Hatano K, Nagano O, Itakura M, et al. Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013;82(2):282–7. doi:10.​1016/​j.​lungcan.​2013.​08.​016. Trial design of advancing from gefitinib to erlotinib prior to salvage XRT that resulted in delayed XRT 17.9m.PubMedCrossRef
24.
go back to reference Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, 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. 2009;65(3):351–4. doi:10.1016/j.lungcan.2008.12.011.PubMedCrossRef Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, 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. 2009;65(3):351–4. doi:10.​1016/​j.​lungcan.​2008.​12.​011.PubMedCrossRef
25.
go back to reference • Zhang Q, Zhang X, Yan H, Jiang B, Xu C, Yang J, et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016;7(6):648–54. doi:10.1111/1759-7714.12379. Retrospective study of upfront TKI and salvage radiotherapy.PubMedPubMedCentralCrossRef • Zhang Q, Zhang X, Yan H, Jiang B, Xu C, Yang J, et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016;7(6):648–54. doi:10.​1111/​1759-7714.​12379. Retrospective study of upfront TKI and salvage radiotherapy.PubMedPubMedCentralCrossRef
27.
go back to reference Togashi Y, Masago K, Fukudo M, Terada T, Fujita S, Irisa K, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol. 2010;5(7):950–5. doi:10.1097/JTO.0b013e3181e2138b.PubMedCrossRef Togashi Y, Masago K, Fukudo M, Terada T, Fujita S, Irisa K, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol. 2010;5(7):950–5. doi:10.​1097/​JTO.​0b013e3181e2138b​.PubMedCrossRef
28.
go back to reference Deng Y, Feng W, Wu J, Chen Z, Tang Y, Zhang H, et al. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol. 2014;2(1):116–20. doi:10.3892/mco.2013.190.PubMed Deng Y, Feng W, Wu J, Chen Z, Tang Y, Zhang H, et al. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol. 2014;2(1):116–20. doi:10.​3892/​mco.​2013.​190.PubMed
29.
go back to reference Weber B, Winterdahl M, Memon A, Sorensen BS, Keiding S, Sorensen L, et al. Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol. 2011;6(7):1287–9. doi:10.1097/JTO.0b013e318219ab87.PubMedCrossRef Weber B, Winterdahl M, Memon A, Sorensen BS, Keiding S, Sorensen L, et al. Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol. 2011;6(7):1287–9. doi:10.​1097/​JTO.​0b013e318219ab87​.PubMedCrossRef
30.
go back to reference Olmez I, Donahue BR, Butler JS, Huang Y, Rubin P, Xu Y. Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis. Lung Cancer. 2010;70(2):174–9. doi:10.1016/j.lungcan.2010.01.018.PubMedCrossRef Olmez I, Donahue BR, Butler JS, Huang Y, Rubin P, Xu Y. Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis. Lung Cancer. 2010;70(2):174–9. doi:10.​1016/​j.​lungcan.​2010.​01.​018.PubMedCrossRef
33.
go back to reference • Lee SM, Lewanski CR, Counsell N, Ottensmeier C, Bates A, Patel N, et al. Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J Natl Cancer Inst. 2014;106(7) doi:10.1093/jnci/dju151. Prospective trial with no survival benefit to combination of eroltinib and WBRT in EGFRwt patients. • Lee SM, Lewanski CR, Counsell N, Ottensmeier C, Bates A, Patel N, et al. Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J Natl Cancer Inst. 2014;106(7) doi:10.​1093/​jnci/​dju151. Prospective trial with no survival benefit to combination of eroltinib and WBRT in EGFRwt patients.
37.
go back to reference • Yu HA, Sima C, Feldman D, Liu LL, Vaitheesvaran B, Cross J, et al. Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann Oncol. 2016; doi:10.1093/annonc/mdw556. Phase I pulse dosing of erlotinib with BrM response and no CNS progression. • Yu HA, Sima C, Feldman D, Liu LL, Vaitheesvaran B, Cross J, et al. Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann Oncol. 2016; doi:10.​1093/​annonc/​mdw556. Phase I pulse dosing of erlotinib with BrM response and no CNS progression.
