title: Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis.
abstract: Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: William J
authors.initials: WJ
authors.lastname: Magnuson
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Nataniel H
authors.initials: NH
authors.lastname: Lester-Coll
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Wu
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: T Jonathan
authors.initials: TJ
authors.lastname: Yang
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Lockney
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Naamit K
authors.initials: NK
authors.lastname: Gerber
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beal
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Arya
authors.initials: A
authors.lastname: Amini
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Tejas
authors.initials: T
authors.lastname: Patil
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Kavanagh
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Braunstein
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Boreta
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Balasubramanian
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Manmeet S
authors.initials: MS
authors.lastname: Ahluwalia
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Niteshkumar G
authors.initials: NG
authors.lastname: Rana
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Albert
authors.initials: A
authors.lastname: Attia
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Scott N
authors.initials: SN
authors.lastname: Gettinger
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Contessa
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: James B
authors.initials: JB
authors.lastname: Yu
authors.affiliation: William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Chiang
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016634:Radiosurgery; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors