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External Validity of a Nomogram and Recursive Partitioning Analysis to Predict for Distant Brain Failure After Stereotactic Radiosurgery Alone for Brain Metastases: Multi-institutional Analysis
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Volume 99 Number 2S Supplement 2017 W.J. Curran Jr,3 H.K.G. Shu,1 G.L. Sica,5 and K.A. Higgins6; 1Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 2Bioinformatics and Biostatistics, Winship Cancer Institute, Emory University, Atlanta, GA, 3Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 4Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 5Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, 6Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA Purpose/Objective(s): Treatment for advanced non-small cell lung cancer (NSCLC) is increasingly personalized with the use of targeted therapies for tumors with EGFR mutations and ALK translocations. We sought to investigate outcomes of NSCLC brain metastases (BM) treated with radiation therapy based on molecular testing using modern sequencing techniques. Materials/Methods: With IRB approval, records of all patients treated with radiation therapy for BM at Emory University from 1/2010-1/2016 were identified. Patients with BM from non-squamous cell carcinoma of the lung who had available genetic testing were retrospectively reviewed. Clinical variables examined included age, gender, race, performance status, active systemic disease, presence of extracranial disease, use of systemic therapy, number of brain metastases treated, surgical resection, presence of symptoms at diagnosis, lesion size, radiation modality, and genetic testing. SNaPshot genotyping was performed prior to 1/2014 at which time Next Generation Sequencing (NGS) was utilized, along with FISH lung cancer panel. Molecular aberrations examined include the following: EGFR, ALK rearrangement, RET rearrangement, ROS1 rearrangement, TP53, KRAS, NRAS, MET amplification, PTEN, BRAF, FBXW7, MAP2K1, APC, PIK3CA, CTNNB1, and SMAD4. Univariable analyses were performed using Cox proportional hazards models and logrank tests to identify factors associated with overall survival (OS), local recurrence (LR), distant brain failure (DBF), intracranial failure (IF) (i.e. local or distant), and salvage whole brain radiotherapy (WBRT). Cumulative incidence of each outcome was estimated with competing risk analysis. Patients treated with upfront WBRT were excluded from the salvage WBRT analyses. Results: 92 patients were included for analysis. Median age was 62 (32-90 years). 52.2% and 47.8% of patients were treated with whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS), respectively. For all patients with known KRAS status, presence of KRAS mutation was not associated with an increased risk of DBF (HRZ0.60 95% CI 0.271.36), however, in patients treated with upfront SRS (nZ38), presence of KRAS mutation was associated with an increased risk for DBF (HRZ3.17 95% CI 1.25-8.05), IF (HRZ2.98 95% CI 1.17-7.54), and need for salvage WBRT (HRZ11.7 95% CI 2.5-54.6) (all p<0.05). The 6-month cumulative incidence of salvage WBRT for KRAS mutation positive and negative patients was 35.7% and 4.6%, respectively (pZ0.0004). There was no difference in OS (HR 1.54 95% CI 0.57-4.16, pZ0.39). No other mutations were associated with risk of DBF or need for salvage WBRT. Conclusion: Patients with KRAS mutant NSCLC who develop BM appear to be at increased risk of distant brain failure and need for salvage WBRT after upfront SRS. These select patients may benefit less from upfront SRS. Author Disclosure: R.H. Press: None. X. Zhang: None. R.J. Cassidy: None. M.J. Ferris: None. J. Zhong: None. C. Steuer: None. R. Pillai: None. T.K. Owonikoko: None. S. Ramalingam: None. P.R. Patel: None. W.J. Curran: ; ASCO. H. Shu: Honoraria; Varian Medical Systems. Speaker’s Bureau; Varian Medical Systems. Travel Expenses; Varian Medical Systems. Stock; Apple, Medtronics. ; QIN CTTDWG. G.L. Sica: None. K.A. Higgins: None.
