bluuebunny/crossref_metadata_2025 huggingface dataset:
THER-13. IMMUNOTHERAPY VERSUS STANDARD OF CARE IN MELANOMA BRAIN METASTASES WITH KNOWN BRAF STATUS
Authors: Barnett Addison , Sagar Soumya , Lauko Adam , Wei Wei , Chao Samuel , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet
Published: August 2019

BACKGROUND: A mutation of the BRAF protein is seen in approximately 50% of melanoma patients. Immune checkpoint inhibitors (ICI) are standard therapy in melanoma patients independent of a patient’s BRAF status. The primary objective of this study is to investigate the impact of BRAF status in patients treated with ICI compared to non-ICI systemic therapy on overall survival (OS) in patients with melanoma brain metastasis (MBM). METHODS: We reviewed 351 patients with MBM treated at our tertiary care center between 2000 and 2018. Of these, 144 had known BRAF status, 71 of which were BRAF mutant and 73 were BRAF wild-type. OS was calculated from the date of diagnosis of brain metastasis to compare the efficacy of ICI to other systemic therapies. Many of these patients received multiple lines of treatment including targeted therapies at some point during their care. The log-rank test and Cox proportional hazard model was utilized to determine differences in OS. RESULTS: Eighty-four percent of patients received local therapy that included either surgery, stereotactic radiosurgery or whole brain radiation therapy. In BRAF wild-type patients, 40 received ICI and 33 underwent non-ICI systemic therapy with a median survival (5.6 vs 7.1 months) and 2-year survival (28% vs 32%), respectively (p=0.64). Of the BRAF mutant patients, 33 received ICI and 38 did not with a median survival (17.1 vs 9.0 months) and 2-year survival (36% and 19%), respectively (p=0.014). When controlling for age, KPS, ECM, and number of lesions, BRAF mutant MBM patients treated with ICI compared to non-ICI had an OS hazard ratio, HR=0.4 (95% CI=0.21 – 0.78, p=0.0069). CONCLUSIONS: ICI therapy in BRAF mutant MBM patients results in improved OS compared to those with non-ICI systemic therapy. No such difference was observed in the BRAF wild-type cohort.
THER-14. INFLUENCE OF CLINICAL PARAMETERS ON THE EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER BRAIN METASTASES (NSCLCBM)
Authors: Lauko Adam , Thapa Bicky , Muhsen Baha’eddin , Borghei-Razavi Hamid , Wei Wei , Chao Samuel , Stevens Glen , Peereboom David , Yu Jennifer , Murphy Erin , Angelov Lilyana , Mohammadi Alireza , Suh John , Barnett Gene , Pennell Nathan , Ahluwalia Manmeet
Published: August 2019

INTRODUCTION: Non-small cell lung cancer brain metastases (NSCLCBM) patients have a dismal prognosis. Immune checkpoint inhibitors (ICI) have resulted in improved outcomes in a subset of patients, although limited information exists on the impact of ICI in patients with NSCLCBM. METHODS: We reviewed 121 NSCLCBM (2012–2018) patients treated at our tertiary care center. All patients received at least 2 cycles of ICI therapy after diagnosis of NSCLCBM. Overall survival (OS) and progression-free survival (PFS) were calculated from the start of ICI therapy to date of death, progression or last follow up. Kaplan-Meier curves were used to estimate survival and were analyzed using the Wilcoxon test. RESULTS: Median age was 62 years (39–81) and median KPS was 90. Eighty-six patient received Nivolumab, 7 Atezolizumab, 25 Pembrolizumab, and 3 patients received multiple ICI over the course of their treatment for NSCLCBM. One hundred and twelve patients underwent stereotactic radiosurgery. Nine patients were treated with ICI alone and 25 patients underwent surgical resection. Median OS for the entire cohort was 558 (303–1159) days and median PFS was 220 (114–512) days. Twenty-four patients received oral steroids within the first 28 days of ICI (median prednisone equivalent dose of 27 mg). Patients on upfront steroid therapy had a median PFS of 148 days vs 301 days in patients not on upfront steroids (p-value .0095). Complete blood count at the start of ICI was available for 87 patients and neutrophil to lymphocyte ratios (NLR) were calculated. Patients with NLR at the start of ICI above 5 (n=33) had a median overall survival of 337 days compared to 558 days when NLR was below 5 (p-value .038). CONCLUSION: Use of steroids at initiation or within first 28 days of ICI therapy and NLR of greater than 5 are associated with worse outcomes in NSCLCBM treated with ICI.
MLTI-01. IMMUNOLOGICAL REPROGRAMMING IN THE CNS TUMOR MICROENVIRONMENT AND THERAPEUTIC EFFICACY OF RADIOTHERAPY WITH STAT3 BLOCKADE
Authors: Ott Martina , Hashimoto Yuuri , Marisetty Anantha , Wei Jun , Zamler Daniel , Leu Jia-Shiun , Kong Ling-Yuan , Zhou Shouhao , Fuller Gregory , de Groot John , Priebe Waldemar , Sulman Erik , Heimberger Amy
Published: August 2019

