bluuebunny/crossref_metadata_2025 huggingface dataset:
LPTO-08. INTRATHECAL TRASTUZUMAB PLUS/MINUS IT TOPOTECAN FOR PATIENTS WITH HER2+ BREAST CANCER AND LEPTOMENINGEAL METASTASIS
Authors: Trevino Christopher R , Murthy Rashmi K , Raghavendra Akshara Singareeka , Loghin Monica , Seligman Christa , Ferguson Sherise , Kamiya-Matsuoka Carlos , Harrison Rebecca , Sinicrope Kaylyn D , Valero Vicente , Tummala Sudhakar , Hess Kenneth , Tripathy Debu , de Groot John , O’Brien Barbara
Published: August 2019

BACKGROUND: Leptomeningeal metastasis (LM) is an aggressive complication of cancer. No standard therapies exist, although at our institution we commonly use IT topotecan in good-risk patients. We report our experience in patients with HER2+ breast cancer (BC) LM treated with intrathecal (IT) trastuzumab +/- IT topotecan. METHODS: We retrospectively reviewed records of patients managed with IT trastuzumab at MD Anderson Cancer Center from 2016–2019. Demographics, clinical course, and outcomes data (Kaplan-Meier) were collected and analyzed. RESULTS: 14 female patients (median age 49, range 33–67) with HER2+ BC (29% hormone receptor (HR) positive, 71% negative) were treated with IT trastuzumab (titrated to 40 mg -100 mg/week); 8 (57%) received concurrent IT topotecan. LM diagnosis was made in 64% by MRI alone, and 36% by both MRI and CSF cytology; 79% had brain metastases (BM), and of those, 55% (6/11) had active BM at LM diagnosis; 57% received WBRT prior to initiation of IT therapy. Median KPS was 90 (range, 60–100). Of those with initially positive cytology, 50% (4/8) converted to negative during treatment. MRI findings improved in 79%; 79% were symptomatic at diagnosis (most commonly ataxia, cranial neuropathy, headache); 70% (7/10) had symptom improvement on IT therapy. The only IT-associated symptom reported was mild nausea that occurred in 29%. Median time from diagnosis of metastatic BC was 10.7 mos. (range 0–83 mos); 36% had active extra-CNS disease and 86% received concurrent systemic therapy; 57% underwent change in systemic therapy during IT treatment; 91% were progression-free at 6 months, 32% at 24 months. Median overall survival from LM diagnosis was 24.7 months (95% CI 10.7, NR). CONCLUSIONS: IT trastuzumab is a safe and promising therapy for patients with HER2+ BC and LM. Dual IT therapy with trastuzumab and topotecan was well-tolerated and warrants further investigation in a larger study.
TRLS-04. NEAR INFRARED FLUORESCENT DYE LOCALIZES BRAIN METASTASIS PRIOR TO DURAL OPENING AND IS MORE SENSITIVE THAN WHITE LIGHT IN BRAIN METASTASIS SURGERY
Authors: Buch Love , Cho Steve , Salinas Ryan , Hussain Jasmin , Lee John
Published: August 2019

INTRODUCTION: To improve surgical resection of brain tumors, our lab has pioneered a novel fluorescent dye technique, Second-Window Indocyanine-Green (SWIG), that relies on passive delivery and accumulation of indocyanine-green (ICG) in neoplastic tissue via the enhanced permeability and retention effect. We hypothesize that SWIG can provide early localization of brain metastasis prior to dural opening and can improve identification of surgical margins. METHODS: Subjects were prospectively enrolled in clinical trial after informed consent. Approximately 24 hours prior surgery, subjects were infused intravenously with 2.5mg/kg or 5mg/kg of ICG. Intraoperatively, a dedicated near-infrared (NIR) camera was used to detect ICG signal. After bone flap removal, the NIR imaging system was positioned above the presumed location of tumor. Additional NIR images were obtained after dural opening, corticectomy, and after conventional white-light surgical resection. RESULTS: We enrolled 50 patients with 51 total intraparenchymal brain metastases (23 lung, 7 breast, 8 GU/GI, 4 melanoma, and 7 others). Prior to dural opening, NIR signal was identified in 35 patients at an average depth of 4.3mm with SBR = 5.3 + 3.7. In the seven patients where NIR signal could not be identified prior to dural opening, tumor depth was an average of 8.4mm from cortical surface. Upon dural opening and tumor identification, all 51 tumors demonstrated strong NIR signal with SBR = 6.2 + 2.8. With white light alone, sensitivity/specificity/PPV/NPV for tumor detection was 83%, 94%, 98%, 57%. With NIR, sensitivity/specificity/PPV/NPV for tumor detection was 100%, 29%, 85%, 100%. DISCUSSION: NIR fluorophores are superior to visible light fluorophores in their depth of penetration. All contrast-enhancing brain metastasis accumulate ICG using our SWIG technique, and NIR fluorescence could be used to localize brain metastasis prior to dural opening. NIR fluorophores are likely to represent the next phase in tumor visualization given the rapid growth of fluorophores targeted to systemic cancers.
TRLS-05. EARLY RESULTS FROM A PROSPECTIVE PHASE I/II DOSE ESCALATION STUDY OF NEOADJUVANT RADIOSURGERY FOR BRAIN METASTASES
Authors: Murphy Erin , Yang Kailin , Suh John , Yu Jennifer , Schilero Cathy , Mohammadi Alireza , Stevens Glen , Angelov Lilyana , Vogelbaum Michael , Barnett Gene , Ahluwalia Manmeet , Neyman Gennady , Chao Samuel
Published: August 2019

OBJECTIVES: Single-session stereotacic radiosurgery (SRS) alone for brain metastases larger than 2cm in maximal dimension results in local control of only 50%. Surgical resection followed by SRS to the resection cavity can result in leptomeningeal failure (LMD). This Phase I/II study aims to determine the safety and local control of neoadjuvant SRS at escalating doses followed by surgical resection of brain metastases greater than 2 cm. METHODS: Radiosurgery dose was escalated at 3 Gy increments from currently accepted RTOG standard. If no dose-limiting toxicities (DLT) were observed, the dose was escalated. Patients underwent surgical resection of brain metastases within 2 weeks and were followed with brain MRIs and neurologic evaluations every 3 months. RESULTS: 27 patients were enrolled. For tumor size >2.0–3.0 cm, 2 patients completed treatment at 18 Gy and 3 patients at 21Gy. For tumor size >3.0–4.0 cm, 4 patients were treated at 15 Gy and 9 patients were treated at 18 Gy and 1 patient at 21 Gy. For tumor size >4.0–5.0 cm, 1 patient was treated at 12 Gy and 7 patients at 15 Gy. No DLT have occurred. With a mean follow-up of 13.1 months, the 6 and 12 month local control was 93.8% and 72.3%, respectively. Six and 12 month distant brain control was 38.6% and 25.8%. Overall survival at 12 months was 53.5%. One patient developed LMD 5 months following SRS. 4 patients (15%) had acute grade 1/2 toxicity, and no grade 3/4 toxicity was observed. CONCLUSIONS: Neoadjuvant SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm results in local control comparable to postoperative SRS or WBRT, and demonstrates acceptable acute toxicity. A low rate of LMD failure was found. The Phase II portion of the trial will be conducted at the maximum tolerated SRS doses.
TRLS-08. CNS PENETRATION AND PRELIMINARY EFFICACY OF SACUTIZUMAB GOVITECAN IN BREAST BRAIN METASTASIS AND GLIOBLASTOMA: A SURGICAL STUDY
Authors: Brenner Andrew , Floyd John , Surapaneni Prathiba , Madhusudanan-Kunnuparampil Vinu , Tiziani Stefano
Published: August 2019

Sacituzumab govitecan (SG) is an antibody drug conjugate (ADC) that targets Trop-2 for the selective delivery of SN-38 to tumors. SG carries SN-38, a topoisomerase inhibitor active in the nanomolar range for most cells (including TNBC and GBM) and freely cross the blood brain barrier. SN-38 is conjugated to SG by a linker designated CL2A which is sensitive to acidic conditions. SG has since been granted priority review designation by the FDA, with approval anticipated for triple negative breast cancer. Brain metastases is a significant concern in this patient population, but whether this agent is able to target the CNS through the blood brain barrier is unknown. Based upon the characteristics of this specific ADC, including the use of a pH labile linker and a payload with good CNS penetration, it is our specific hypothesis that the SG can achieve intratumoral concentrations of SN-38 sufficient to achieve therapeutic benefit in patients with neoplastic involvement of the brain. We further hypothesize that while total concentration of SN-38 will correlate with expression of trop2, free SN-38 will correlate more strongly with intratumoral hypoxia. To address this, we are performing a non-randomized, prospective study of SG in subjects with CNS involvement and planned surgical resection. SG is given as single dose at 10mg/kg pre-operatively on Day-1. Surgery will be followed by post-operative treatment with sacituzumab govitecan given intravenously with standard dose of 10 mg/kg on day1 and day 8 of 21-day cycle, until disease progression. Approximately 20 patients, 2 cohorts of 10 patients each with GBM and breast brain tumors, will be enrolled. Tumors will be analyzed for total antibody, free SN-38, and total SN-38 (free SN-38 + Antibody-SN38) concentrations in tumor tissue. Correlations will be made to Trop2 expression and hypoxia. Interim results will be presented.
TRLS-09. RTOG1119: PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY / STEREOTACTIC RADIOSURGERY IN COMBINATION WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASIS FROM HER2-POSITIVE BREAST CANCER
Authors: Kim In Ah , Winter Kathryn , Peereboom David , Sperduto Paul , De Los Santos Jennifer , Ogunleye Tomi , Boulter Daniel , White Julia , Mehta Minesh
Published: August 2019

The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients with HER2 positive breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastasis in these patients. Half of these patients die of intracranial disease progression rather than extracranial disease. Therefore, strategies to improve survival must include increased CNS disease control in these patients. Lapatinib crosses the BBB and demonstrates modest activity against intracranial metastases. Based upon preclinical data and results of a phase I study, we hypothesized that lapatinib plus WBRT /SRS can improve the intracranial disease control compared to WBRT / SRS alone. A randomized phase II trial of WBRT (37.5 Gy/3 weeks) or SRS plus or minus concurrent lapatinib (daily 1000 mg for 6 weeks) was initiated. CNS penetrating HER2 targeted therapy is permitted throughout the study, but patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after completion of protocol treatment. Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain metastasis. The two populations targeted for accrual include patients with 1) newly diagnosed, multiple brain metastases or 2) progressive brain metastases after stereotactic radiosurgery (SRS) or surgical resection of 1–3 metastases. Prior lapatinib is allowed. Patients are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; and prior SRS or surgical resection. The primary endpoint is complete response rate in the brain 12 weeks after WBRT. Secondary endpoints include objective response rate, lesion-specific response rate, CNS progression-free survival, and overall survival. 140 of 143 target accrual have enrolled (4/22/2019).
THER-01. PRECLINICAL DEVELOPMENT OF EO1001, A NOVEL IRREVERSIBLE BRAIN PENETRATING PAN-ErbB INHIBITOR
Authors: Shen Wang , Bacha Jeffrey , Brown Dennis , Kanekal Sarath , Sankar Neil , Wang ZhenZhong , Pedersen Harry , Butowski Nicholas , Nicolaides Theodore , Sarkaria Jann , James C David , Giles Francis
Published: August 2019