2239 External Validity of a Nomogram and Recursive Partitioning Analysis to Predict for Distant Brain Failure After Stereotactic Radiosurgery Alone for Brain Metastases: Multi-institutional Analysis R.H. Press,1 D.M. Boselli,2 K. Patel,3 J.T. Symanowski,2 S.P. Lankford,4 R.J. McCammon,4 B.J. Moeller,4 J.H. Heinzerling,4 C. Fasola,4 A. Asher,5
A.L. Sumrall,6 W.J. Curran, Jr,3 H.K.G. Shu,1 I.R. Crocker,1 S.H. Burri,7 and R.S. Prabhu4; 1Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 2Department of Biostatistics, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, 3 Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 4Southeast Radiation Oncology Group, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, 5Carolina Neurosurgery and Spine Associates, Charlotte, NC, 6Department of Oncology, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, 7 Southeast Radiation Oncology Group, Levine Cancer Institute, Charlotte, NC Purpose/Objective(s): Patients (pts) with brain metastases (BM) treated with stereotactic radiosurgery (SRS) alone are at increased risk of distant brain failure (DBF). A nomogram and recursive partitioning analysis (RPA) designed to predict for DBF at 1 year (yr) after SRS alone from a single institution Canadian tertiary care hospital was recently published (Rodrigues et al., Radio and Oncol 2014). We sought to evaluate the external validity of these tools using a multi-institutional independent validation cohort (VC). Materials/Methods: The records of consecutive pts with BM treated with SRS alone at 2 tertiary care cancer institutes between 2005-2013 were reviewed. Inclusion criteria were identical to the Canadian study and included pts treated with initial SRS alone, up to 3 BM, and no previous cranial irradiation. The nomogram variables included age, number of BM, largest lesion volume (cc), and WHO performance status (PS) to calculate probability of 1-yr DBF using the Kaplan-Meier method. The RPA defined 3 risk categories (low [LR], intermediate [IR], and high risk [HR]) based on PS, age, and number of BM. Discrimination was assessed using Harrell’s c-index and calibration was assessed using calibration plots and correlation between expected and observed DBF. Results: After exclusions, a total of 282 pts with 390 BM and 303 pts with 416 BM were eligible for the nomogram and RPAVC, respectively. Median age was 60 years old, median tumor volume was 1.35 cc, and median number of BM was 1. Primary disease site was lung 44%, melanoma 20.2%, breast 17.4%, renal 7.8%, GI 2.8%, and other 11.6%. One-year actuarial DBF for the nomogram VC was 50.9% compared to 43.9% in the Canadian study. The Harrell’s c-index for the DBF nomogram using the VC was 0.56 compared to 0.69 in the Canadian study, indicating poor discrimination ability. Calibration plots for the nomogram demonstrated good correlation between predicted and observed DBF (r2Z0.92), but with systematic underestimation of DBF risk by an average of 19.6% across all risk levels. RPA risk groups LR, IR, and HR had 1-yr DBF rates of 39%, 62%, and 51.8%, compared to Canadian rates of 25.1%, 45.9%, and 69.1%, respectively. RPA risk groups did demonstrate significantly different actuarial DBF rates (log-rank pZ0.0008), but IR had a higher 1-yr DBF rate than HR and would have been categorized as high risk in the Canadian publication (> 40%). The accuracy of the RPA classification was 53% compared with 75% in the Canadian study. Conclusion: In an independent multi-institutional cohort, the Canadian nomogram and RPA classification were not found to be externally valid, had limited ability to accurately differentiate DBF at 1-yr, and generally underestimated risk of DBF. We currently recommend caution in using these tools to predict individualized risk of 1-yr DBF after SRS alone. Author Disclosure: R.H. Press: None. D.M. Boselli: None. K. Patel: None. J.T. Symanowski: None. S.P. Lankford: None. R.J. McCammon: None. B.J. Moeller: Independent Contractor; Novant Health. J.H. Heinzerling: None. C. Fasola: None. A. Asher: None. A.L. Sumrall: None. W.J. Curran: ; ASCO. H. Shu: None. I.R. Crocker: None. S.H. Burri: Partner; Southeast Radiation Oncology. board member; Brain Tumor Fund for the Carolinas. R.S. Prabhu: None.