BACKGROUND: Patients with central nervous system (CNS) tumors are typically treated with radiation therapy, but this is not curative and results in the upregulation of p-STAT3 that drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of the STAT3 pathway that is currently in clinical trials (WP1066) and whole-brain radiation therapy (WBRT) in murine models of CNS malignancy. METHODS: C57BL/6 mice underwent intracerebral implantation of either B16 melanoma or GL261 glioma cells, WBRT, and treatment with WP1066 a blood-brain barrier penetrant inhibitor of the STAT3 pathway or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune incompetent backgrounds, immune monitoring, and nanostring gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the CNS tumor microenvironment. RESULTS: The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy. Immunological memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. Therapeutic efficacy was completely lost in immune incompetent mice. Extensive functional immune monitoring and nanostring profiling followed by bioinformatic processing revealed that the most robust immunological responses were located in the CNS tumor microenvironment rather than the periphery. An unbiased analysis of the immune-cell heat maps of the combination therapy relative to monotherapy were notable for upregulation of T-cell functional genes, dendritic cell function, MHC expression, and antigen presentation in the CNS tumor. These data highly suggest that antigen presentation and T-cell effector function are requirements within the tumor microenvironment of the CNS for full antitumor immune-mediated activities. CONCLUSION: This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against established tumors in the CNS by inducing dendritic cell maturation and activation in the CNS tumor.
MLTI-02. A PHASE I TRIAL OF SORAFENIB WITH WHOLE BRAIN RADIOTHERAPY (WBRT) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES AND A CORRELATIVE FLT-PET BRAIN IMAGING STUDY IN PATIENTS RECEIVING WBRT +/- SORAFENIB
Authors: Morikawa Aki , Grkovski Milan , Patil Sujata , Jhaveri Komal , Tang Kendrick , Humm John , Holodny Andrei , Beal Kathryn , Schoder Heiko , Seidman Andrew
Published: August 2019

BACKGROUND: Sorafenib has demonstrated anti-tumor efficacy in breast cancer and radiosensitizing activity preclinically. [18F] 3’deoxy-3’-fluorothymidine (FLT) is a PET tracer which correlates with cellular proliferation and may improve response assessment. METHODS: A phase I trial of whole brain radiotherapy (WBRT)+sorafenib was conducted using a 3 + 3 design. Sorafenib was given daily at the start of WBRT for 21 days (dose levels: 200mg, 400mg, and 600mg). The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment. A correlative serial FLT-PET imaging study was conducted to assess radiographic changes among pts receiving WBRT +/- sorafenib, in parallel with MRI. RESULTS:13 pts in the dose escalation were evaluable for dose-limiting toxicity (DLT). DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was 200mg. Six additional pts were treated in an expansion cohort without additional DLT. 14 pts were evaluable for response. The overall response rate was 71%: 4 complete + 6 partial responses. Median follow up was 14 months (range: 3–44). Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT+sorafenib and 5 WBRT) were enrolled in the FLT-PET study: all had baseline FLT-PET, 14 with follow up at 7–10 days post WBRT (FU1), and 9 with followup at 12 weeks post WBRT (FU2). 55 baseline lesions were observed and analyzed: 38 at FU1 and 15 at FU2. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib pts and 2/4 (50%) of WBRT only pts at FU1. CONCLUSIONS: Concurrent WBRT+sorafenib appears safe at 200mg daily dose with clinical activity. This combination should be considered for further efficacy evaluation. NCT01724606 and NCT01621906.
MLTI-10. ESTABLISHMENT OF A MULTIDISCIPLINARY BRAIN METASTASIS CLINIC TO FACILITATE PATIENT-CENTERED CARE AND COORDINATED RESEARCH
Authors: Li Jing , Lang Frederick F , Guha-Thakurta Nandita , Weinberg Jeffrey S , Rao Ganesh , Heimberger Amy , Ferguson Sherise , Prabhu Sujit , Sawaya Raymond , Yeboa Debra N , McAleer Mary Frances , Chung Caroline , Briere Tina , Davies Michael , de Groot John , Glitza Isabella , Murthy Rashmi K , Rodon Jordi , O’Brien Barbara , Dumbrava Ecaterina , Yung W K Alfred , Vining David , Schomer Donald , Wang Yan , Suki Dima , Wozny Mark , Zaebst Denise , Austin Wendy , Nguyen Alissa , Burton Elizabeth , Davis Suzanne , Tawbi Hussein
Published: August 2019

BACKGROUND: ~30% cancer patients develop brain metastases (BM), reflected by ~1600 BM patients treated at MD Anderson Cancer Center annually. With advances in systemic therapy and extracranial disease control, BM is a growing challenge. Multi-disciplinary BM management is critical and complex requiring coordination of multiple oncology sub-specialties. There is limited data on pragmatic clinic models to streamline and advance care. METHODS: Recognizing deficiency in BM treatment and research, a steering committee was formed at MDACC to establish an interdisciplinary BM clinic (BMC), with a multi-disciplinary BM research retreat held in 2016. The goal of BMC was to centralize patient referrals, improve patient outcomes and experience, and advance research by developing clinical trials and biomarker discovery programs. Meetings were held to address BMC format, workflow, EMR integration, data collection infrastructure, and staffing model. RESULTS: MDACC BMC clinic opened in 01/2019 with two half-day clinics staffed by neurosurgery, neuro-radiation oncology, neuro-radiology and medical/neuro oncology. A dedicated advanced practice provider screens the referrals according to a well-developed algorithm. A multidisciplinary conference is held immediately before each clinic where patient images are reviewed, cases are discussed and consensus recommendations are developed. The treatment plan and follow up appointments are arranged at the completion of the clinic visit to expedite care. ~50 patients have been seen with excellent patient satisfaction response and reduced time to treatment. ~20% patients had major change in treatment plan following multi-disciplinary evaluation. Additional efforts to develop a central BM database along with clinical and translational research programs are on-going. CONCLUSIONS: Establishment of a multi-disciplinary BMC to facilitate care and centralize research programs addresses a critical need for coordinated patient-centered BM management. This endeavor has enhanced patient experience through multi-specialty collaboration. Our program demonstrates the feasibility and effectiveness of a dedicated BMC in the treatment of this complex patient population.
MLTI-14. A SYSTEMATIC REVIEW OF TREATMENT PARADIGMS FOR PATIENTS WITH BREAST CANCER AND ONE OR MORE BRAIN METASTASES
Authors: Ellenbogen Yosef , Brar Karanbir , Warsi Nebras , Badhiwala Jetan , Mansouri Alireza
Published: August 2019

