INCIDENCE AND TREATMENT OF BRAIN METASTASES ARISING FROM LUNG, BREAST, OR SKIN CANCERS: REAL-WORLD EVIDENCE FROM PRIMARY CANCER REGISTRIES AND MEDICARE CLAIMS by MUSTAFA STEVEN ASCHA Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Clinical Translational Science CASE WESTERN RESERVE UNIVERSITY May 2019 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of MUSTAFA STEVEN ASCHA, MS Candidate for the degree of Doctor of Philosophy Committee Chair Fredrick R. Schumacher, Ph.D. Faculty Advisor Jill S. Barnholtz-Sloan, Ph.D. Committee Member Jeremy S. Bordeaux, M.D. Committee Member Andrew E. Sloan, M.D. Date of Defense March 18, 2019 * We also certify that written approval has been obtained for all proprietary material contained therein. 2 Dedication This work is dedicated to: the women in my family who brave, have braved, or pre-empted breast cancer, whose strength and selflessness inspires and motivates me; to Nizar N. Zein, MD, who ten years ago began mentoring me in the discipline I study with this dissertation; and to Jill S. Barnholtz-Sloan, PhD who three years ago helped me begin and later complete this work. 3 Contents Dedication ............................. .................................................................... ............. 3 List of Tables .............................................................................................. ............. 7 List of Figures ............................................................................................ ............. 9 List of Abbreviations ................................................................................... ........... 10 Acknowledgements .................................................................................... ........... 12 Abstract ...................................................................................................... ........... 13 Chapter 1 – Introduction ..................................................................................... 14 1.1 The changing nature of brain metastases epidemiology ................................... 14 1.2 Brain metastases treatment .............................................................................. 17 1.2.1 Localized treatment ....................................................................................... 17 1.2.2 Systemic treatment ........................................................................................ 20 1.3 Data sources .................................................................................................... 22 1.3.1 Data descriptions and considerations ............................................................ 22 1.3.2 Data source-specific selection criteria ........................................................... 24 1.4 Methodological rigor in computational and secondary data research ................ 25 1.4.1 Openness and version control ....................................................................... 26 1.5 Specific Aims .................................................................................................... 27 Chapter 2 - Identifying incidence of brain metastases ...................................... 28 2.1 Abstract ............................................................................................................ 28 2.2 Introduction ...................................................................................................... 30 2.3 Materials and methods ..................................................................................... 31 2.3.1 Data description ............................................................................................ 31 4 2.3.2 Identifying patients with brain metastases ..................................................... 32 2.3.3 Study Population ........................................................................................... 33 2.3.4 Study Variables ............................................................................................. 33 2.3.5 Analysis ......................................................................................................... 34 2.3.6 Reproducibility ............................................................................................... 35 2.4 Results ............................................................................................................. 36 2.5 Discussion ........................................................................................................ 38 Chapter 3 - Bevacizumab for the treatment of brain metastases ...................... 45 3.1 Abstract ............................................................................................................ 45 3.2 Introduction ...................................................................................................... 47 3.3 Materials and methods ..................................................................................... 48 3.3.1 Dataset .......................................................................................................... 48 3.3.2 Data-derived definitions ................................................................................. 49 3.3.3 Population ..................................................................................................... 50 3.3.4 Treatment patterns ........................................................................................ 51 3.3.5 Treatment efficacy ......................................................................................... 51 3.3.6 Rigor and Reproducibility .............................................................................. 53 3.4 Results ............................................................................................................. 53 3.4.1 Clinical and demographic characteristics ........................................... ........... 53 3.4.2 Treatment patterns ............................................................................ ........... 53 3.4.3 Survival analysis............................................................................................ 54 3.5 Discussion ........................................................................................................ 55 3.6 Conclusions...................................................................................................... 58 Chapter 4 - Stereotactic radiosurgery for the treatment of brain metastases . 60 5 4.1 Abstract ............................................................................................................ 59 4.2 Introduction ...................................................................................................... 62 4.2 Materials and Methods ..................................................................................... 63 4.2.1 Dataset .......................................................................................................... 63 4.2.2 Population ..................................................................................................... 64 4.2.3 Outcomes ...................................................................................................... 64 4.2.4 Definitions and covariates ............................................................................. 65 4.2.5 Statistical Analysis ......................................................................................... 65 4.2.6 Rigor and reproducibility ................................................................................ 67 4.3 Results ............................................................................................................. 67 4.3.1 Treatment patterns ........................................................................................ 67 4.4.3 Survival analysis............................................................................................ 68 4.5 Discussion ........................................................................................................ 69 Chapter 5 - Conclusions and future directions .................................................. 73 5.1 Summary and translational impact ................................................................... 73 5.2 Claims data limitations and future directions..................................................... 74 5.3 Brain metastases incidence and treatment ....................................................... 76 Bibliography ........................................................................................................ 145 6 List of Tables Table 1-1 Frequencies and median survival for patients with synchronous brain metastases ............................................................................................................. 80 Table 1-2 Diagnosis and procedure codes used to identify BM and its treatment... 81 Table 2-1 Medicare claims brain metastasis classification accuracy, SEER- Medicare population 2010-2012 ............................................................................. 84 Table 2-2 Diagnosis code-only algorithms performance, SEER-Medicare population 2010-2012 .............................................................................................................. 88 Table 2-3 Incidence of primary cancer associated with brain metastases, SEER- Medicare population 2008-2012 ............................................................................. 92 Table 2-4 Lung cancer demographics and clinical characteristics,