Dysregulation of ErbB-mediated signaling is observed in up to 90% of solid tumors. ErbB family cross-talk is implicated in the development of resistance and metastasis, including CNS metastases. Inhibition of multiple ErbB receptors may result in improved patient outcomes. EO1001 is a novel, patented, oral, brain-penetrating, irreversible pan-ErbB inhibitor targeting EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). METHODS: (1) In vitro testing. EO1001 demonstrates high specificity for the ErbB family of receptors with excellent, balanced equipotent activity against EGFR, HER2 and HER4 (0.4 to 7.4 nM). EO1001 inhibits signaling downstream of wild type EGFR, mutant EGFR (T790M, L858R and d746-750) and HER2. (2) PK and toxicity. In rodent studies in vivo, EO1001 exhibited a half-life of 16–20 hours. EO1001 rapidly enters the CNS and penetrates tumor tissue at higher concentrations relative to plasma. Safety of EO1001 was evaluated by repeat-dosing studies in SD rats and beagle dogs. Toxicities typical of the ErbB inhibitor class, including gastro-intestinal effects, weight loss and decreased activity were observed at higher dose groups in both species. Mortality was observed in SD rats at higher dose groups. (3) In vivo efficacy studies. EO1001 was studied following oral administration in several erbB-positive mouse xenograft models including N87 (Her2+), H1975 (EGFR/T790M), GBM12 (EGFR+), GBM39 (EGVRvIII+). Following oral administration, treatment with EO1001 resulted in a statistically significant improvement in outcomes compared to positive and negative controls in both CNS and systemic tumor models. EO1001 was well-tolerated with no gastrointestinal side effects observed at efficacious doses in these models. CONCLUSION: Based on research to date, EO1001 has the potential to be a best-in-class CNS-penetrating pan-ErbB inhibitor with a safety and pharmacokinetic profile amenable for use as a single agent and in combination with other agents. EO1001 is poised to enter phase 1-2a clinical testing in the second-half of 2019.
THER-04. THE USE OF AN ADENOSINE A2 AGONIST TO IMPROVE THE PREVENTION AND TREATMENT OF BRAIN METASTASES
Authors: Grossman Stuart , Romo Carlos , O’Connell Kaelin
Published: August 2019

As systemic therapies for cancer become increasingly effective, there is generally a rise in the incidence of brain metastases as a site of first recurrence. This occurs because most antineoplastic agents do not reach the brain in therapeutic concentrations. Many approaches have been studied to improve drug distribution to the central nervous system (CNS) such as intra-arterial administration, osmotic blood-brain barrier (BBB) disruption, focused ultrasound, convection-enhanced delivery, development of CNS penetrant pro-drugs, and the use of vasoactive peptides to transiently disrupt the BBB. However, none of these has improved the prevention or treatment of CNS metastases. Regadenoson is an adenosine A2 agonist that is FDA approved for use in cardiac stress tests. In animals, it has been shown to transiently increase BBB permeability allowing high molecular weight dextran and chemotherapy to enter brain in higher concentrations. A clinical study designed to determine if regadenoson will perform similarly in humans has been CTEP approved and will soon be accruing patients through the Adult Brain Tumor Consortium. If the results are encouraging, future studies will focus on administering regadenoson concurrently with systemically administered chemotherapy in an effort to reduce the incidence of CNS metastases and to improve CNS drug delivery in patients with known brain metastases. This presentation will focus on the available pre-clinical and clinical data supporting this approach and the potential advantages and risks associated with transient BBB disruption in this setting.
THER-05. SOLITARY CEREBRAL METASTASIS FROM TRANSITIONAL CELL CARCINOMA OF THE BLADDER
Authors: Jimenez Lissette , Hanefeld-Fox Liliana , Huang Bryan , Andryka Michael
Published: August 2019

INTRODUCTION: Brain metastasis is the most common neurological neoplasia seen in adults. They typically metastasize from primary lung or breast but very seldom is bladder cancer the culprit. Transitional cell carcinoma (TCC) of the bladder accounts for less than 1% of brain metastasis and few cases have been reported in literature. Here we present a rare case of TCC presenting with signs of neurological impairment. CASE DESCRIPTION: A 75-year-old male with history of TCC presented to the emergency department with right upper extremity hemiparesis and dysarthria of 5 hours duration. He had undergone cystoscopy with resection of tumor 3 years prior followed by gemcitabine chemotherapy and combination radiotherapy/immunotherapy. CT imaging revealed a hyperdense 3.3 cm mass in the left frontoparietal region with internal hemorrhage measuring 1.4 cm and surrounding vasogenic edema. He was immediately treated with high dose corticosteroids and antiepileptics which did not result in improvement of his symptoms. Metastatic workup which included contrast enhanced CT of chest, abdomen and pelvis revealed no evidence of local or metastatic recurrence. Due to rapid worsening of his status, respiratory failure and encephalopathy, family did not want to pursue additional treatment and decided on inpatient hospice. The patient died 3 weeks later due to rapid neurological decline. DISCUSSION: According to literature, CNS involvement of disseminated TCC varies from 0.6% - 8%, and bladder carcinoma accounts for 0.5% of all intracranial metastases. Incidence of CNS involvement without evidence of recurrence or disseminated disease is extremely uncommon. Aggressive multitherapeutic regimens, which include gemcitabine, have been favored for its penetration of the blood-brain barrier but even with its use disease may present years later with an unfavorable prognosis. Although metastasis from TCC of the bladder is rare any decline in neurological status should warrant further investigation in these patients.
MLTI-07. PREOPERATIVE VERSUS POSTOPERATIVE STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: AN INTERNATIONAL META-ANALYSIS
Authors: Garcia Henry Ruiz , Lehrer Eric , Bhargav Adip , Peterson Jennifer , Chaichana Kaisorn , Quinones-Hinojosa Alfredo , Harrell Anna , Routman David , Burns Terry , Zaorsky Nicholas , Trifiletti Daniel
Published: August 2019