BACKGROUND: Upwards of 50% of patients with advanced breast cancer are diagnosed with brain metastases (BM). Treatment options for these patients have been rapidly evolving due to increased understanding of the tumor pathophysiology and its genetic underpinnings. This systematic review of randomized controlled trials (RCTs) aims to clarify the evidence guiding the treatment of brain metastases from breast cancer. METHODS: MEDLINE, EMBASE, Cochrane Controlled Register of Trials, ClincialTrials.gov, and Web of Science were searched from inception to October 2018 for RCTs comparing treatments for breast cancer BM. We screened studies, extracted data, and assessed risk of bias independently and in duplicate. Outcomes assessed were overall survival (OS), progression-free survival (PFS), and adverse events (Grade 3+). RESULTS: Among 3188 abstracts, only 3 RCTs (N=412; mean sample size per group N=54.7) meeting inclusion criteria were identified. The studies were phase II or III open-label parallel superiority trials. Inclusion criteria among these trials consisted of age >18 with radiologic evidence of >1 BM. Exclusion criteria consisted of poor-performance functional status (ECOG >2 or KPS < 70). The treatment groups included whole-brain radiation therapy (WBRT) vs WBRT + Temozolomide, WBRT vs WBRT + Efaproxiral, and Afatinib vs Vinorelbine vs investigators’ choice (86% of these patients received WBRT or SRS prior to study enrolment). While two trials found no significant difference in OS, one trial found significant improvement in OS with Efaproxiral in addition to WBRT compared to WBRT alone (HR 0.52; 95%CI 0.332–0.816). No significant differences were found with PFS or rate of adverse events amongst treatment groups. CONCLUSION: Considering the high prevalence of breast cancer BM and our improved understanding of genomic/molecular features of these tumors, a greater number of RCTs dedicated at this disease are needed.
MLTI-18. PRECISION IMAGING OF METASTATIC AND PRIMARY BRAIN TUMORS AFTER RADIATION WITH 18F-FDOPA PET-MRI IS FEASIBLE AND COST EFFECT
Authors: Aboian Mariam , Ravanfar Vahid , Bahroos Emma , Tong Elizabeth , Taylor Jennie , Oberheim Bush Nancy Ann , Seo Youngho , Cha Soonmee , Pampaloni Miguel Hernandez
Published: August 2019

PURPOSE: Post-radiation changes in the brain can mimic tumor recurrence on MRI, requiring multiple short term follow-ups to differentiate tumor progression from radiation necrosis. We propose combining functional and anatomic imaging with FDOPA PET tracer in hybrid PET-MRI to improve detection of tumor recurrence. MATERIALS AND METHODS: Seventeen adult patients treated with radiation therapy were identified - four with metastatic disease from breast and lung cancer and thirteen with primary brain glioma (11 IDH wildtype glioblastoma and 2 astrocytoma). Patients were scanned on hybrid PET-MRI (GE Healthcare) with clinical MRI brain sequences and dynamic FDOPA uptake. Dynamic FDOPA uptake within these tumors over 45 minutes after tracer injection was analyzed and compared to ADC histogram analysis. RESULTS: For each of the patients, clinical multi sequence gadolinium enhanced MRI and dynamic PET imaging for up to 45 minutes with 18F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in groups was 51.4% ($28,321), as opposed to the cost of individual radiosynthesis performed for each study. Quantitative analysis of tracer uptake in striatum, internal carotid artery, and superior sagittal sinus were performed with appropriate accumulation and subsequent washout of tracer respectively. Successful dynamic FDOPA uptake within the tumor was seen in all patients and ratio of tumor to contralateral ROI were found to range from 1.8–4.5. While raw SUV values did not differentiate between recurrent tumor and radiation changes, T/C SUVmax ratios were elevated to 4.5 in recurrent glioblastoma, 2.5 in hypoxic treated glioblastoma, and 1.8 in non-recurrent metastatic breast cancer after gamma knife treatment. CONCLUSION: Batch imaging of patients with [18F]FDOPA PET-MRI is feasible and cost effective. Understanding radionuclide synthesis process is critical for increasing accessibility of novel PET tracers to patients and results in significant cost savings.
OTHR-03. ENHANCEMENT OF T1W-GAD MRI IS ASSOCIATED WITH POST-SRS LOCAL CONTROL OF NSCLC BRAIN METASTASES
Authors: Milchenko Mikhail , LaMontagne Pamela , Abraham Christopher , Robinson Clifford , Marcus Daniel
Published: August 2019