38.
go back to reference Zhou L, He J, Xiong W, Liu Y, Xiang J, Yu Q, et al. Impact of whole brain radiation therapy on CSF penetration ability of icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: results of phase I dose-escalation study. Lung Cancer. 2016;96:93–100. doi:10.1016/j.lungcan.2016.04.003.PubMedCrossRef Zhou L, He J, Xiong W, Liu Y, Xiang J, Yu Q, et al. Impact of whole brain radiation therapy on CSF penetration ability of icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: results of phase I dose-escalation study. Lung Cancer. 2016;96:93–100. doi:10.​1016/​j.​lungcan.​2016.​04.​003.PubMedCrossRef
39.
go back to reference Fan Y, Huang Z, Fang L, Miao L, Gong L, Yu H, et al. A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non-small cell lung cancer. Cancer Chemother Pharmacol. 2015;76(3):517–23. doi:10.1007/s00280-015-2760-5.PubMedCrossRef Fan Y, Huang Z, Fang L, Miao L, Gong L, Yu H, et al. A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non-small cell lung cancer. Cancer Chemother Pharmacol. 2015;76(3):517–23. doi:10.​1007/​s00280-015-2760-5.PubMedCrossRef
40.
go back to reference Yang JC, Sequist LV, Zhou C, Schuler M, Geater SL, Mok T, et al. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol. 2016; doi:10.1093/annonc/mdw322. Yang JC, Sequist LV, Zhou C, Schuler M, Geater SL, Mok T, et al. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol. 2016; doi:10.​1093/​annonc/​mdw322.
41.
go back to reference Schuler M, Wu YL, Hirsh V, O’Byrne K, Yamamoto N, Mok T, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016;11(3):380–90. doi:10.1016/j.jtho.2015.11.014.PubMedCrossRef Schuler M, Wu YL, Hirsh V, O’Byrne K, Yamamoto N, Mok T, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016;11(3):380–90. doi:10.​1016/​j.​jtho.​2015.​11.​014.PubMedCrossRef
43.
go back to reference Kashima J, Okuma Y, Miwa M, Hosomi Y. Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors. Med Oncol. 2016;33(11):129. doi:10.1007/s12032-016-0843-8.PubMedCrossRef Kashima J, Okuma Y, Miwa M, Hosomi Y. Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors. Med Oncol. 2016;33(11):129. doi:10.​1007/​s12032-016-0843-8.PubMedCrossRef
44.
go back to reference Zheng MH, Sun HT, Xu JG, Yang G, Huo LM, Zhang P, et al. Combining whole-brain radiotherapy with gefitinib/erlotinib for brain metastases from non-small-cell lung cancer: a meta-analysis. Biomed Res Int. 2016;2016:5807346. doi:10.1155/2016/5807346.PubMedPubMedCentral Zheng MH, Sun HT, Xu JG, Yang G, Huo LM, Zhang P, et al. Combining whole-brain radiotherapy with gefitinib/erlotinib for brain metastases from non-small-cell lung cancer: a meta-analysis. Biomed Res Int. 2016;2016:5807346. doi:10.​1155/​2016/​5807346.PubMedPubMedCentral
45.
go back to reference Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al. 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. 2012;77(3):556–60. doi:10.1016/j.lungcan.2012.05.092.PubMedCrossRef Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al. 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. 2012;77(3):556–60. doi:10.​1016/​j.​lungcan.​2012.​05.​092.PubMedCrossRef
46.
go back to reference Park K, Tan E-H, O’Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–89. doi:10.1016/s1470-2045(16)30033-x.PubMedCrossRef Park K, Tan E-H, O’Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–89. doi:10.​1016/​s1470-2045(16)30033-x.PubMedCrossRef
47.
go back to reference Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31(27):3335–41. doi:10.1200/JCO.2012.45.0981.PubMedCrossRef Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31(27):3335–41. doi:10.​1200/​JCO.​2012.​45.​0981.PubMedCrossRef
48.