PURPOSE: Preoperative stereotactic radiosurgery (SRS) for symptomatic brain metastases has arisen as a therapeutic option for patients with brain lesions, potentially reducing radionecrosis risk, leptomeningeal disease risk, as well as delays in systemic therapy after craniotomy. The purpose of our work is to analyze the current evidence regarding 1-year local control (LC) and RN rates in the preoperative and postoperative settings. METHODS AND MATERIALS: Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were used to select articles in which patients had “large” brain metastases (>4 cm3 or >2 cm in diameter) solely treated with preoperative or postoperative SRS and 1-year LC and/or rates of RN reported. Radiosurgery was stratified by timing: preoperatively or postoperatively. Random effects meta-analyses using timing of SRS relative to surgery as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size on the summary estimate, where the null hypothesis was rejected for p < 0.05. RESULTS: Fifteen studies were included (of 314 screened), published between 2012 and 2018 with 854 brain metastases. Preoperative SRS was delivered in 229 lesions. The 1-year LC random effects estimate was 79.1% (95% confidence interval [CI]: 55.9–95.0%; I  2 = 80%) for preoperative SRS and 80.5% (95% CI: 66.3–91.5%; I  2 = 93%) for postoperative SRS (p=0.9). Radionecrosis incidence random effects estimate was 2.1% (95% CI: 0.1–8.6%; I  2 = 36%) for preoperative SRS and 6.3% (95% CI: 1.1–15.4%; I  2 = 90%) for postoperative SRS (p=0.52). CONCLUSIONS: Rates of 1-year LC and RN incidence are similar after preoperative SRS as compared to postoperative SRS for large brain metastases. Results from ongoing prospective clinical trials studying preoperative SRS are important to further investigate these two techniques.
MLTI-09. UNDERWEIGHT AND WEIGHT LOSS ARE PREDICTORS OF POOR OUTCOME IN PATIENTS WITH BRAIN METASTASIS
Authors: Weller Michael , Lareida Anna , Terziev Robert , Grossenbacher Bettina , Andratschke Nicolaus , Roth Patrick , Rohrmann Sabine , Stahel Rolf , Guckenberger Matthias , Le Rhun Emilie , Wolpert Fabian
Published: August 2019

BACKGROUND: Despite increased risk of comorbidities, overweight may be associated with improved outcome in patients with metastatic cancer. Conversely, tumor cachexia has been identified as a negative predictor of outcome in patients with brain metastasis (BM) from lung cancer. Here we evaluate the association of abnormal body mass index (BMI) and weight change with outcome in patients with BM from different primary tumors. METHODS: Patients with a diagnosis of BM diagnosed and treated at the University Hospital Zurich (n=703) were assessed for associations of BMI, weight change, comorbidities and survival. RESULTS: Compared with patients with normal BMI of 18.5–24.9 kg/m2 who experienced a median overall survival (OS) of 9 months (95% confidence interval (CI) 7.5–10.5), OS was inferior in patients with BMI< 18.5 kg/m2 (OS 6 months, 95% CI 1.6–10.3, p=0.04), but superior in patients with BMI >25 kg/m2 (OS 13 months, 95% CI 11.0–15.0; p=0.033). For patients with documented weight course (n=173 of 703), we report a median relative weight loss of 5% within the first 6 months of BM diagnosis (95% CI 3.3–6.5). Reduction above the median was associated with an unfavorable outcome in this subgroup (weight loss ≧5% 22.0 months, 95% CI 19.2–24.8; weight loss < 5% 14.0 months, 95% CI 11.9–16.). CONCLUSIONS: Despite being associated with a worse cardiovascular risk profile, high BMI is associated with preferable and underweight with poor outcome in BM patients. Conversely, weight loss above median may be a predictor of poor outcome. Future studies need to address the question whether vigorous treatment of tumor cachexia, e.g. by specific nutrition management, might improve outcome of BM patients. In contrast, regimens that are associated with weight loss such as ketogenic diet may be detrimental.
MLTI-15. A CASE SERIES OF PRE-OPERATIVE GAMMA-KNIFE RADIOSURGERY FOR RESECTABLE BRAIN METASTASES
Authors: Takezaki Tatsuya , Yamamoto Haruaki , Shinojima Naoki , Kuroda Jun-ichiro , Yamashiro Shigeo , Mukasa Akitake
Published: August 2019

Recent advances in the systemic treatment of various cancers have resulted in longer survival and higher incidence of brain metastases. Phase 3 trials in north America and in Japan have demonstrated that stereotactic radiosurgery will be a standard adjuvant modality following surgery for resectable brain metastases. However, we don’t know the optimal sequence of this combination therapy. We hypothesized that pre-operative stereotactic radiosurgery for resectable brain metastases provides favorable rates of local control, overall survival, leptomeningeal dissemination and symptomatic radiation necrosis. We have experienced 4 cases of resected brain metastases within 1–7 days after Gamma-knife surgery (median margin dose:22Gy) and have been following their clinical course. We will show the repressive cases.
MLTI-19. VENOUS THROMBOEMBOLIC EVENTS IN PATIENTS WITH BRAIN METASTASES: THE PICOS SCORE
Authors: Wolpert Fabian , Grossenbacher Bettina , Lareida Anna , Roth Patrick , Neidert Marian , Andratschke Nicolaus , Le Rhun Emilie , Weller Michael
Published: August 2019