BACKGROUND: Local control (LC) of brain metastasis (BM) is an important clinical endpoint. To date predictors of LC have been limited to patient and treatment related factors. Quantitative imaging features predictive of LC have not been well described for BMs treated by stereotactic radiosurgery (SRS). This study aimed primarily at assessing quantitative imaging predictors of LC that may be used for tailored SRS treatment of BM patients. METHODS: A cohort of non-small cell lung cancer (NSCLC) treated with SRS alone were identified. Post-operative SRS, radiosurgical boost, or prior WBRT cases were excluded. All patients underwent pre-SRS and follow-up T1-Gad MR imaging (termed here T1-SRS and T1-FWU). BM regions were outlined using T1-SRS during treatment planning. LC was assessed for each treated lesion by a Radiation Oncologist. Intensity histograms were normalized to account for inter-individual brain signal heterogeneity. For each BM, computed predictor factors were derived from established LC markers (volume), features associated with tumor shape (compactness, eccentricity), and signal intensity distribution in BM region (percentiles, standard deviation). RESULTS: A total of 106 NSCLC BMs in 82 participants (41 female) were examined. Mean follow-up time was 9±9 months (median 6.5 months). Kaplan-Meier (KM) curves for LC were split by the predictor factors, with split threshold ranging between -0.5 and 0.5 of sample standard deviation, optimized to maximize the difference between lower and upper curves. KM curves for lower volume (p=0.02), lower eccentricity (p=0.004), higher intensity standard deviation (p=0.02), and higher 95th intensity percentile (p=0.05) resulted in significantly higher LC. CONCLUSION: Volume, eccentricity, intensity standard deviation, and 95th intensity percentile were found to predict LC. Intensity standard deviation and intensity percentile as predictors of LC merit validation in larger, independent datasets or in future prospective studies.
OTHR-05. THE ABILITY TO MAKE INFORMED TREATMENT DECISIONS IS COMPROMISED IN ADULTS WITH ADVANCED STAGE CANCER
Authors: Triebel Kristen , Mulhauser Kyler , Gammon Meredith , Gerstenecker Adam , Nabors L Burt , Fiveash John
Published: August 2019

OBJECTIVE: To investigate medical decision-making capacity (MDC) in patients with advanced stage cancer. METHODS: Participants were 113 newly diagnosed adults with brain metastases and 41 adults with metastatic cancer without brain metastases who were recruited from an academic medical center and 40 demographically-matched healthy controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument (CCTI) Vignette B and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant using cutoff scores derived statistically from the performance of the control group. RESULTS: Both of the metastatic cancer groups (with and without brain metastasis) performed significantly below controls on consent standards of understanding and reasoning. The brain metastasis group performed below the non-metastatic cancer group on understanding. Capacity compromise was defined as performance ≤1.5 standard deviations (SD) below the control group mean. Using this definition, approximately 65% of the participants with brain metastases and 51% of participants with metastatic cancer without brain metastases were impaired on at least one MDC standard. CONCLUSION: Over half of participants with metastatic cancer regardless of whether they have brain disease have reduced capacity to make treatment decisions. The finding of impaired MDC in patients without brain metastases is surprising and suggests this group likely exhibits cognitive deficits that impact their ability to understand and reason about different treatment options. The reasons underlying this impairment will be investigated. This highlights the importance of routine clinical assessment of MDC in all patients with metastatic cancer when important treatment decisions are being discussed. These results also indicate a need for the development and investigation of interventions to support or improve MDC in this patient population.
OTHR-08. PREDICTION OF RISK OF CENTRAL NERVOUS SYSTEM METASTASIS FOR AJCC 8TH EDITION STAGE III MELANOMA PATIENTS
Authors: Haydu Lauren , Lo Serigne , McQuade Jennifer , Glitza Isabella , Tawbi Hussein , Carlino Matteo , Menzies Alexander , Long Georgina , Lazar Alexander , Tetzlaff Michael , Scolyer Richard , Gershenwald Jeffrey , Thompson John , Davies Michael
Published: August 2019

Among common solid tumors, melanoma has the highest risk of CNS metastasis. Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for at-risk patients. Clinical data were extracted from two institutions for AJCC 8th edition stage III melanoma patients, diagnosed from 1998–2014 who had negative baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death from stage III presentation, and at benchmark time points 1-, 2-, and 5-years post-diagnosis. The cohort (N=1,918) consisted of patients from major melanoma centers in the US (50.6%) and Australia (49.4%). The first site of distant metastasis was CNS only for 3.9%, CNS and extra-cranial sites (ECS) for 1.9%, and ECS only for 31.2% of patients (N=1918); 15.5% of patients who developed distant metastases (N=708) had CNS involvement at first diagnosis of stage IV disease. Cumulative incidence of CNS metastasis from stage III diagnosis was 3.7% (95% Confidence Interval (CI): 2.9–4.6) at 1-year; 9.6% (95% CI: 8.3–11.0) at 2-years; and 15.9% (95% CI: 14.2–17.7) at 5-years. In multivariable analyses, risk of CNS metastasis was significantly higher for males; younger patients; increasing AJCC stage group; scalp primary tumor site, acral melanoma subtype, and increased primary tumor mitotic rate. Conditional analyses showed that only high primary tumor mitotic rate (>9 per mm2) was significantly associated with risk of subsequent CNS metastasis among patients who survived without CNS recurrence 1-, 2-, and 5-years after the diagnosis of stage III disease. Similar rates of CNS metastasis were observed between these two large, geographically-distinct stage III melanoma patient cohorts. These results provide a framework for developing evidence-based surveillance strategies and for evaluating the impact of contemporary adjuvant therapies on the risk of melanoma CNS metastasis.
OTHR-17. PHYLOGENETIC RESOLUTION OF TISSUE-SPECIFIC METASTOGENIC CLONES IN RENAL CELL CARCINOMA
Authors: Moss Nelson , Berman Samuel , Piscuoglio Salvatore , Ng Charlotte , Selenica Pier , Kumar Rahul , Filho Jorge Reis , Brennan Cameron
Published: August 2019