go back to reference Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S, et al. Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol. 2009;4(11):1415–9. doi:10.1097/JTO.0b013e3181b62572.PubMedCrossRef Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S, et al. Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol. 2009;4(11):1415–9. doi:10.​1097/​JTO.​0b013e3181b62572​.PubMedCrossRef
49.
go back to reference Nonagase Y, Okamoto K, Iwasa T, Yoshida T, Tanaka K, Takeda M, et al. Afatinib-refractory brain metastases from EGFR-mutant non-small-cell lung cancer successfully controlled with erlotinib: a case report. Anti-Cancer Drugs. 2016;27(3):251–3. doi:10.1097/CAD.0000000000000317.PubMedCrossRef Nonagase Y, Okamoto K, Iwasa T, Yoshida T, Tanaka K, Takeda M, et al. Afatinib-refractory brain metastases from EGFR-mutant non-small-cell lung cancer successfully controlled with erlotinib: a case report. Anti-Cancer Drugs. 2016;27(3):251–3. doi:10.​1097/​CAD.​0000000000000317​.PubMedCrossRef
50.
go back to reference Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M, et al. 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. 2015;10(1):156–63. doi:10.1097/JTO.0000000000000380.PubMedCrossRef Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M, et al. 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. 2015;10(1):156–63. doi:10.​1097/​JTO.​0000000000000380​.PubMedCrossRef
51.
go back to reference Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Nanjo S, et al. Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013;119(24):4325–32. doi:10.1002/cncr.28364.PubMedCrossRef Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Nanjo S, et al. Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013;119(24):4325–32. doi:10.​1002/​cncr.​28364.PubMedCrossRef
53.
go back to reference Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2016; doi:10.1056/NEJMoa1612674. Randomized trial with benefit in PFS for osimertinib compared to conventional chemotherapy in EGFRact+ patients 30% of had asymptomtic BrM.PubMed Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2016; doi:10.​1056/​NEJMoa1612674. Randomized trial with benefit in PFS for osimertinib compared to conventional chemotherapy in EGFRact+ patients 30% of had asymptomtic BrM.PubMed
54.
go back to reference Reichegger H, Jochum W, Forbs D, Hader C, Fruh M. Rapid intracranial response to osimertinib in a patient with epidermal growth factor receptor T790M-positive adenocarcinoma of the lung. Oncol Res Treat. 2016;39(7–8):461–3. doi:10.1159/000446759.PubMedCrossRef Reichegger H, Jochum W, Forbs D, Hader C, Fruh M. Rapid intracranial response to osimertinib in a patient with epidermal growth factor receptor T790M-positive adenocarcinoma of the lung. Oncol Res Treat. 2016;39(7–8):461–3. doi:10.​1159/​000446759.PubMedCrossRef
55.
go back to reference Ricciuti B, Chiari R, Chiarini P, Crino L, Maiettini D, Ludovini V, et al. Osimertinib (AZD9291) and CNS response in two radiotherapy-naive patients with EGFR-mutant and T790M-positive advanced non-small cell lung cancer. Clin Drug Investig. 2016;36(8):683–6. doi:10.1007/s40261-016-0411-1.PubMedCrossRef Ricciuti B, Chiari R, Chiarini P, Crino L, Maiettini D, Ludovini V, et al. Osimertinib (AZD9291) and CNS response in two radiotherapy-naive patients with EGFR-mutant and T790M-positive advanced non-small cell lung cancer. Clin Drug Investig. 2016;36(8):683–6. doi:10.​1007/​s40261-016-0411-1.PubMedCrossRef
56.
go back to reference Yang J, Kim DW, Kim SW, Cho BC, Lee J, Ye X, et al., editors. Osimertinib activity in patients with leptomeningeal disease from non-small cell lung cancer: updated results from the BLOOM study. Chicago, IL: ASCO Annual Meeting 2015; 2016. Yang J, Kim DW, Kim SW, Cho BC, Lee J, Ye X, et al., editors. Osimertinib activity in patients with leptomeningeal disease from non-small cell lung cancer: updated results from the BLOOM study. Chicago, IL: ASCO Annual Meeting 2015; 2016.