BACKGROUND: Venous thromboembolic events are significant complications in patients and possibly associated with an unfavorable outcome. Thrombosis risk is poorly defined for patients with brain metastasis, and available risk calculation scores are not validated for these patients. METHODS: We identified 811 patients with brain metastasis followed at our institution and screened electronic charts retrospectively for the occurrence of venous thromboembolic events, along with candidate risk factors. Risk factors were tested in uni- and multivariate analyses and finally integrated in a score model for risk prediction. RESULTS: Venous thromboembolic events were documented in 97 of 811 patients (12.0%). Primary tumors with high thrombogenicity (p=0.02, odds ratio 1.7, 95% CI 1.1–2.8), dexamethasone (p=0.011, odds ratio 2.27, 95% CI 1.5–4.5), chemotherapy (p=0.005, odds ratio 3.4, 95% CI 1.6–7.5), BMI > 35 kg/m2 (p=0.002, odds ratio 3.4, 95% CI 1.6–7.5) and immobilization (p=0.003, odds ratio 2.4, 95% CI 1.3–4.3) were confirmed as independent predictors of VTE. We derived a score model for venous thromboembolic event prediction, the PICOS (thrombogenic Primary, Immobilization, Chemotherapy, Obesity, Steroids) score (0–7 points). Receiver Operating Characteristic Curve Analysis demonstrated its prognostic accuracy (AUC=0.71, 95% CI 0.64–0.77), and its predictive capability was superior to that of other scores proposed for the evaluation of venous thromboembolic event risk such as the Khorana (AUC=0.51) or CONKO (AUC=0.52) scores. CONCLUSIONS: We report a rate of venous thrombotic events of 12.0% in our cohort of 811 patients with brain metastasis. We define a risk model for prediction in of venous thrombotic events in patients with BM, the PICOS score. It may become a valuable tool for the identification of brain metastasis patients at high risk for venous thromboembolic events and be helpful for guidance of clinicians towards decision whether to start thrombosis prophylaxis. Further, the PICOS score might be used for stratification in controlled studies.
OTHR-07. ESTIMATING INCIDENCE PROPORTION OF BRAIN METASTASES AT DIAGNOSIS AND LIFETIME INCIDENCE AMONG CANCER PATIENTS DIAGNOSED FROM 2010–2015 IN CANADA
Authors: Paudel Yuba Raj , Walker Emily , Smith Trenton , Yuan Yan , Nichol Alan , Davis Faith
Published: August 2019

INTRODUCTION: The incidence of brain metastases (BM) among Canadian cancer patients is unknown. We aimed to estimate the incidence proportion (IP) of BM at the time of all cancer diagnoses and during follow-up of cancer patients with the top six primary tumours that are most likely to metastasize to the brain. METHODS: Data on BM at diagnosis from 2010–2015 was obtained from the Canadian Cancer Registry (CCR). Site-specific IPs of BM was estimated for patients from provincial registries that achieved ≥90% complete data. These estimates were applied to the total number of newly diagnosed primary cancers to estimate total number of BM at diagnosis from 2010–2015 in Canada. To estimate the number of lifetime BM that arise from six selected primary cancers including lung, breast, skin melanoma, colorectal, kidney/renal pelvis and esophagus, we applied IP estimates reported in the literature. RESULTS: We identified 1,105,905 cancer cases in the CCR from 2010–2015, of which 519,950 (47%) were from the six primaries. The annual average number of patients with BMs at diagnosis from all cancer sites was approximately 2,800 and was highest for lung cancer(2,400).The site-specific IPs of BM at diagnosis were: lung (9.6%;95% CI: 9.3–10.0%), esophageal (2%;95%CI:1.5–2.7%), kidney/renal pelvis (1.3%;95%CI:1.0–1.5%), skin melanoma (1.1%;95%CI:0.9–1.3%), colorectal (0.3%;95%CI:0.2–0.3%), and breast (0.2%;95%CI:0.2–0.3%).Using clinical and population data from the literature, we estimated that nearly 7,400 lifetime BM cases occur annually for these six primaries. CONCLUSIONS: Each year in Canada, approximately 2,800 BMs from all primary cancers are found at the time of diagnosis and approximately 7,400 lifetime BM occur annually from the six selected primary tumours.
OTHR-13. A DEEP LEARNING APPROACH TO DETECT CANCER METASTASES TO THE BRAIN IN MRI
Authors: Zhang Min , Young Geoffrey , Chen Huai , Qin Lei , Cao Xinhua , Wu Xian , Xu Xiaoyin
Published: August 2019

BACKGROUND AND OBJECTIVE: Brain metastases have been found to account for one-fourth of all cancer metastases seen in clinics. Magnetic resonance imaging (MRI) is widely used for detecting brain metastases. Accurate detection of the brain metastases is critical to design radiotherapy to treat the cancer and monitor their progression or response to the therapy and prognosis. However, finding metastases on brain MRI is very challenging as many metastases are small and manifest as objects of weak contrast on the images. In this work we present a deep learning approach integrated with a classification scheme to detect cancer metastases to the brain on MRI. MATERIALS AND METHODS: We retrospectively extracted 101 metastases patients, equal to 1535 metastases on 10192 slices of images in a total of 336 scans from our PACS and manually marked the lesions on T1-weighted contrast enhanced MRI as the ground-truth. We then randomly separated the cases into training, validation, and test sets for developing and optimizing the deep learning neural network. We designed a 2-step computer-aided detection (CAD) pipeline by first applying a fast region-based convolutional neural network method (R-CNN) to sequentially process each slice of an axial brain MRI to find abnormal hyper-intensity that may correspond to a brain metastasis and, second, applying a random under sampling boost (RUSBoost) classification method to reduce the false positive metastases. RESULTS: The computational pipeline was tested on real brain images. A sensitivity of 97.28% and false positive rate of 36.25 per scan over the images were achieved by using the proposed method. CONCLUSION: Our results demonstrated the deep learning-based method can detect metastases in very challenging cases and can serve as CAD tool to help radiologists interpret brain MRIs in a time-constrained environment.
RADI-01. PROGNOSTIC FACTORS OF SHORT SURVIVAL FOR BRAIN METASTASES TREATED WITH SRS WITHOUT WBRT.
Authors: Harat Maciej , Blok Maciej , Makarewicz Roman , Roszkowski Krzysztof
Published: August 2019