2240 The Impact of Timing of Immunotherapy with Cranial Irradiation on Early Distant Brain Progression and Overall Survival in Patients with Melanoma Brain Metastases R. Rahman,1 A. Cortes,2 K.S. Oh,2 K.T. Flaherty,2 D.P. Lawrence,2 R.J. Sullivan,2 and H.A. Shih2; 1Harvard Radiation Oncology Program, Boston, MA, 2Massachusetts General Hospital, Boston, MA
Volume 99 Number 2S Supplement 2017 W.J. Curran Jr,3 H.K.G. Shu,1 G.L. Sica,5 and K.A. Higgins6; 1Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 2Bioinformatics and Biostatistics, Winship Cancer Institute, Emory University, Atlanta, GA, 3Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 4Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 5Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, 6Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA Purpose/Objective(s): Treatment for advanced non-small cell lung cancer (NSCLC) is increasingly personalized with the use of targeted therapies for tumors with EGFR mutations and ALK translocations. We sought to investigate outcomes of NSCLC brain metastases (BM) treated with radiation therapy based on molecular testing using modern sequencing techniques. Materials/Methods: With IRB approval, records of all patients treated with radiation therapy for BM at Emory University from 1/2010-1/2016 were identified. Patients with BM from non-squamous cell carcinoma of the lung who had available genetic testing were retrospectively reviewed. Clinical variables examined included age, gender, race, performance status, active systemic disease, presence of extracranial disease, use of systemic therapy, number of brain metastases treated, surgical resection, presence of symptoms at diagnosis, lesion size, radiation modality, and genetic testing. SNaPshot genotyping was performed prior to 1/2014 at which time Next Generation Sequencing (NGS) was utilized, along with FISH lung cancer panel. Molecular aberrations examined include the following: EGFR, ALK rearrangement, RET rearrangement, ROS1 rearrangement, TP53, KRAS, NRAS, MET amplification, PTEN, BRAF, FBXW7, MAP2K1, APC, PIK3CA, CTNNB1, and SMAD4. Univariable analyses were performed using Cox proportional hazards models and logrank tests to identify factors associated with overall survival (OS), local recurrence (LR), distant brain failure (DBF), intracranial failure (IF) (i.e. local or distant), and salvage whole brain radiotherapy (WBRT). Cumulative incidence of each outcome was estimated with competing risk analysis. Patients treated with upfront WBRT were excluded from the salvage WBRT analyses. Results: 92 patients were included for analysis. Median age was 62 (32-90 years). 52.2% and 47.8% of patients were treated with whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS), respectively. For all patients with known KRAS status, presence of KRAS mutation was not associated with an increased risk of DBF (HRZ0.60 95% CI 0.271.36), however, in patients treated with upfront SRS (nZ38), presence of KRAS mutation was associated with an increased risk for DBF (HRZ3.17 95% CI 1.25-8.05), IF (HRZ2.98 95% CI 1.17-7.54), and need for salvage WBRT (HRZ11.7 95% CI 2.5-54.6) (all p<0.05). The 6-month cumulative incidence of salvage WBRT for KRAS mutation positive and negative patients was 35.7% and 4.6%, respectively (pZ0.0004). There was no difference in OS (HR 1.54 95% CI 0.57-4.16, pZ0.39). No other mutations were associated with risk of DBF or need for salvage WBRT. Conclusion: Patients with KRAS mutant NSCLC who develop BM appear to be at increased risk of distant brain failure and need for salvage WBRT after upfront SRS. These select patients may benefit less from upfront SRS. Author Disclosure: R.H. Press: None. X. Zhang: None. R.J. Cassidy: None. M.J. Ferris: None. J. Zhong: None. C. Steuer: None. R. Pillai: None. T.K. Owonikoko: None. S. Ramalingam: None. P.R. Patel: None. W.J. Curran: ; ASCO. H. Shu: Honoraria; Varian Medical Systems. Speaker’s Bureau; Varian Medical Systems. Travel Expenses; Varian Medical Systems. Stock; Apple, Medtronics. ; QIN CTTDWG. G.L. Sica: None. K.A. Higgins: None.