57.
go back to reference • Tan CS, Cho BC, Soo RA. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. Lung Cancer. 2016;93:59–68. doi:10.1016/j.lungcan.2016.01.003. Review of currently available and pipline TKIs.PubMedCrossRef • Tan CS, Cho BC, Soo RA. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. Lung Cancer. 2016;93:59–68. doi:10.​1016/​j.​lungcan.​2016.​01.​003. Review of currently available and pipline TKIs.PubMedCrossRef
58.
go back to reference Ahn MJ, Kim DW, Kim TM, Lin C, Ratnayake J, Carlile DJ, et al., editors. Phase I study (BLOOM) of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM). Chicago, IL: ASCO Annual Meeting 2016; 2016. Ahn MJ, Kim DW, Kim TM, Lin C, Ratnayake J, Carlile DJ, et al., editors. Phase I study (BLOOM) of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM). Chicago, IL: ASCO Annual Meeting 2016; 2016.
59.
go back to reference Stapleton SL, Reid JM, Thompson PA, Ames MM, McGovern RM, McGuffey L, et al. Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol. 2007;59(4):461–6. doi:10.1007/s00280-006-0285-7.PubMedCrossRef Stapleton SL, Reid JM, Thompson PA, Ames MM, McGovern RM, McGuffey L, et al. Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol. 2007;59(4):461–6. doi:10.​1007/​s00280-006-0285-7.PubMedCrossRef
60.
go back to reference Dinglin XX, Huang Y, Liu H, Zeng YD, Hou X, Chen LK. 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 Neuro-Oncol. 2013;112(3):461–6. doi:10.1007/s11060-013-1079-5.CrossRef Dinglin XX, Huang Y, Liu H, Zeng YD, Hou X, Chen LK. 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 Neuro-Oncol. 2013;112(3):461–6. doi:10.​1007/​s11060-013-1079-5.CrossRef
61.
go back to reference Barlesi F, Gervais R, Lena H, Hureaux J, Berard H, Paillotin D, 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. 2011;22(11):2466–70. doi:10.1093/annonc/mdr003.PubMedCrossRef Barlesi F, Gervais R, Lena H, Hureaux J, Berard H, Paillotin D, 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. 2011;22(11):2466–70. doi:10.​1093/​annonc/​mdr003.PubMedCrossRef
62.
go back to reference Ortuzar W, Hanna N, Pennella E, Peng G, Langer C, Monberg M, et al. Brain metastases as the primary site of relapse in two randomized phase III pemetrexed trials in advanced non-small-cell lung cancer. Clin Lung Cancer. 2012;13(1):24–30. doi:10.1016/j.cllc.2011.05.007.PubMedCrossRef Ortuzar W, Hanna N, Pennella E, Peng G, Langer C, Monberg M, et al. Brain metastases as the primary site of relapse in two randomized phase III pemetrexed trials in advanced non-small-cell lung cancer. Clin Lung Cancer. 2012;13(1):24–30. doi:10.​1016/​j.​cllc.​2011.​05.​007.PubMedCrossRef
63.
go back to reference Zhu W, Roe OD, Wu C, Li W, Guo R, Gu Y, et al. Activity of pemetrexed-based regimen as first-line chemotherapy for advanced non-small cell lung cancer with asymptomatic inoperable brain metastasis: a retrospective study. J Chemother. 2015;27(4):221–6. doi:10.1179/1973947815Y.0000000005.PubMedCrossRef Zhu W, Roe OD, Wu C, Li W, Guo R, Gu Y, et al. Activity of pemetrexed-based regimen as first-line chemotherapy for advanced non-small cell lung cancer with asymptomatic inoperable brain metastasis: a retrospective study. J Chemother. 2015;27(4):221–6. doi:10.​1179/​1973947815Y.​0000000005.PubMedCrossRef
64.