Nowadays multiple brain metastases (up to 10–15 tumors) are treated with SRS alone. The most common diagnosis-specific Graded Prognostic Assessment and Score for Radiosurgery indices are based on data regarding limited brain metastases (1–4). Moreover, many of patients included in that analyses were treated with WBRT or combination of WBRT and SRS and some relevant data were not included due to a retrospective analysis of large datasets. SRS may increase intracranial control of disease, however, treatment of patients with a prognosis of fewer than 3 months survival after SRS may not be clinically reliable. Therefore we conducted an analysis of prospective registry to find the factors that correlate with very short survival after SRS. Materials and methods, A consecutive cohort of 84 patients treated with SRS only for brain metastases between 04.2018-03.2019. Data prospectively collected and introduced into a registry of patients treated with SRS in our department were analyzed. The analyzed factors are age, primary site, histopathology, previous surgery, molecular results, systemic therapy, duration of SRS planning, the extent of extracerebral metastatic disease, number of brain metastases, mass effect and neurological symptoms/ We performed a univariate analysis and multivariate Cox regression model to find a correlation between clinical and molecular data and survival in brain metastases patients treated with SRS only. Factors predicted early death and correlated with survival will be presented at the conference
RADI-07. GAMMA KNIFE RADIOSURGERY FOR SMALL CELL LUNG CANCER: PROGNOSTIC FACTORS INCLUDING ADDITIONAL LESIONS IDENTIFIED ON THE DAY OF RADIOSURGERY
Authors: Chaung Kevin , Kharouta Michael , Shamp Stephen , Machtay Mitchell , Sloan Andrew , Bhatt Aashish , Mansur David , Hodges Tiffany , Zhang Yuxia , Choi Serah
Published: August 2019

OBJECTIVES: Prophylactic cranial irradiation (PCI) and whole brain radiation (WBRT) are standard of care for intracranial disease in small cell lung cancer (SCLC) patients. We sought to identify predictors of overall survival (OS) in SCLC patients treated with salvage Gamma Knife radiosurgery (GKRS) for brain metastases after prior WBRT or PCI. METHODS: Retrospective analyses were conducted on 26 SCLC patients treated with GKRS at one institution between May 2010 and June 2018. Factors predictive of OS were analyzed using Cox proportional hazards regression and Wilcoxon sum-rank testing. RESULTS: Median follow-up and median OS following GKRS was 6.6 mos (range 0.7–24.2 mos). Median OS was 21.4 mos from initial diagnosis (range 7.3–49.3 mos). Presence of extracranial metastases at the time of GKRS was not significantly associated with median OS after GKRS (5.8 mos for patients with extracranial metastases vs 7.2 mos for patients without, p=0.425). Mean number of lesions was 2.7 (range 1–10) on diagnostic brain MRIs and 4.1 (range 1–12) on GKRS planning MRIs. Eleven patients (42%) had the same number of lesions between diagnostic MRI and GKRS MRI, and 15 patients (58%) had additional lesions on the GKRS MRI. Number of lesions treated and total tumor volume were not associated with median OS. Patients who had additional lesions on GKRS MRI compared to diagnostic MRI had lower median OS from initial diagnosis of SCLC (29.9 mos vs 18.1 mos, p=0.0182) and a trend toward lower median OS from time of GKRS (7.3 mos vs 4.8 mos, p=0.0547) compared to patients who did not have additional lesions. CONCLUSIONS: Finding additional brain metastases on GKRS planning MRIs is associated with decreased OS in SCLC patients treated with salvage GKRS. Presence of extracranial metastases at the time of GKRS and number or total volume of brain metastases were not associated with OS.
RADI-12. LEPTOMENINGEAL FAILURE AFTER PREOPERATIVE VERSUS POSTOPERATIVE RADIOSURGERY
Authors: Fiveash John , Riley Kristen , Markert James , Guthrie Bart , Foreman Paul , Popple Richard , Marcrom Sam , Strickler Scott , Willey Christopher , McDonald Andrew , Thomas Evan , Stewart John , Bredel Markus
Published: August 2019