Genomic factors predictive of organ-specific tropism have been established in several models of cancer. However, the evolutionary dynamics at work in metastatic carcinoma have yet to be characterized in detail. We identified a cohort of clear cell renal cell carcinoma (RCC) patients who also had multiple metastasectomies, and performed deep sequencing and statistical inference of subclonal populations to infer phylogeny and essential genetic features acquired prior to systemic dissemination and site-specific colonization. Exome capture and deep sequencing were performed on tissues from 3 patients with polymetastatic RCC (including 12 metastases, multiple regions of primary tumors, and paired germline tissue) to a mean depth of 250x. Somatic point mutations were called with Mutect, and insertions and deletions with Strelka and VarScan. Validation was performed with a custom NimbleGen panel hybridized to a custom sequence library and sequenced to a mean depth of >500x. Allele-specific copy number and clonal prevalence were established using ABSOLUTE, and analyzed with Pyclone across primary and metastatic lesions to determine clonal architecture. Phylogenetic reconstruction identified ancestral clones, with attendant driver mutations in RCC tumor suppressors (including VHL, SETD2, PBRM1, MTOR) and independent subclonal populations in the metastases of all 3 patients. In an index case with multiple metastases separated spatially and temporally, bone and soft tissue metastases demonstrate apparent independent ancestors. Convergent loss of known tumor suppressors was also noted in all cases, and in several cases found in conjunction with de novo mutations in known RCC driver genes acquired late in tumor development. In this demonstration of subclonal and evolutionary analysis of multiple paired multi-organ RCC metastases, we identified subclonal populations characterized by alteration of several tumor suppressors which subsequently exhibited organ-specific patterns of metastasis.
RADI-04. PRETREATMENT VOLUME OF MRI-DETERMINED WHITE MATTER INJURY (WMI) PREDICTS COGNITIVE DECLINE AFTER HIPPOCAMPAL AVOIDANT (HA) WBRT FOR BRAIN METASTASES: SECONDARY ANALYSIS OF NRG ONCOLOGY RTOG 0933
Authors: Bovi Joseph , Pugh Stephanie , Sabesevitz David , Robinson Clifford , Paulson Eric , Mehta Minesh , Gondi Vinai , Kundapur Vijayananda , Pinover Wayne , Chao Samuel , Machtay Mitchell , DeNittis Albert , Laack Nadia , Greenspoon Jeffrey , Mannel Robert , Huang Jiayi , Dominello Michael , Kachnic Lisa
Published: August 2019

PURPOSE: RTOG 0933 demonstrated benefits to memory following HA-WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity playing a role. WMI has been implicated in RT-induced cognitive decline. This secondary analysis explored the relationship between pre-treatment WMI and memory following HA-WBRT. METHODS AND MATERIALS: 113 patients received HA-WBRT. Standardized cognitive assessments were performed at baseline, 2, 4, and 6 months. The primary endpoint was Hopkins Verbal Learning Test Delayed Recall (HVLT-DR) at 4 mos. Secondary endpoints included HVLT Total Recall (HVLT-TR) and Recognition (HVLT-Recog). Of 113 patients, 34 underwent pre-treatment and 4-month post-treatment HVLT testing and pre-treatment post-contrast volumetric T1 and axial T2/FLAIR MRI. Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pre-treatment MRI. Correlational analyses were performed examining the relationship between pre-treatment WMI and HVLT outcomes following HA-WBRT. RESULTS: Correlation was found between larger volumes of pre-treatment WMI and decline in HVLT-Recog (r=.54, p< .05) and a correlational trend was observed between larger volume of pre-treatment WMI and decline in HVLT-DR (r=.31, p=.08). Patients with higher pre-treatment disease burden experienced a greater magnitude of stability or positive shift in HVLT-recall and –delayed recall following HA-WBRT. (r=-.36 and r=-.36, p’s < .05), compared to the magnitude of stability/positive shift in those with lesser disease burden. CONCLUSION: In patients receiving HA-WBRT, pre-treatment-WMI predicts memory decline, suggesting white matter integrity pre-treatment contributes to the pathogenesis of post-WBRT cognitive toxicity independent of hippocampal stem cell radiosensitivity. Less decline or improvement in HVLT following HA-WBRT for patients with higher pre-treatment intracranial metastatic burden supports the importance of WBRT-induced intracranial control on cognition. These imaging biomarkers for cognitive toxicity will be further explored on NRG CC001 and CC003, phase III trials of WBRT with or without HA.
RADI-05. FRACTIONATED TREATMENT OF BRAIN METASTASES WITH GAMMA KNIFE ICON
Authors: Mendel Jameson , Patel Ankur , Patel Toral , Timmerman Robert , Dan Tu , Nedzi Lucien , Wardak Zabi
Published: August 2019

PURPOSE/OBJECTIVE(S): Stereotactic radiosurgery with Gamma Knife is a common treatment modality for patients with brain metastasis. The Gamma Knife ICON allows for immobilization with an aquaplast mask, permitting fractionated treatments. We describe one of the first experiences utilizing this technique with brain metastasis and evaluate outcomes. MATERIALS/METHODS: From June 2017 to November 2018, 29 patients with 43 separate intracranial lesions were treated with fractionated stereotactic radiotherapy using the gamma knife ICON at a single institution. Patients received between 20–30 Gy in 3–5 fractions with no margin over the course of 5 to 23 days. Local control was physician assessed. Local failure over time was modeled using cumulative incidence; lesions were censored at last radiographic follow up. RESULTS: Median tumor volume and prescription isodose was 7.7 cm3 (range 0.3–43.9) and 50% (range 40–65), respectively. Median radiographic follow-up was 7 months and median survival was 9 months. Radiation necrosis occurred in 3/3 patients treated with 27 Gy in 3 fractions, one requiring therapeutic resection. Incidence of local failure for all treated lesions was 9% at 1 year. Tumor volume >7 cm3 was associated with local failure on univariate analysis (p=0.025). 100% (2/2) lesions treated with 20 Gy in 5 fractions developed local recurrence. CONCLUSION: Fractionated stereotactic radiotherapy with the Gamma Knife ICON provides excellent local control for small and large brain metastases with minimal toxicity. Tumors >7 cm3 should receive at least 30 Gy in 5 fractions for optimal control. Treatment with 27 Gy in 3 fractions appears to have high rates of treatment related toxicity and should be avoided.
RADI-09. DEFINING PROGRESSION IN PATIENTS TREATED WITH TEN OR MORE BRAIN METASTASES FOLLOWING STEREOTACTIC RADIOSURGERY
Authors: Viswanatha Sirisha Devi , Rana Zaker , Ehrlich Matthew , Schulder Michael , Goenka Anuj
Published: August 2019