2239 External Validity of a Nomogram and Recursive Partitioning Analysis to Predict for Distant Brain Failure After Stereotactic Radiosurgery Alone for Brain Metastases: Multi-institutional Analysis R.H. Press,1 D.M. Boselli,2 K. Patel,3 J.T. Symanowski,2 S.P. Lankford,4 R.J. McCammon,4 B.J. Moeller,4 J.H. Heinzerling,4 C. Fasola,4 A. Asher,5
A.L. Sumrall,6 W.J. Curran, Jr,3 H.K.G. Shu,1 I.R. Crocker,1 S.H. Burri,7 and R.S. Prabhu4; 1Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 2Department of Biostatistics, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, 3 Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 4Southeast Radiation Oncology Group, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, 5Carolina Neurosurgery and Spine Associates, Charlotte, NC, 6Department of Oncology, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, 7 Southeast Radiation Oncology Group, Levine Cancer Institute, Charlotte, NC Purpose/Objective(s): Patients (pts) with brain metastases (BM) treated with stereotactic radiosurgery (SRS) alone are at increased risk of distant brain failure (DBF). A nomogram and recursive partitioning analysis (RPA) designed to predict for DBF at 1 year (yr) after SRS alone from a single institution Canadian tertiary care hospital was recently published (Rodrigues et al., Radio and Oncol 2014). We sought to evaluate the external validity of these tools using a multi-institutional independent validation cohort (VC). Materials/Methods: The records of consecutive pts with BM treated with SRS alone at 2 tertiary care cancer institutes between 2005-2013 were reviewed. Inclusion criteria were identical to the Canadian study and included pts treated with initial SRS alone, up to 3 BM, and no previous cranial irradiation. The nomogram variables included age, number of BM, largest lesion volume (cc), and WHO performance status (PS) to calculate probability of 1-yr DBF using the Kaplan-Meier method. The RPA defined 3 risk categories (low [LR], intermediate [IR], and high risk [HR]) based on PS, age, and number of BM. Discrimination was assessed using Harrell’s c-index and calibration was assessed using calibration plots and correlation between expected and observed DBF. Results: After exclusions, a total of 282 pts with 390 BM and 303 pts with 416 BM were eligible for the nomogram and RPAVC, respectively. Median age was 60 years old, median tumor volume was 1.35 cc, and median number of BM was 1. Primary disease site was lung 44%, melanoma 20.2%, breast 17.4%, renal 7.8%, GI 2.8%, and other 11.6%. One-year actuarial DBF for the nomogram VC was 50.9% compared to 43.9% in the Canadian study. The Harrell’s c-index for the DBF nomogram using the VC was 0.56 compared to 0.69 in the Canadian study, indicating poor discrimination ability. Calibration plots for the nomogram demonstrated good correlation between predicted and observed DBF (r2Z0.92), but with systematic underestimation of DBF risk by an average of 19.6% across all risk levels. RPA risk groups LR, IR, and HR had 1-yr DBF rates of 39%, 62%, and 51.8%, compared to Canadian rates of 25.1%, 45.9%, and 69.1%, respectively. RPA risk groups did demonstrate significantly different actuarial DBF rates (log-rank pZ0.0008), but IR had a higher 1-yr DBF rate than HR and would have been categorized as high risk in the Canadian publication (> 40%). The accuracy of the RPA classification was 53% compared with 75% in the Canadian study. Conclusion: In an independent multi-institutional cohort, the Canadian nomogram and RPA classification were not found to be externally valid, had limited ability to accurately differentiate DBF at 1-yr, and generally underestimated risk of DBF. We currently recommend caution in using these tools to predict individualized risk of 1-yr DBF after SRS alone. Author Disclosure: R.H. Press: None. D.M. Boselli: None. K. Patel: None. J.T. Symanowski: None. S.P. Lankford: None. R.J. McCammon: None. B.J. Moeller: Independent Contractor; Novant Health. J.H. Heinzerling: None. C. Fasola: None. A. Asher: None. A.L. Sumrall: None. W.J. Curran: ; ASCO. H. Shu: None. I.R. Crocker: None. S.H. Burri: Partner; Southeast Radiation Oncology. board member; Brain Tumor Fund for the Carolinas. R.S. Prabhu: None.
2240 The Impact of Timing of Immunotherapy with Cranial Irradiation on Early Distant Brain Progression and Overall Survival in Patients with Melanoma Brain Metastases R. Rahman,1 A. Cortes,2 K.S. Oh,2 K.T. Flaherty,2 D.P. Lawrence,2 R.J. Sullivan,2 and H.A. Shih2; 1Harvard Radiation Oncology Program, Boston, MA, 2Massachusetts General Hospital, Boston, MA