INTRODUCTION: Postoperative stereotactic radiosurgery (postop SRS) is potentially complicated by difficulty defining the target volume and the risk of leptomeningeal seeding at the time of surgery. It is hypothesized that preop SRS may render cells less viable to disseminate in the leptomeningeal space. This retrospective study compares the leptomeningeal dissemination (LMD) rate for preop versus postop radiosurgery METHODS: We identified 140 patients with brain metastases who underwent resection and radiosurgery at the University of Alabama at Birmingham including 91 postop patients (2005–2015) and 49 preop patients (2011–2018). The preop group included 19 patients enrolled in a phase I trial of preoperative radiosurgery (12–15 Gy) for tumors 2–6 cm in greatest diameter. In that study 15 Gy was found to be safe in the preop setting but further escalation was not attempted. An additional 30 patients received preop SRS off-study (median dose 15 Gy). The median postop dose was 16 Gy. LMD recurrence was defined as focal pachymeningeal or diffuse leptomeningeal enhancement of the brain, spinal cord, or cauda equina, dural enhancement beyond 5 mm from the index metastasis, subependymal enhancement, or enhancement of cranial nerves. This definition is not limited to carcinomatosis. All events were categorized and confirmed by at least two physicians. RESULTS: 40/140 (29%) patients developed new focal or diffuse LMD. Preop SRS was associated with a higher freedom from leptomeningeal recurrence (84% vs 60% at one year, p=0.021 Breslow, p=0.128 log-rank). Since later LMD may not be related to surgery, a second analysis censoring follow-up at one year was performed and confirmed this trend (p=0.008 Breslow, p=0.014 log-rank). CONCLUSIONS: Preoperative SRS is associated with a reduction in the risk of LMD compared to postop SRS. Focal pachymeningeal dissemination may not always be recognized as related to surgery. A randomized trial of preop vs postop SRS is warranted.
RADI-16. ECONOMIC IMPLICATIONS OF PREOPERATIVE VERSUS POSTOPERATIVE STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES
Authors: Ward Matthew , Prabhu Roshan , Asher Anthony , Wait Scott , Sumrall Ashley , Shah Chirag , Burri Stuart
Published: August 2019

OBJECTIVE: Retrospective data suggests preoperative stereotactic radiosurgery (preSRS) reduces radiation necrosis (RN) and leptomeningeal disease (LMD) failure after resection of brain metastases (BM) as compared to postoperative SRS (postSRS). We evaluated the potential financial impact of a reduction in symptomatic RN (SRN) and LMD, should preSRS become a national standard. METHODS: A decision tree was designed to evaluate the two strategies: preSRS vs. postSRS. We assumed no difference in survival and that a reduction in SRN and LMD exists on par with retrospective data. Effectiveness was not considered given unclear health utilities. Treatments for SRN considered were dexamethasone, bevacizumab, surgical resection, or hyperbaric oxygen (HBO). Treatments for LMD considered included conventional radiation, SRS, systemic therapy (lapatinib/capecitabine), or no therapy. Probabilities were extracted from the 2-year LMD/SRN rates and subsequent treatment patterns observed in retrospective data. Treatment costs were based on the 2019 Medicare physician fee schedule and published data in 2019 US dollars without discounting. National costs to the healthcare system were estimated by assuming 200,000 BM cases per year with a surgical utilization rate of 16%. Deterministic and probabilistic sensitivity analyses (PSA) were performed. RESULTS: The incorporated rate of LMD and SRN for postSRS was 22.4% and 16.4% and 4.3% and 4.9% for preSRS, respectively. The expected mean costs were $3,129 for postSRS and $810 for preSRS. Deterministic sensitivity analysis demonstrated that the model was sensitive to only LMD/SRN rates. PSA demonstrated that in 95% of simulations, the expected savings ranged from $770-$6,429/patient. Therefore, the national healthcare system stands to save approximately $74 million per year if preSRS was a national standard (range $25–206 million). CONCLUSIONS: A prospective randomized trial demonstrating the effectiveness of preSRS in the reduction of LMD and/or SRN would carry a significant return on investment through the reduction of subsequent treatment costs.
RADI-19. EVALUATION OF BRAIN METASTASIS LOCAL CONTROL POST RADIOSURGERY VIA MACHINE LEARNING AND RADIOMICS
Authors: Dise Joseph , Abraham Christopher , Caruthers Douglas , Mutic Sasa , Robinson Clifford
Published: August 2019

Stereotactic radiosurgery can be used to treat multiple, surgically inaccessible, metastatic brain lesions in a single, minimally invasive outpatient procedure. For brain metastasis, stereotactic radiosurgery can provide excellent local control depending on the robustness of the treatment plan. Previous studies have been performed correlating key radiation planning factors to higher local control probability such as tumor size and maximum dose. However, a separate non-inferiority study demonstrated that higher prescription isodose lines (in excess of 70% or higher) did not correlate to local failure. The previous works were limited to shallow feature levels regarding only the dicom plan information and lacked a predictive model. In order to address these conflicting conclusions and to support clinical decision making, we propose a radiosurgery informatics pipeline to support testing these hypotheses with observational data. First, a multidisciplinary team generated a mind-map of relevant information to inform database design. Portions of this mind-map were implemented in a relational database system (PorstgreSQL), and populated with information from 1024 patients treated for brain metastasis via stereotactic radiosurgery. Clinical information were derived from curated databases and the array of intervention variables were mined from the DICOM RT plans, structure sets, images and dose via MATLAB scripts. These factors include, but are not limited to, radiation dosimetry, prior whole brain radiation, radiomic imaging features, prior radiosurgery status, and physician determined local control status. From this pipeline, we plan to use a multi-level feature-based supervised machine learning approach that will be created via boosting to predict local control in patients using local failure timing, or lack thereof, provided by physician. To control for local failure observer bias, an unsupervised machine learning model via random trees will be created to predict clusters of patient parameters with similar local control rates.
RADI-20. RETROSPECTIVE OUTCOME ANALYSIS OF INTRAOPERATIVE RADIOTHERAPY (IORT) FOR SURGICALLY RESECTED BRAIN METASTASES: AN INTERNATIONAL COOPERATIVE STUDY.
Authors: Cifarelli Christopher , Vargo J Austin , Hack Joshua , Kahl K Henning , Brehmer Stefanie , Sarria Gustavo , Giordano Frank
Published: August 2019