BACKGROUND: An increasing trend has been to elect for Stereotactic Radiosurgery (SRS) for the treatment of brain metastases. Progression following treatment is typically defined as a 20% increase in the initial lesion volume treated. Challenges in defining progression can arise as the reported incidence of pseudoprogression or radiation necrosis following treatment ranges from 5%-30%. The purpose of this study was to assess patterns of failure in patients treated with 10 or more brain metastases. METHODS: From March 2014 to April 2018, fifty-five patients with 10 or more total brain metastases were retrospectively reviewed following frame-based radiosurgery to a dose of 12–20 Gy. Post-treatment MRI scans were used to assess tumor response in 3 month intervals. Tumor control was defined as tumor volume ≤ 1.2 times the baseline tumor volume at each measured interval. RESULTS: Fifty-five patients received 75 total radiosurgery treatments to 692 tumors. Forty patients received synchronous treatment, while 15 received metachronous treatment. 20 patients (36%) and 72 tumors (10%) experienced progression following treatment. 46 tumors were larger after first MRI in 15 patients (28%). Of these 15 patients, eight had complete resolution in 15 tumors on subsequent scan. Of the eight patients who had resolution, six patients received immunotherapy during and after treatment and all but one patient saw an initial increase >100% of their initial tumor volume. Median overall survival was 11 months. Univariate analysis revealed an association between larger brain volumes irradiated with 12 Gy and decreased overall survival (p < 0.05). CONCLUSION: It is important to consider tumor growth velocity and concurrent therapy when assessing true progression after SRS treatment of brain metastases.
RADI-13. IMPACT OF CITV AND BRAF MUTATION ON MELANOMA METASTASIS RESPONSE TO STEREOTACTIC RADIOSURGERY
Authors: Alattar Ali , Joshi Rushikesh , HIrshman Brian , Carroll Kate , Nagano Osamu , Aiyama Hitoshi , Serizawa Toru , Yamamoto Masaaki , Chen Clark
Published: August 2019

INTRODUCTION: Survival prognostication is an important aspect of personalizing oncologic care for patients with melanoma brain metastasis (BM). We previous demonstrated the utility of a cumulative intracranial tumor volume modified diagnosis-specific graded prognostic assessment scale (CITV-dsGPA) for SRS-treated melanoma BM patients. Pertinent prognostic variables in this model included age, Karnofsky performance status (KPS), and CITV. Here we determined whether the incorporation of BRAF mutation status into this CITV-modified scale further enhanced its prognostic accuracy. METHODS: We collated the survival pattern of 331 melanoma BM patients with known BRAF mutation status treated with stereotactic radiosurgery (SRS) and validated our findings in an independent cohort of 174 patients. All patients with BRAF mutation were treated with BRAF inhibitors. The prognostic utility of the model with and without BRAF mutation information was compared using the net reclassification index (NRI > 0) and integrated discrimination improvement (IDI) metric. RESULTS: Presence of the BRAF mutation was associated with a reduced hazard of death in univariate Cox proportional hazards survival analysis (hazard ratio (HR) 0.74, p< 0.001). This effect persisted in a multivariate model that controlled for age, KPS, and CITV (HR 0.72, p< 0.001). Addition of BRAF mutation status to the CITV-ds-GPA model for melanoma significantly improved its prognostic value, with NRI >0 of 0.294 (p=0.01) and IDI of 0.017 (p=0.02). We validated these findings in an independent cohort of 174 melanoma patients. CONCLUSIONS: Optimal survival prognostication for SRS-treated patients with melanoma BM requires an integrated assessment of age, KPS, CITV, and BRAF mutation status.
RADI-15. CLUSTERING AND GROUPING OF BRAIN METS IN RADIOSURGERY TREATMENTS
Authors: Salah Khaled , Mckenna John , Jozsef Gabor , Knisely Jonathan
Published: August 2019

INTRODUCTION: Radiosurgical treatment of numerous lesions in the brain with ‘single-isocenter’ radiosurgery on a linac often requires using multiple isocenters. With our TPS (Elements, Brainlab) multiple plans need to be generated for each set of lesions, and a sum plan calculated. We investigated how to distribute multiple lesions into two groups for two isocenters to achieve a good summed dose distribution. METHODS: The DICOM RS file is exported and the PTV data is extracted by a MATLAB program that calculates the convex hulls, estimated radii, and the centers of mass for each PTV. Two approaches were tried: (1) Lesions close to each other (closer than a certain limit) are put in different groups and (2) Create clusters by kMeans clustering, which allows close lesions but the groups are distant from each other. MATLAB programs were written for all approaches. Treatment plans were generated for three patients (20, 13, 15 lesions) using each method and compared with the actual treatment plan used to treat the patient based on the intuitive grouping of lesions by the planners. Dose maximums outside the lesions, and volumes in the normal tissue exceeding 75, 50 and 25% of the prescription dose were evaluated. RESULTS AND DISCUSSION: The coverage of all lesions for all plans were 95% of the prescription dose. The first approach allowed lowering the maximum dose between lesions, but with summing dose distributions this advantage disappeared. The maximum dose and the 75, 50 and 25% dose volumes were also all worse than in plans generated by experienced planners and higher normal brain doses are delivered if closely spaced lesions are separated into different isocenters for treatment. However, the clustering approach resulted in the same or better values of these same parameters, i.e. improved dose distributions over the dosimetrist’s intuitively chosen separation.
RADI-21. STEREOTACTIC RADIOSURGERY FOR 10 OR MORE BRAIN METASTASES PROVIDES EXCELLENT RATES OF INTRACRANIAL DISEASE CONTROL WITH SUPERIOR HIPPOCAMPAL SPARING
Authors: Susko Matthew , Garcia Michael , Ma Lijun , Nakamura Jean , Raleigh David , Fogh Shannon , Golden Encouse , Theodosopoulos Philip , McDermott Michael , Sneed Penny , Braunstein Steve
Published: August 2019