go back to reference Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31(23):2895–902. doi:10.1200/JCO.2012.47.1102.PubMedCrossRef Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31(23):2895–902. doi:10.​1200/​JCO.​2012.​47.​1102.PubMedCrossRef
65.
go back to reference Soria JC, Wu Y-L, Nakagawa K, Kim S-W, Yang J-J, Ahn M-J, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990–8. doi:10.1016/s1470-2045(15)00121-7.PubMedCrossRef Soria JC, Wu Y-L, Nakagawa K, Kim S-W, Yang J-J, Ahn M-J, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990–8. doi:10.​1016/​s1470-2045(15)00121-7.PubMedCrossRef
68.
go back to reference •• 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. doi:10.1016/S1470-2045(16)30053-5. Open label phase 2 of use of checkpoint inhibitor, pembrolizumab in NSCLC with brain metastasis.PubMedCrossRef •• 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. doi:10.​1016/​S1470-2045(16)30053-5. Open label phase 2 of use of checkpoint inhibitor, pembrolizumab in NSCLC with brain metastasis.PubMedCrossRef
69.
go back to reference Kanai O, Fujita K, Okamura M, Nakatani K, Mio T. Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases. Ann Oncol. 2016; doi:10.1093/annonc/mdw148. Kanai O, Fujita K, Okamura M, Nakatani K, Mio T. Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases. Ann Oncol. 2016; doi:10.​1093/​annonc/​mdw148.
70.
go back to reference Soria JC, Mauguen A, Reck M, Sandler AB, Saijo N, Johnson DH, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013;24(1):20–30. doi:10.1093/annonc/mds590.PubMedCrossRef Soria JC, Mauguen A, Reck M, Sandler AB, Saijo N, Johnson DH, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013;24(1):20–30. doi:10.​1093/​annonc/​mds590.PubMedCrossRef
71.
go back to reference • Besse B, Le Moulec S, Mazieres J, Senellart H, Barlesi F, Chouaid C, et al. Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study. Clin Cancer Res. 2015;21(8):1896–903. doi:10.1158/1078-0432.CCR-14-2082. Phase II study of use of BEV in patients with untreated non-squamous NSCLC BrM.PubMedCrossRef • Besse B, Le Moulec S, Mazieres J, Senellart H, Barlesi F, Chouaid C, et al. Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study. Clin Cancer Res. 2015;21(8):1896–903. doi:10.​1158/​1078-0432.​CCR-14-2082. Phase II study of use of BEV in patients with untreated non-squamous NSCLC BrM.PubMedCrossRef
72.
go back to reference Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236–44. doi:10.1016/s1470-2045(14)70381-x.PubMedCrossRef Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236–44. doi:10.​1016/​s1470-2045(14)70381-x.PubMedCrossRef
74.
go back to reference Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583–90. doi:10.1002/ana.410330605.PubMedCrossRef Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583–90. doi:10.​1002/​ana.​410330605.PubMedCrossRef
76.
go back to reference Barker 2nd FG. Craniotomy for the resection of metastatic brain tumors in the U.S., 1988-2000: decreasing mortality and the effect of provider caseload. Cancer. 2004;100(5):999–1007. doi:10.1002/cncr.20058.PubMedCrossRef Barker 2nd FG. Craniotomy for the resection of metastatic brain tumors in the U.S., 1988-2000: decreasing mortality and the effect of provider caseload. Cancer. 2004;100(5):999–1007. doi:10.​1002/​cncr.​20058.PubMedCrossRef
77.
go back to reference •• Lim SH, Lee JY, Lee MY, Kim HS, Lee J, Sun JM, et al. A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer. Ann Oncol. 2015;26(4):762–8. doi:10.1093/annonc/mdu584. PhaseIII trial examining upfront SRS to conventional chemotherapy. Study was closed early due to approval of TKIs as first line, but did not show a benefit to early SRS.PubMedCrossRef •• Lim SH, Lee JY, Lee MY, Kim HS, Lee J, Sun JM, et al. A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer. Ann Oncol. 2015;26(4):762–8. doi:10.​1093/​annonc/​mdu584. PhaseIII trial examining upfront SRS to conventional chemotherapy. Study was closed early due to approval of TKIs as first line, but did not show a benefit to early SRS.PubMedCrossRef
78.