BACKGROUND & OBJECTIVE: The ideal delivery of adjuvant radiation to the surgical cavity of brain metastases (BMs) remains the subject of debate. Risks of leptomeningeal dissemination (LMD), local failure (LF) and radiation necrosis (RN) have prompted a reappraisal of the timing and/or modality of this critical component of BM management. IORT delivered at the time of resection for BMs requiring surgery offers the potential for improved LC and decreased LMD afforded by the elimination of delay in time to initiation of radiation following surgery and the possibility of dose escalation beyond that seen in stereotactic radiosurgery (SRS). This study provides a retrospective analysis with identification of potential predictors of outcomes. METHODS: Retrospective data was collected on patients treated with IORT immediately following surgical resection of BMs at three institutions according to the approval of individual IRBs. All patients were treated with the Zeiss Intrabeam device (Carl Zeiss Meditech, Germany) using spherical applicators ranging from 1.5 to 4.0cm with 50kV output. Statistical analyses were performed using SPSS (IBM) with endpoints of LF, DBF, incidence of RN, and overall survival (OS) and p< 0.05 considered significant. RESULTS: 54 patients were treated with IORT with a median age of 64 years. The most common primary diagnosis was non-small cell lung cancer (40%) with the most common location in the frontal lobe (38%). Median follow-up was 7.2 months and 1-year LC, DBF, and OS were 88%, 58%, and 73%, respectively. LMD was identified in 2 patients (3%) and RN present in 4 patients (7%). The only predictor of LC was extent of resection with 1-yr LC of 94% for GTR vs 62% for STR (p=0.049). CONCLUSIONS: IORT is a safe and effective means of delivering adjuvant radiation to the BM resection cavities with high rates of LC and low incidence of RN.
RADI-28. UP-FRONT SINGLE SESSION RADIOSURGERY FOR LARGE BRAIN METASTASES - VOLUMETRIC RESPONSES AND OUTCOMES
Authors: Benjamin Carolina , Mureb Monica , Nakamura Aya , Mullen Reed , Pacione Donato , Silverman Joshua , Kondziolka Douglas
Published: August 2019

OBJECTIVE: Patients presenting with large brain metastases (LBM), described in the literature as ≥2.5 cm in maximum diameter or ≥10cm3in volume, pose a management challenge. For patients not compromised by mass effect, corticosteroid therapy followed by SRS allows for efficient, minimal access care that facilitates immediate institution of systemic therapy. METHODS: We performed a volumetric-based analysis in order to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Thirty patients over the age of 18 with systemic cancer and brain metastases (≥2.7cm in greatest diameter or ≥10cm3in volume) who underwent single session SRS were included. Serial tumor volumes, clinical outcomes, and medication requirements were studied. RESULTS: Among 30 patients, 70% of patients had either lung, melanoma, or breast cancer. Median initial tumor size (maximum diameter) was 32mm (range 28–43) and median initial tumor volume was 9.32cm3 (range 1.09–25.31). Median marginal dose was 16Gy (range 12–18). Average percent decrease in tumor volume was 50% on imaging at 4–8 weeks, 60% at 4–6 months, 48% at 6–8 months, and 67% at >8 months compared to initial imaging. Only one patient required a subsequent craniotomy 4 years after SRS for an enlarging cyst which was granulation tissue consistent with radiation effects on pathology. There were no adverse events immediately following SRS. Median corticosteroid use after SRS was 21 days. There was no statistically significant difference in KPS score between treatment day and last follow up, suggesting relative safety and maintenance of function. CONCLUSION: Initial high dose corticosteroid therapy followed by prompt single session SRS is a safe and efficacious method of managing patients with large brain metastases (defined in our study as ≥2.7cm or ≥10cm3), if the clinical condition of the patient is acceptable at presentation.
RADI-37. CLINICAL RISK FACTORS FOR INTRACRANIAL HEMORRHAGE OF SOLID MELANOMA BRAIN METASTASES AFTER RADIOSURGERY
Authors: Okoukoni Catherine , LeCompte Michael , Hughes Ryan , McTyre Emory , Cramer Christina , Whitlow Christopher , Chan Michael
Published: August 2019

PURPOSE: Melanoma brain metastases (MBM) are among the most common solid tumors associated with intracranial hemorrhage (ICH). Our objective is to investigate risk factors for post-radiosurgery intracranial hemorrhage (PRH). METHODS: We collected demographic, clinical, treatment, toxicity, survival, and imaging data for patients with solid MBM who underwent SRS between 2000 and 2016 at our institution. Bleed free survival (BFS) and overall survival (OS) analyses were performed using Kaplan–Meier methods. Logistic regression was used to identify PRH risk factors. RESULTS: From 2000 to 2016, 107 patients with a total of 548 solid MBM received SRS. Median patient age at time of SRS was 63.2 years. Median MBM volume was 2.8 cm3 (range 0.01–21.3 cm3). MBM were in the cortex (n = 431), cerebellum (n= 85), basal ganglia (n= 23), and brain stem (n= 9). MBM were treated to a median dose of 20 Gy (range 14–20 Gy). Seventeen patients received immunotherapy (IT) within 1 year of SRS, 7 patients received concurrent immunotherapy (XR-IT). Median follow-up and OS was 13.5 months and 10.8 months, respectively. Median BFS was 8.3 months. PRH occurred in 123 MBM (22%). MBM volume (p= 0.0001), total MBM volume (p= 0.0006), IT (p= 0.04), and XR-IT (p= 0.03) were associated with increased PRH. PRH cumulative incidence within 24 mo of SRS was increased in MBM > 2.8 cm3 compared with patients with smaller MBM: 27.5% verse 5.3%, respectively. Age, sex, hypertension, MBM location, total MBM number, and marginal dose (p > 0.05) did not significantly impact risk of PRH. No significant difference in 6, 12, or 24 mo actuarial OS rates were observed in patients with PRH (p > 0.05). CONCLUSIONS: Patients with larger MBM volume and IT within 1 year of SRS have the greatest risk of PRH. PRH did not significantly impact OS in this study.