BACKGROUND: Recent evidence supports hippocampal sparing during whole brain radiotherapy (HS-WBRT) to improve neurocognitive outcomes in patients with brain metastases (BM). This study sought to quantify the hippocampal dosimetry and treatment efficacy of stereotactic radiosurgery (SRS) to 10 or greater BM to clarify the roles of SRS and WBRT. METHODS: Patients at a single institution treated with SRS to 10 or more BM without WBRT from 1999 to 2016 were retrospectively reviewed. Treatment-related outcomes including overall survival (OS), freedom from progression (FFP), freedom from new metastases (FFNM), and adverse radiation effect (ARE) were quantified. Hippocampal volumes were retrospectively delineated and dosimetry was evaluated in patients treated with upfront SRS. RESULTS: 143 patients with a total of 2198 lesions met criteria for inclusion with 75 patients treated with upfront SRS and 68 treated as salvage from prior WBRT. Median age was 57 (IQR: 46–65) and median KPS 80 (IQR: 70–90). Histologies included breast (n=52), lung (n=49), melanoma (n=30), and other (n=12). Median number of lesions per patient was 13 (IQR 11–17) with median total volume of treatment of 4.1 cc (IQR 2.0–9.9). 12-month FFP per lesion for upfront and salvage treatment was 96.8% (95% CI: 95.5–98.1) and 83.6% (95% CI: 79.9–87.5) respectively (p < 0.001). 12-month FFNM for upfront and salvage FFSRS was 18.8% (95% CI: 10.9–32.3) versus 19.2% (95% CI: 9.7–37.8) respectively (p = 0.90). Mean hippocampal dose was 150 cGy (IQR 100–202). Symptomatic ARE was observed in 2% of patients or 1% of treated lesions. CONCLUSIONS: High rates of local control can be achieved when treating patients with greater than 10 BM with hippocampal doses that are dramatically lower than for HS-WBRT. Hippocampal sparing is readily achievable with expected rates of new metastatic lesions developing in treated patients with low rates of symptomatic ARE.
RADI-22. CHARACTERIZING CLINICAL SURVIVAL PATTERNS USING MACHINE LEARNING: AN ANALYSIS OF BRAIN METASTASIS PATIENTS TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Alattar Ali , Joshi Rushikesh , HIrshman Brian , Carroll Kate , Nagano Osamu , Aiyama Hitoshi , Serizawa Toru , Yamamoto Masaaki , Chen Clark
Published: August 2019

INTRODUCTION: Increased sophistication in machine-learning algorithms and artificial intelligence have begun to unveil patterns that would be otherwise unappreciated in clinical medicine. Here we applied one such algorithm, Iterative Factorial Analysis of Mixed Data (IFAMD), to better understanding combinations of clinical variables that influence clinical survival of brain metastasis (BM) patients treated with stereotactic radiosurgery (SRS). METHODS: A dataset of 6,326 BM patients was collated from four SRS centers (University of California, San Diego, Katsuta Hospital Mito GammaHouse, Tsukiji Neurological Clinic, and Melanoma Institute of Australia). IFAMD was applied to the analysis of the following clinical variables: age, Karnofsky Performance Status (KPS), cumulative intracranial tumor volume (CITV), total number of metastases, histology (breast, gastrointestinal (GI) cancer, renal cell carcinoma (RCC), melanoma, and lung cancer), systemic disease control, and survival in months. RESULTS: Our machine learning algorithm defined three groups of patients who exhibited differential survival. The group who is most likely to die within 3 months of SRS included patients with lower KPS, poor systemic disease control, higher CITV, higher number of metastasis, and who carried a diagnosis of GI cancer. Patients who are most likely to survive beyond twelve months of SRS fall into two distinct categories. The first consisted of subsets of lung and breast cancer patients with higher KPS, controlled systemic disease, and lower CITV. The second consisted of young breast cancer patients with systemic disease control, independent of KPS, CITV, and the number of metastases. CONCLUSION: Clinical survival after SRS for BM is defined by combinations of known prognostic factors. A prognostic factor critical for survival prognosis in one sub-population of BM patients may bear little relevance in another patient sub-population.
RADI-25. REPEAT STEREOTACTIC RADIOSURGERY FOR RECURRENT BRAIN METASTASES
Authors: Krivosheya Daria , Borghei-Razavi Hamid , Grabowski Matthew , Angelov Lilyana , Barnett Gene , Vogelbaum Michael , Chao Samuel , Murphy Erin , Yu Jennifer , Ahluwalia Manmeet , Suh John , Mohammadi Alireza
Published: August 2019