go back to reference •• Magnuson WJ, Yeung JT, Guillod PD, Gettinger SN, Yu JB, Chiang VL. Impact of deferring radiation therapy in patients with epidermal growth factor receptor-mutant non-small cell lung cancer who develop brain metastases. Int J Radiat Oncol Biol Phys. 2016;95(2):673–9. doi:10.1016/j.ijrobp.2016.01.037. Retrospective study with survival benefit to upfront SRS with TKI compared to salvage SRS.PubMedCrossRef •• Magnuson WJ, Yeung JT, Guillod PD, Gettinger SN, Yu JB, Chiang VL. Impact of deferring radiation therapy in patients with epidermal growth factor receptor-mutant non-small cell lung cancer who develop brain metastases. Int J Radiat Oncol Biol Phys. 2016;95(2):673–9. doi:10.​1016/​j.​ijrobp.​2016.​01.​037. Retrospective study with survival benefit to upfront SRS with TKI compared to salvage SRS.PubMedCrossRef
79.
go back to reference Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280(17):1485–9.PubMedCrossRef Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280(17):1485–9.PubMedCrossRef
80.
go back to reference Robinet G, Thomas P, Breton JL, Lena H, Gouva S, Dabouis 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. 2001;12(1):59–67.PubMedCrossRef Robinet G, Thomas P, Breton JL, Lena H, Gouva S, Dabouis 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. 2001;12(1):59–67.PubMedCrossRef
81.
go back to reference Cai L, Zhu J-f, Zhang X-w, Lin S-x, Su X-d, Lin P, et al. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer. J Neuro-Oncol. 2014;120(2):423–30. doi:10.1007/s11060-014-1570-7.CrossRef Cai L, Zhu J-f, Zhang X-w, Lin S-x, Su X-d, Lin P, et al. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer. J Neuro-Oncol. 2014;120(2):423–30. doi:10.​1007/​s11060-014-1570-7.CrossRef
82.
go back to reference Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, 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. 2013;85(5):1312–8. doi:10.1016/j.ijrobp.2012.11.042.PubMedPubMedCentralCrossRef Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, 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. 2013;85(5):1312–8. doi:10.​1016/​j.​ijrobp.​2012.​11.​042.PubMedPubMedCentralCrossRef
83.
go back to reference • Soon YY, Leong CN, Koh WY, Tham IW. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015;114(2):167–72. doi:10.1016/j.radonc.2014.12.011. Meta-analysis suggesting benefit to upfront radiotherapy compared to salvage stratedy.PubMedCrossRef • Soon YY, Leong CN, Koh WY, Tham IW. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015;114(2):167–72. doi:10.​1016/​j.​radonc.​2014.​12.​011. Meta-analysis suggesting benefit to upfront radiotherapy compared to salvage stratedy.PubMedCrossRef
84.
go back to reference •• Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, et al., editors. 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; doi:10.1016/s0140-6736(16)30825-x. No benefit to WBRT compared to steroids and best supportive care in patients who were not canidates for other local therapy. Study period largely pre-dated use of TKIs. •• Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, et al., editors. 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; doi:10.​1016/​s0140-6736(16)30825-x. No benefit to WBRT compared to steroids and best supportive care in patients who were not canidates for other local therapy. Study period largely pre-dated use of TKIs.
85.
go back to reference Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, et al. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008;14(1):162–8. doi:10.1158/1078-0432.ccr-07-1468.PubMedCrossRef Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, et al. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008;14(1):162–8. doi:10.​1158/​1078-0432.​ccr-07-1468.PubMedCrossRef
86.
go back to reference Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387–95. doi:10.1016/s1470-2045(14)70061-0.PubMedCrossRef Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387–95. doi:10.​1016/​s1470-2045(14)70061-0.PubMedCrossRef
88.
go back to reference 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. 2004;363(9422):1665–72. doi:10.1016/s0140-6736(04)16250-8.PubMedCrossRef 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. 2004;363(9422):1665–72. doi:10.​1016/​s0140-6736(04)16250-8.PubMedCrossRef
90.
