Ashley L. Sumrall

Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi-institutional analysis

Pre-operative stereotactic radiosurgery (pre-SRS) has been shown as a viable treatment option for resectable brain metastases (BM). The aim of this study is to compare oncologic outcomes and toxicities for pre-SRS and post-operative WBRT (post-WBRT) for resectable BM. We reviewed records of consecutive patients who underwent resection of BM and either pre-SRS or post-WBRT between 2005 and 2013 at two institutions. Overall survival (OS) was calculated using the Kaplan–Meier method. Cumulative incidence was used for intracranial outcomes. Multivariate analysis (MVA) was performed using the Cox and Fine and Gray models, respectively. Overall, 102 patients underwent surgical resection of BM; 66 patients with 71 lesions received pre-SRS while 36 patients with 42 cavities received post-WBRT. Baseline characteristics were similar except for the pre-SRS cohort having more single lesions (65.2% vs. 38.9%, pu2009=u20090.001) and smaller median lesion volume (8.3xa0cc vs. 15.3xa0cc, pu2009=u20090.006). 1-year OS was similar between cohorts (58% vs. 56%, respectively) (pu2009=u20090.43). Intracranial outcomes were also similar (2-year outcomes, pre-SRS vs. post-WBRT): local recurrence: 24.5% vs. 25% (pu2009=u20090.81), distant brain failure (DBF): 53.2% vs. 45% (pu2009=u20090.66), and leptomeningeal disease (LMD) recurrence: 3.5% vs. 9.0% (pu2009=u20090.66). On MVA, radiation cohort was not independently associated with OS or any intracranial outcome. Crude rates of symptomatic radiation necrosis were 5.6 and 0%, respectively. OS and intracranial outcomes were similar for patients treated with pre-SRS or post-WBRT for resected BM. Pre-SRS is a viable alternative to post-WBRT for resected BM. Further confirmatory studies with neuro-cognitive outcomes comparing these two treatment paradigms are needed.

Single-Fraction Stereotactic Radiosurgery (SRS) Alone Versus Surgical Resection and SRS for Large Brain Metastases: A Multi-institutional Analysis

PURPOSEnStereotactic radiosurgery (SRS) dose is limited by brain metastasis (BM) size. The study goal was to retrospectively determine whether there is a benefit for intracranial outcomes and overall survival (OS) for gross total resection with single-fraction SRS versus SRS alone for patients with large BMs.nnnMETHODS AND MATERIALSnA large BM was defined as ≥4xa0cm3 (2xa0cm in diameter) prior to the study. We reviewed the records of consecutive patients treated with single-fraction SRS alone or surgery with preoperative or postoperative SRS between 2005 and 2013 from 2 institutions.nnnRESULTSnOverall, 213 patients with 223 treated large BMs were included; 66 BMs (30%) were treated with SRS alone and 157 (70%) with surgery and SRS (63 preoperatively and 94 postoperatively). The groups (SRS vs surgery and SRS) were well balanced except regarding lesion volume (median, 5.9xa0cm3 vs 9.6xa0cm3; P<.001), median number of BMs (1.5 vs 1, P=.002), median SRS dose (18xa0Gy vs 15xa0Gy, P<.001), and prior whole-brain radiation therapy (33% vs 5%, P<.001). The local recurrence (LR) rate was significantly lower with surgery and SRS (1-year LR rate, 36.7% vs 20.5%; P=.007). There was no difference in radiation necrosis (RN) by resection status, but there was a significantly increased RN rate with postoperative SRS versus with preoperative SRS and with SRS alone (1-year RN rate, 22.6% vs 5% and 12.3%, respectively; P<.001). OS was significantly higher with surgery and SRS (2-year OS rate, 38.9% vs 19.8%; P=.01). Both multivariate adjusted analyses and propensity score-matched analyses demonstrated similar results.nnnCONCLUSIONSnIn this retrospective study, gross total resection with SRS was associated with significantly reduced LR compared with SRS alone for patients with large BMs. Postoperative SRS was associated with the highest rate of RN. Surgical resection with SRS may improve outcomes in patients with a limited number of large BMs compared with SRS alone. Further studies are warranted.

External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiotherapy after Stereotactic Radiosurgery for Brain Metastases

BACKGROUNDnA scoring system using pretreatment factors was recently published forxa0predicting the risk of early (≤6xa0months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3xa0cm3, with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population.nnnMETHODSnWe reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence.nnnRESULTSnThe low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3xa0cm3xa0(P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53).nnnCONCLUSIONnThe 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR [combined IR and HR]) for early (≤6xa0months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted.