INTRODUCTION: Mainstream modality of treatment of oligo-metastatic disease is stereotactic radiosurgery (SRS). While the local control rate is nearing 90%, 7% of lesions and 10 to 15% of patients develop radiation necrosis post treatment. In the face of increasing lesion size and evidence of recurrence, re-treatment of the enlarging lesion with radiosurgery can be attempted. The aim of the project is to evaluate outcomes of lesions treated with repeat SRS. METHODS: We conducted a retrospective review of all patients that were treated with Gamma Knife radiosurgery at our institution from 2000 to 2018. Fifty-one lesions in 39 patients were identified that had recurrence during follow-up period and were treated with a second single-fraction SRS. RESULTS: A combination of imaging studies, such as PET and/or perfusion studies, lesion biopsy, and clinical course were used to make the diagnosis of lesion recurrence. The average radiation dose at first treatment was 21 Gy, and the average dose at second treatment was 19 Gy. The median time between treatments was 16.8 months, ranging from 2.5 to 75.3 months, and the median follow-up after second treatment was 10.2 months. Of 51 lesions that received two SRS treatments, 49% (25 lesions) continued to progress at a median interval of 4.8 months post treatment, of which 35% (18 lesions) were diagnosed as radiation necrosis based on biopsy results or advanced brain imaging. The overall rate of radiation necrosis post second SRS treatment was determined to be 16% per lesion and 21% per patient. CONCLUSION: Recurrent brain metastases that are re-treated with single fraction SRS are associated with a higher risk of radiation necrosis. Alternative treatment strategies, including fractionation of subsequent SRS treatments, radiation dose reduction, and combination with laser ablation could be considered to ensure symptom and disease control to reduce the rate of subsequent radiation necrosis.
RADI-32. INTRACRANIAL CONTROL AND RADIONECROSIS IN MELANOMA PATIENTS WITH BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Tjong Michael , Moraes Fabio , Shultz David
Published: August 2019

PURPOSE/OBJECTIVE(S): Melanoma commonly metastasizes to the brain and is radioresistant. Stereotactic radiosurgery (SRS) confers durable local control of brain metastases (BM) while maintaining neurocognitive function. These advantages are increasingly important as survival among these patients improves secondary to advances in systemic therapies. This study investigated the local control (LC), intracranial PFS (iPFS), freedom from radionecrosis (FFRN), and overall survival (OS) among melanoma patients receiving SRS for BM. MATERIALS/METHODS: We retrospectively reviewed clinical outcomes of melanoma patients with brain metastases treated with SRS between October 2008 and January 2017 in a large academic centre. Post-SRS, patients were followed in a multidisciplinary clinic with clinical examination and brain MRI every 3 months. Survival outcomes were estimated using the Kaplan-Meier method. RESULTS: In total, 97 patients with 283 brain metastases (including 12 surgical cavities) treated with SRS were identified. Median age was 60.5 (24.4–90.7). Median follow-up was 9.6 (2.2–74.7) months after first SRS. Median prescription dose was 21 (10–24) Gy delivered in a single fraction. Thirty (30.9%) patients had WBRT post-SRS, 36 (37.1%) patients had BRAF-positive disease. Per lesion (N=283), 1-year LC and FFRN were 84.4%, and 90.1%, respectively; medians were not achieved for either LC or FFRN. Radionecrosis (RN) occurred in 20 (7.1%) lesions. Per patient (N=97), median OS and iPFS were 16.0 and 5.3 months, respectively; 1-year OS and iPFS rates were 62.0%, and 30.1%, respectively. CONCLUSION: SRS resulted in excellent rates of LC, with a low risk of RN. However, most patients developed intracranial progression within 1 year. Further analyses to establish correlates (lesion size, SRS dose, and molecular status) to LC, FFRN, OS, and iPFS will be performed prior to the final presentation.
RADI-39. EFFECT OF RIND-BASED DOSIMETRIC TECHNIQUES FOR SCALP DOSE REDUCTION IN BRAIN IRRADIATION
Authors: No Diana , Julie Diana , Knisely Jonathan
Published: August 2019

OBJECTIVE: Radiation-induced alopecia is an unwanted side effect causing permanent cosmetic distress if hair regrowth does not occur. Rind-based techniques can effectively control dosimetric spread. We evaluated this technique to reduce scalp dose and alopecia while maintaining tumor coverage. METHODS: Ten consecutive brain tumor plans were retrospectively evaluated. All planning tumor volume (PTV) margins were ≤ 15.0mm from the skin surface. Departmental guidelines for fractionation were followed, with minimum 95% PTV coverage receiving 100% dose. Fractionation variation was accounted for with biologically effective dose calculation (alpha/beta=2). Rind structures encompassed 5mm depth from scalp surface; upper dose limits were customized to minimum values without PTV coverage compromise. Standard comparative plans using identical criteria, without rind structures, were calculated. Scalp dose evaluation was defined for tissue from skin to 5mm depth. Paired T-tests were used for comparative evaluation. RESULTS: Median age: 58 (range 27–85); 70% female (n=7). Histologies included gliomas (n=7) and meningiomas (n=3). Median PTV distance to skin surface: 13.5mm (range 8.0–15.0). Median PTV minimum and mean dose for rind-based plans: 88.63% (range 73.14–95.2) and 104.39% (range 102.07–107.38) of prescription and 90.90% (range 68.64–98.21) and 103.02% (range 101.91–107.04) for standard plans, respectively. Statistically significant reduction in scalp maximum and mean dose of 19.65% (p=2.72E-06) and 0.48% (p=0.007), respectively, was seen with rind-based planning. Scalp volume receiving 1000cGy-equivalent increased 6.7cc using rind-based techniques, although insignificant (p=0.33). Volume receiving 1500cGy-equivalent was significantly reduced 3.88cc (p=0.03) using rind-based techniques. With median 28.5 day follow-up, of 5 patients treated using rind-based techniques, 40% (n=2) exhibited acute alopecia compared to 100% of those treated with standard plans. CONCLUSION: Rind-based dosimetric techniques exhibit significant reduction of scalp dose in brain irradiation. 60% of patients treated using this technique experienced no alopecia, versus 0% receiving standard treatment. Further investigation is warranted to better evaluate correlation.