91.
go back to reference Churilla TM, Handorf E, Soffietti R, Kocher M, Aizer AA, Collette L, et al. Does whole-brain radiation therapy for oligometastatic brain metastases translate into a survival benefit for patients with a limited competing risk from extracranial disease? A secondary analysis of EORTC 22952-26001. Int J Radiat Oncol Biol Phys. 96(2):S56–S7. doi:10.1016/j.ijrobp.2016.06.147. Churilla TM, Handorf E, Soffietti R, Kocher M, Aizer AA, Collette L, et al. Does whole-brain radiation therapy for oligometastatic brain metastases translate into a survival benefit for patients with a limited competing risk from extracranial disease? A secondary analysis of EORTC 22952-26001. Int J Radiat Oncol Biol Phys. 96(2):S56–S7. doi:10.​1016/​j.​ijrobp.​2016.​06.​147.
92.
go back to reference Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, 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(11):1037–44. doi:10.1016/s1470-2045(09)70263-3.PubMedCrossRef Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, 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(11):1037–44. doi:10.​1016/​s1470-2045(09)70263-3.PubMedCrossRef
93.
go back to reference Zhuang H, Wang J, Zhao L, Yuan Z, Wang P. The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma. Int J Cancer. 2013;133(10):2277–83. doi:10.1002/ijc.28290.PubMedCrossRef Zhuang H, Wang J, Zhao L, Yuan Z, Wang P. The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma. Int J Cancer. 2013;133(10):2277–83. doi:10.​1002/​ijc.​28290.PubMedCrossRef
94.
go back to reference Chinnaiyan P, Huang S, Vallabhaneni G, Armstrong E, Varambally S, Tomlins SA, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res. 2005;65(8):3328–35. doi:10.1158/0008-5472.can-04-3547.PubMed Chinnaiyan P, Huang S, Vallabhaneni G, Armstrong E, Varambally S, Tomlins SA, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res. 2005;65(8):3328–35. doi:10.​1158/​0008-5472.​can-04-3547.PubMed
95.
go back to reference Liu Y, Deng L, Zhou X, Zhou L, Xu Y, Gong Y, et al. Early radiation therapy combined with EGFR-TKI is associated with longer survival in EGFR-mutated non-small cell lung cancer patients with brain metastases. Int J Radiat Oncol Biol Phys. 2016;96(2):E436. doi:10.1016/j.ijrobp.2016.06.1725.CrossRef Liu Y, Deng L, Zhou X, Zhou L, Xu Y, Gong Y, et al. Early radiation therapy combined with EGFR-TKI is associated with longer survival in EGFR-mutated non-small cell lung cancer patients with brain metastases. Int J Radiat Oncol Biol Phys. 2016;96(2):E436. doi:10.​1016/​j.​ijrobp.​2016.​06.​1725.CrossRef
96.
go back to reference Magnuson WJ, Amini A, Patil T, Kavanagh BD, Camidge DR, Braunstein SE, et al. Deferring radiation therapy for brain metastases in patients with EGFR-mutant non-small cell lung cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys. 2016;96(2S):S57–S8. doi:10.1016/j.ijrobp.2016.06.149.CrossRef Magnuson WJ, Amini A, Patil T, Kavanagh BD, Camidge DR, Braunstein SE, et al. Deferring radiation therapy for brain metastases in patients with EGFR-mutant non-small cell lung cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys. 2016;96(2S):S57–S8. doi:10.​1016/​j.​ijrobp.​2016.​06.​149.CrossRef
97.
go back to reference Stokes TB, Niranjan A, Kano H, Choi PA, Kondziolka D, Dade Lunsford L, et al. White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery. J Neuro-Oncol. 2015;121(3):583–90. doi:10.1007/s11060-014-1670-4.CrossRef Stokes TB, Niranjan A, Kano H, Choi PA, Kondziolka D, Dade Lunsford L, et al. White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery. J Neuro-Oncol. 2015;121(3):583–90. doi:10.​1007/​s11060-014-1670-4.CrossRef
98.