External validity of two nomograms for predicting distant brain failure after radiosurgery for brain metastases in a bi-institutional independent patient cohort

Patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) are at increased risk of distant brain failure (DBF). Two nomograms have been recently published to predict individualized risk of DBF after SRS. The goal of this study was to assess the external validity of these nomograms in an independent patient cohort. The records of consecutive patients with BM treated with SRS at Levine Cancer Institute and Emory University between 2005 and 2013 were reviewed. Three validation cohorts were generated based on the specific nomogram or recursive partitioning analysis (RPA) entry criteria: Wake Forest nomogram (nu2009=u2009281), Canadian nomogram (nu2009=u2009282), and Canadian RPA (nu2009=u2009303) validation cohorts. Freedom from DBF at 1-year in the Wake Forest study was 30% compared with 50% in the validation cohort. The validation c-index for both the 6-month and 9-month freedom from DBF Wake Forest nomograms was 0.55, indicating poor discrimination ability, and the goodness-of-fit test for both nomograms was highly significant (pu2009<u20090.001), indicating poor calibration. The 1-year actuarial DBF in the Canadian nomogram study was 43.9% compared with 50.9% in the validation cohort. The validation c-index for the Canadian 1-year DBF nomogram was 0.56, and the goodness-of-fit test was also highly significant (pu2009<u20090.001). The validation accuracy and c-index of the Canadian RPA classification was 53% and 0.61, respectively. The Wake Forest and Canadian nomograms for predicting risk of DBF after SRS were found to have limited predictive ability in an independent bi-institutional validation cohort. These results reinforce the importance of validating predictive models in independent patient cohorts.

415OALTERNATING ELECTRIC FIELDS THERAPY FOR RECURRENT GLIOBLASTOMA - NOVOTTF-100A SYSTEM: UPDATED OUTCOMES AND TOXICITY BASED ON THE ANALYSIS OF PATIENT REGISTRY DATA

ABSTRACT Aim: To present updated outcomes and toxicity data from patients with recurrent glioblastoma treated with the commercially available NovoTTF-100A System using patient registry database. Methods: The NovoTTF-100A device has been available by prescription at 126 oncology centers in the United States since November 2011. We retrospectively analyzed the outcomes and toxicity data from patients who were prescribed the device from November 2011 to November 2013 as treatment for recurrent glioblastoma. Overall survival (OS) was calculated based on social security death registry data. It was defined as the time from the treatment start until the date of death or last known date patient was alive. We analyzed performance status, compliance records, treatment history and adverse effects for all subjects. Results: There were 148 female and 309 male patients (n = 457) who were treated with NovoTTF-100A System. The median age was 55 years (range 18 to 86). Median Karnofsky Performance Status (KPS) was 80 (range 10-100) and 33% of patients were at their first recurrence when therapy was initiated. Over half of the patients (n = 252) received bevacizumab prior to NovoTTF- 100A therapy. The median OS was 9.6 (95% [CI] 8.0 to 13.7) months and the median treatment duration was 4.1 (95% [CI] 3.5 to 4.8) months. The average patient compliance with the use of the device was 70%. OS was positively correlated with higher compliance (= > 75%) and KPS (70-100), and negatively correlated with recurrence number and prior use of bevacizumab. Debulking surgery prior to the introduction of NovoTTF-100A therapy did not influence OS. The most common device-related adverse events included skin reactions (24.3%), neurological disorders (10.4%), heat sensation (8.9%), electric sensation (7.7%) and headache (5.7%). Conclusions: Treatment with NovoTTF-100A System, as prescribed in the neuro-oncology clinical practice to patients with recurrent glioblastoma offers favorable outcomes when compared to historical data. Patient compliance with the prescribed use of the system is high and positively correlates with improved survival. Bevacizumab naive patients benefit more while patients with poor KPS and multiple prior recurrences benefit less from this treatment. NovoTTF-100A System is well tolerated and has no new unexpected toxicities since its introduction to clinical practice. Disclosure: M.M. Mrugala: On Advisory Board of Novocure. PI on the clinical trial sponsored by Novocure; H.H. Engelhard: I have participated in Novocures Advisory Boards; N. Butowski: I participated in Novocures Advisory Board; D.D. Tran: I have received honorarium from Novocure for advisory board and speaker bureau; Y. Kew: I have participated in Novocures Advisory Boards; R. Cavaliere: I have been a consultant for Novocure; J. Villano: Member of a speakers bureau and served on an advisory board for Novocure. D. Bota: Novocure Advisory Board; S. Kesari: I have received funding for advisory board meetings and clinical trials sponsored by Novocure; J. Rudnick: I have been a consultant for Novocure; A. Sumrall: I have been a Faculty Speaker and participated in an Advisory Board for Novocure; J.J. Zhu: Novocure Advisory Board; E.T. Wong: I received research funding from Novocure.