go back to reference •• Cohen-Inbar O, Melmer P, Lee CC, Xu Z, Schlesinger D, Sheehan JP. Leukoencephalopathy in long term brain metastases survivors treated with radiosurgery. J Neuro-Oncol. 2016;126(2):289–98. doi:10.1007/s11060-015-1962-3. Study looking at rates of leukoencephalopathy in long term survivors for both SRS alone and SRS with history of WBRT.CrossRef •• Cohen-Inbar O, Melmer P, Lee CC, Xu Z, Schlesinger D, Sheehan JP. Leukoencephalopathy in long term brain metastases survivors treated with radiosurgery. J Neuro-Oncol. 2016;126(2):289–98. doi:10.​1007/​s11060-015-1962-3. Study looking at rates of leukoencephalopathy in long term survivors for both SRS alone and SRS with history of WBRT.CrossRef
100.
go back to reference Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncology. 2013;15(10):1429–37. doi:10.1093/neuonc/not114.PubMedPubMedCentralCrossRef Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncology. 2013;15(10):1429–37. doi:10.​1093/​neuonc/​not114.PubMedPubMedCentralCrossRef
102.
go back to reference Gondi V, Hermann BP, Mehta MP, Tome WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85(2):348–54. doi:10.1016/j.ijrobp.2012.11.031.PubMedCrossRef Gondi V, Hermann BP, Mehta MP, Tome WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85(2):348–54. doi:10.​1016/​j.​ijrobp.​2012.​11.​031.PubMedCrossRef
103.
go back to reference Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, et al. 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. 2013;24(4):993–9. doi:10.1093/annonc/mds529.PubMedCrossRef Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, et al. 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. 2013;24(4):993–9. doi:10.​1093/​annonc/​mds529.PubMedCrossRef
104.
106.
go back to reference Zeng Y-D, Zhang L, Liao H, Liang Y, Xu F, Liu J-L, et al. Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study. Asian Pac J Cancer Prev. 2012;13(3):909–14. doi:10.7314/apjcp.2012.13.3.909.PubMedCrossRef Zeng Y-D, Zhang L, Liao H, Liang Y, Xu F, Liu J-L, et al. Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study. Asian Pac J Cancer Prev. 2012;13(3):909–14. doi:10.​7314/​apjcp.​2012.​13.​3.​909.PubMedCrossRef
107.
go back to reference Ge H, Zhu Q, Sun Y. Comparing the clinical efficacy of TKI alone with TKI plus concomitant WBRT for EGFR mutation-positive lung adenocarcinoma patients with brain metastases: a retrospective study. Int J Radiat Oncol Biol Phys. 2016;96(2S):S132. doi:10.1016/j.ijrobp.2016.06.322.CrossRef Ge H, Zhu Q, Sun Y. Comparing the clinical efficacy of TKI alone with TKI plus concomitant WBRT for EGFR mutation-positive lung adenocarcinoma patients with brain metastases: a retrospective study. Int J Radiat Oncol Biol Phys. 2016;96(2S):S132. doi:10.​1016/​j.​ijrobp.​2016.​06.​322.CrossRef
Metadata
Title
A Neuro-oncologist’s Perspective on Management of Brain Metastases in Patients with EGFR Mutant Non-small Cell Lung Cancer
Authors
Tresa McGranahan, MD PhD
Seema Nagpal, MD
Publication date
01-04-2017
Publisher
Springer US
Published in
Current Treatment Options in Oncology / Issue 4/2017
Print ISSN: 1527-2729
Electronic ISSN: 1534-6277
DOI
https://doi.org/10.1007/s11864-017-0466-0

Other articles of this Issue 4/2017

Current Treatment Options in Oncology 4/2017 Go to the issue

Lung Cancer (HA Wakelee, Section Editor)

Optimal Radiation Therapy for Small Cell Lung Cancer

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine