Large Brain Metastases Research Articles

EP-1133: Multifraction Radiosurgery for Large Brain Metastasis: Initial Results from Brazilian Experience

EP-1133: Multifraction Radiosurgery for Large Brain Metastasis: Initial Results from Brazilian Experience

EP-1540: Optimal fractionation schemes for radiosurgery of large brain metastases

EP-1540: Optimal fractionation schemes for radiosurgery of large brain metastases

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

Stereotactic radiosurgery (SRS) dose is limited by brain metastasis (BM) size. The study goal was to retrospectively determine whether there is a benefit for intracranial outcomes and overall survival (OS) for gross total resection with single-fraction SRS versus SRS alone for patients with large BMs. A large BM was defined as ≥4cm3 (2cm in diameter) prior to the study. We reviewed the records of consecutive patients treated with single-fraction SRS alone or surgery with preoperative or postoperative SRS between 2005 and 2013 from 2 institutions. Overall, 213 patients with 223 treated large BMs were included; 66 BMs (30%) were treated with SRS alone and 157 (70%) with surgery and SRS (63 preoperatively and 94 postoperatively). The groups (SRS vs surgery and SRS) were well balanced except regarding lesion volume (median, 5.9cm3 vs 9.6cm3; P<.001), median number of BMs (1.5 vs 1, P=.002), median SRS dose (18Gy vs 15Gy, P<.001), and prior whole-brain radiation therapy (33% vs 5%, P<.001). The local recurrence (LR) rate was significantly lower with surgery and SRS (1-year LR rate, 36.7% vs 20.5%; P=.007). There was no difference in radiation necrosis (RN) by resection status, but there was a significantly increased RN rate with postoperative SRS versus with preoperative SRS and with SRS alone (1-year RN rate, 22.6% vs 5% and 12.3%, respectively; P<.001). OS was significantly higher with surgery and SRS (2-year OS rate, 38.9% vs 19.8%; P=.01). Both multivariate adjusted analyses and propensity score-matched analyses demonstrated similar results. In this retrospective study, gross total resection with SRS was associated with significantly reduced LR compared with SRS alone for patients with large BMs. Postoperative SRS was associated with the highest rate of RN. Surgical resection with SRS may improve outcomes in patients with a limited number of large BMs compared with SRS alone. Further studies are warranted.

The radiosurgery fractionation quandary: single fraction or hypofractionation?

Stereotactic radiosurgery (SRS), typically administered in a single session, is widely employed to safely, efficiently, and effectively treat small intracranial lesions. However, for large lesions or those in close proximity to critical structures, it can be difficult to obtain an acceptable balance of tumor control while avoiding damage to normal tissue when single-fraction SRS is utilized. Treating a lesion in 2 to 5 fractions of SRS (termed "hypofractionated SRS" [HF-SRS]) potentially provides the ability to treat a lesion with a total dose of radiation that provides both adequate tumor control and acceptable toxicity. Indeed, studies of HF-SRS in large brain metastases, vestibular schwannomas, meningiomas, and gliomas suggest that a superior balance of tumor control and toxicity is observed compared with single-fraction SRS. Nonetheless, a great deal of effort remains to understand radiobiologic mechanisms for HF-SRS driving the dose-volume response relationship for tumors and normal tissues and to utilize this fundamental knowledge and the results of clinic studies to optimize HF-SRS. In particular, the application of HF-SRS in the setting of immunomodulatory cancer therapies offers special challenges and opportunities.

Outcome appraisal of patients with limited brain metastases (BMs) from non small cell lung cancer (NSCLC) treated with different local therapeutic strategies: a single institute evaluation.

To evaluate the outcome of patients with non-small-cell lung cancer (NSCLC) with limited brain metastases (BMs) treated with local approaches omitting whole-brain radiation therapy (WBRT). Surgery was performed in case of a single, large BM, controlled extracranial disease and Karnofsky Performance Status (KPS) 90-100; stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiosurgery (HSRS) was performed in all other cases. The prescribed dose was 24 Gy/1 fraction for lesions <2.5 cm, and a median of 30 Gy (24-40 Gy) in 3-5 fractions for lesions >2.5 cm. 156 patients treated for 228 BMs were retrospectively evaluated. The median age was 62 years. The majority of patients had a KPS 90-100, recursive partitioning analysis Class II, diagnosis-specific graded prognostic assessment score 2.5-3 and 1-2 BMs. Surgical resection was performed in 18 cases, and SRS/HSRS was performed in 210 cases. The 1-2-year local control was 87.2 ± 3.0% and 72.8 ± 5.0%; the 1.2-year brain distant failure was 30.8 ± 4.0% and 58.1 ± 6.0%; the 1-2-year overall survival was 60.9 ± 3.9% and 31.4 ± 4.0%. On univariate and multivariate analysis, the following factors influenced survival: age (p = 0.01), the presence of lymph node involvement (p = 0.03), KPS (p << 0.01), the presence of extracranial metastases at the time of BM treatment (p < 0.01), the number of BMs (p = 0.02) and the treatment performed (p < 0.01). The choice of an adequate local treatment can impact on survival in patients with limited BMs from NSCLC. A careful evaluation of prognostic and predictive factors is a pivotal additional aid. Advances in knowledge: Radiosurgery or surgery followed by radiosurgery on the tumour bed in place of WBRT proved to be an effective treatment influencing outcome. Surgical resection followed by SRS on the tumour bed has to be considered for lesions ≥15 mm, in patients with good KPS, age ≤70 years, adenocarcinoma histology and oligometastatic disease.

143PD Hypofractionated radiotherapy combined with temozolomide for large brain metastases: A prospective trial

143PD Hypofractionated radiotherapy combined with temozolomide for large brain metastases: A prospective trial

RTHP-39. SURVIVAL OUTCOME OF LONG-TERM RESPONDERS TO FRACTIONATED VERSUS SINGLE-DOSE STEREOTACTIC RADIOSURGERY (SRS)

Treatment of brain metastases with fractionated stereotactic radiosurgery (F-SRS) is predicated on intent to reduce radiation toxicity without compromising local control. In patients with large brain metastases, F-SRS has been suggested to have improved local control compared to single-fraction stereotactic radiosurgery (S-SRS) with acceptable toxicity. The differences, though, between patients who undergo S-SRS and F-SRS that survive well beyond the one-year time frame are still unclear. Here we present a retrospective review of brain-metastatic lung and breast cancer patients that survived at least one year from initial SRS. A total of 91 patients, 58 lung- and 33 breast-primary, were treated between September 2006 and October 2014 with a median overall survival from initial SRS (SRS-mOS) of 24.9 months (range, 12.1-84.9 months). 203 lesions were irradiated in 86 patients (range, 1 to 9). The S-SRS group included 34 patients (26 lung, 8 breast) and the F-SRS group had 57 patients (32 lung, 25 breast). The S-SRS group received total doses ranging from 15-20 Gy (median, 17 Gy) and the F-SRS group received total doses ranging from 20-25 Gy in 3-5 fractions (median, 21 Gy). The median age was 59.6 yo (range, 31.2-85.1 yo). Kaplan-Meier analyses revealed no significant difference between single-dose and fractionation (S-SRS, 28.3 mo; and F-SRS,31.8 mo; p=0.5735) even when adjusted for primary cancer site. No differences were seen between primary site (p=0.3284) or 1-4 vs. 5 or more brain metastases (p=0.8364). The similarity in survival between S-SRS and F-SRS suggests that fractionation may be used without compromising survival, although it remains to be seen how other prognostic factors influence outcomes in this cohort.

Can Individualized Isotoxic Dose Prescription Improve the Therapeutic Ratio of Stereotactic Radiation Therapy in Large Brain Metastases?

Can Individualized Isotoxic Dose Prescription Improve the Therapeutic Ratio of Stereotactic Radiation Therapy in Large Brain Metastases?

P13.11 Outcome evaluation of oligometastatic patients with single, large brain metastases treated with gross total resection (GTR) followed by hypofractionated stereotactic radiosurgery (HSRS) on the tumor bed

AbstractIntroduction:In case of large brain metastases (BMs), treatment option include whole-brain-radiation-therapy (WBRT), surgery, single dose radiosurgery (SRS) or Hypofractionated stereotactic radiosurgery (HSRS). None of these, when given as a single modality are able to obtain and adequate local control rate. Therefore a combined approach, if feasible, is recommended. The aim of this study was to evaluate the benefit of a combined treatment, gross total resection (GTR) followed by adjuvant hypofractionated-stereotactic-radiosurgery (HSRS) on the tumor bed, in oligometastatic patients with single, large BMs.Methods and Materials:From January 2011 to March 2015, 69 patients with single, large BMs, controlled primary tumor and extracranial disease were treated. All patients underwent gross total resection (GTR) followed by HSRS on the tumor bed with a total dose of 30 Gy in 3 daily fractions. Clinical outcome was evaluated by neurological examination and MRI 2 months after RT and then every 3 months. Local progression was defined as radiographic increase of the enhancing abnormality in the treated brain volume and brain distant progression (BDP) as the presence of new brain metastases or leptomeningeal enhancement outside the treated brain volume. Surgical morbidity and radiation-therapy toxicity, local control (LC), brain distant progression (BDP), and overall survival (OS) were evaluated.Results:The median preoperative volume and maximum diameter of BMS was 18.45 cm3 (range 4.06–64.23 cm3) and 3.6 cm (range 2.1–5.4 cm); the median clinical target volume (CTV) was 29 cm3 (range 4.06–203.10 cm3) and the median planning target volume (PTV) was 55.19 cm3 (range 17.18–282.90 cm3). The median follow-up was 24 months (range 4–33 months). The 1-and 2-year LC in site of treatment was 100%; the median, 1-and 2-year BDP was 11.9 months, 19.6% and 33 %; the median, 1-and 2-year OS was 24 months (range 4–33 months), 91.3% and 73%. No severe postoperative morbidity or radiation toxicity occurred in our series.Conclusions:Multimodal approach, surgery followed by HSRS, can be an effective treatment option for selected patients with single, large brain metastases from different solid tumors.Keywords: brain metastases, surgical resection, hypofractionated-stereotactic-radiosurgery

Evaluation of Dose-Staged Gamma Knife Radiosurgical Treatment Method for High-Risk Brain Metastases

The study aim was to evaluate the utility of 2-fraction, dose-staged Gamma Knife radiosurgery (GKRS) in patients with large, high-risk brain metastases (BMs). A total of 63 large BMs in eloquent areas in 61 patients were treated with GKRS in 2 reduced doses. Treatment planning was conducted on the 50% isodose line and included the whole tumor volume as seen on T1 contrast-enhanced and T2-weighted magnetic resonance imaging sections. The median margin and central dose were 12 Gy and 24 Gy, respectively, for both fractions. Patients were assessed using the Graded Prognostic Assessment, Recursive Partitioning Analysis, and Score Index for Radiosurgery. Thirty-two patients (53%) had been diagnosed with multiple BMs, and extracranial metastases were present in a majority of patients before GKRS treatment. Significant decreases in tumor volume were observed between the first and second treatment stages. At 3-month follow-up, a majority of patients presented with stable or decreased lesion volumes. The remaining patients showed intralesional hemorrhaging or increasing edema that was managed conservatively. Three patients were diagnosed with tumor progression at the last follow-up and received microsurgical treatment. The median time to radiologic progression was 7 months. The median survival time after initial BM diagnosis was 6 months. Survival times were significantly longer than 3 of 4 calculated prognostic survival estimates. The new 2-fraction, dose-staged GKRS concept seems to be a well-tolerated and effective treatment option for large BMs. This method may be indicated in elderly patients or patients with surgical contraindications with large or high-risk brain metastases.

Hypo-fractionated stereotactic radiotherapy alone using volumetric modulated arc therapy for patients with single, large brain metastases unsuitable for surgical resection.

BackgroundHypo-fractionated stereotactic radiotherapy (HSRT) is emerging as a valid treatment option for patients with single, large brain metastases (BMs). We analyzed a set of our patients treated with HSRT. The aim of this study was to evaluate local control (LC), brain distant progression (BDP), toxicity and overall survival (OS).MethodsFrom July 2011 to May 2015, 102 patients underwent HSRT consisting of 27Gy/3fractions for lesions 2.1–3 cm and 32Gy/4 fractions for lesions 3.1–5 cm. Local progression was defined as increase of the enhancing abnormality on MRI, and distant progression as new brain metastases outside the irradiated volume. Toxicity in terms of radio-necrosis was assessed using contrast enhanced T1MRI, T2 weighted-MRI and perfusion- MRI.ResultThe median maximum diameter of BM was 2.9 cm (range 2.1–5 cm), the median gross target volume (GTV) was 16.3 cm3 and the median planning target volume (PTV) was 33.7 cm3 The median,1,2-year local control rate was 30 months, 96, 96 %; the median, 1–2-year rate of BDP was 24 months, 12, 24 %; the median,1,2-year OS was 14 months, 69, 33 %. KPS and controlled extracranial disease were associated with significant survival benefit (p <0.01). Brain radio-necrosis occurred in six patients (5.8 %).ConclusionIn patients with single, large BMs unsuitable for surgical resection, HSRT is a safe and feasible treatment, with good brain local control and limited toxicity.

Single fraction stereotactic radiosurgery (SRS) alone versus surgical resection and SRS boost for large brain metastases: A multi-institutional analysis.

2076Background: SRS dose is typically limited by brain metastasis (BM) size. Any benefit for the addition of surgery to SRS for large BM in patients (pts) with oligometastatic brain disease is not ...

Efficacy of hypofractionated stereotactic radiotherapy combined with temozolomide for large brain metastases: a prospective clinical study

Objective To analyze the efficacy and safety of hypofractionated stereotactic radiotherapy (FSRT) combined with temozolomide (TMZ) for large brain metastases (BMs) in a prospective phase Ⅱ clinical trial. Methods From 2010 to 2015, a total of 33 patients were enrolled as subjects. The median Karnofsky Performance Status scores before and after treatment were 70 and 80, respectively. The major primary tumor was non-small cell lung cancer (57.6%). The brain metastasis had a diameter of ≥3 cm or a volume of ≥6 cm3. The radiation dose was 52 Gy in 13 fractions or 52.2 Gy in 15 fractions. Patients received TMZ at a dose of 75 mg/m2 per day concurrently. The radiotherapy was followed by 6 cycles of adjuvant treatment with TMZ (150 mg/m2, days 1-5, 28 days per cycle). Patients were reexamined by magnetic resonance imaging (MRI) during the treatment. The radiation field would be shrunk if the gross target volume (GTV) was reduced by ≥20%. The treatment outcomes were evaluated by MRI at 2-3 months after treatment. Results The total numbers of tumors and GTVs were 95 and 38, respectively. Twenty-four (63%) out of the 38 GTVs had a volume larger than 10 cm3 and the median GTV was 15.3 cm3(5.7-142.8 cm3). Twenty-two (67%) out of the 33 patients achieved field shrinking during the treatment, and the median reduction rate of GTV was 44%(21%-88%). The median total dose was 59.5 Gy, and 100% and 21.2% of patients completed the concurrent and adjuvant treatment with TMZ, respectively. In all patients, the overall response rate was 97.0%; the 1-year local control, intracranial progression-free survival, and overall survival rates were 97%, 70%, and 62%, respectively; the median survival time was 15.3 months. The main adverse reactions were grade 1-2 nausea and vomiting. One patient got grade 3 liver function impairment. Conclusions FSRT combined with TMZ is a safe and effective approach for treating large BMs. More than 50% of patients can achieve field shrinking to shorten treatment duration and reduce toxicity. Clinical Trial Registry ClinicalTrials.gov, registration number: NCT02654106. Key words: Neoplasms, brain metastases/radiotherapy; Radiotherapy, hypofractionated; Neoplasms, brain metastases/chemotherapy; Chemotherapy, temozolomide; Large volume

Features stereotactic radiosurgical treatment large brain metastatic lesions of the brain with hypoxic radiosensitizers

Objective : Follow the dynamics of early reduction of tumor volume after stereotactic radiosurgery using hypoxic radiosensitizers and without radiosensitization, a comparison of these data with predictor of prolonged local control and median follow-up. Materials and methods: 107 patients (173 lesions) with large brain metastases (≥10cm 3 ) accounted for the main and control group of our research. Of these, the basic group (with radiosensitizers) 77 included, in the control group — 30 patients. Of the 77 patients, 40 patients (66 lesions) was used as a radiosensitizer metronidazole (M+), 37 (60 lesions) — nimorazol (H+). The average volume of metastases was 20.0cm 3 (range 10–60.0cm 3 ). SRS in one fraction to the average dose of 14 Gy (range 10–18 Gy), conducted an average of 4 fractions (range 3–5 fractions), with a mean dose of 26.5 Gy (range 21–40 Gy). Are taken into account only those patients who have at least passed the first compulsory MRI investigation a week after the SRS, with a further observation of 1.5 and 3 months. Results: During the term of supervision in metastases which considerably diminished in a volume already in a week after SRS, the signs of local control and median follow-up, unlike a control group, without of radiosensitizers at which it was not marked early and rapid reduction of tumour (r = .003, OR = 0.424; 95% confidence interval, 0.203-0.935), also in a group with radiosensitization the indexes of survivability were higher (19.0 months against 10.0, 95% [CI], 12.876-22.124 and 7.330-12.670, р=.0008 аnd р=.0001, respectively). Conclusions: Early reduction large brain metastases week after radiosurgery using hypoxic radiosensitizers may be a predictor of long-term local tumor control.

Ceritinib enables stereotactic radiosurgery to a previously untreatable symptomatic brain metastasis in a patient with ALK rearranged non-small cell lung cancer

Abstract Brain metastases are common in non-small cell lung cancer (NSCLC) and traditionally have been treated with whole brain radiation therapy, surgery, or stereotactic radiosurgery, with a limited role for systemic therapy. However, the development of highly active small molecule tyrosine kinase inhibitors for patients with NSCLC characterized by key driver mutations has generated interest in the use of systemic therapy as an alternative to potentially morbid local therapy for brain metastases. We present the case of a 59 year old Caucasian female with anaplastic lymphoma kinase (ALK) rearranged NSCLC who developed a large symptomatic brain metastasis not initially amenable to stereotactic radiosurgery (SRS) while receiving the ALK inhibitor crizotinib. The lesion regressed quickly after initiation of ceritinib, a next generation ALK inhibitor with known activity against crizotinib refractory ALK rearranged NSCLC, thereby allowing SRS as an alternative to standard craniotomy and consolidative whole brain radiation therapy.

ATNT-22A PHASE 1 STUDY OF TPI 287 CONCURRENT WITH FRACTIONATED STEREOTACTIC RADIOTHERAPY (FSRT) IN TREATMENT OF BRAIN METASTASES FROM ADVANCED BREAST AND NON-SMALL CELL LUNG (NSCL) CANCER

BACKGROUND: TPI 287, a member of taxanes diterpenoid (taxoid) family, is a microtubule-stabilizer with significant cytotoxic activity. In vivo studies have demonstrated that TPI 287 penetrates the blood brain barrier and significantly reduces the formation of large brain metastases in models of human breast cancer brain metastasis. The radiosensitizing effect of taxanes has been well established. METHODS: This phase I study (3 + 3 design) explores the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), and antitumor activity (local control rate, distant intra-cranial control rate, progression-free survival) of TPI 287 administered concurrently with FSRT (NCT02187822). Patients with up to 3 untreated brain metastases (maximum diameter of each brain lesion ≤ 5 cm, maximum tumor volume ≤ 120 cc) from breast cancer or NSCLC are eligible. Eligible patients are treated with FSRT to target brain metastases (25 Gy in 5 daily fractions). TPI 287 is administered intravenously once per week, for total of 3 doses. The first dose of TPI 287 is given concurrently with the first fraction of FSRT. Once the RP2D is determined, an additional 10 patients will be enrolled in an expansion safety cohort, for a planned total enrollment of 36 patients. Effect of treatment on quality of life measures will be evaluated. RESULTS: As of June 2015, a total of 4 patients have been enrolled in the first two dose escalation cohorts (14 and 28 mg/m2). No treatment-related grade 3/4 adverse events (AEs) have been observed. No dose limiting toxicity has been reported, and maximal tolerated dose has not been reached. TPI 287 dose escalation continues. CONCLUSIONS: Preliminary data to date indicate that administration of TPI 287 concurrent with FSRT is well tolerated. Updated safety and efficacy results will be presented.

RTRB-06TIME BETWEEN DIAGNOSTIC MRI AND FRAME-FIXED STEREOTACTIC RADIOSURGERY PLANNING MRI IS ASSOCIATED WITH BRAIN METASTASIS GROWTH BUT NOT WORSE LOCAL CONTROL

RTRB-06. TIME BETWEEN DIAGNOSTIC MRI AND FRAME-FIXED STEREOTACTIC RADIOSURGERY PLANNING MRI IS ASSOCIATED WITH BRAIN METASTASIS GROWTH BUT NOT WORSE LOCAL CONTROL Michael Garcia, Sai Duriseti, Shannon Fogh, Jean Nakamura, David Larson, Philip Theodosopoulos, Michael McDermott, Penny Sneed, and Steve Braunstein; University of California, San Francisco, San Francisco, CA, USA BACKGROUND: Frame-fixed stereotactic radiosurgery (FFSRS) and frameless SRS precisely target brain metastases (BM). Seymour et al. recently showed patients treated with frameless SRS planned on MRI completed ≥ 14 days before treatment delivery have worse local control. An advantage of FFSRS is acquisition of planning MRI on day of SRS. We sought to describe BM growth (BMG) before SRS by comparing the preceding diagnostic MRI (dMRI) and FFSRS MRI scans. METHODS: Patients treated with FFSRS for BM at our institution from 2010 through 2013 were retrospectively reviewed. We identified 256 patients (1302 BM) without upfront surgical resection who had a dMRI for comparison of BM size on FFSRS MRI. Post-FFSRS local failure free progression (LFFP) and overall survival (OS) were compared by log-rank tests. RESULTS: Median imaging follow up was 10 months. Mean size [95%CI] of largest BM was 1.4cm [1.2-1.5]. BMG was observed on FFSRS MRI compared to dMRI for 30% patients. Mean time interval between dMRI and FFSRS was 25 days, and time interval was associated with BMG (Pearson’s r 1⁄4 0.14, p 1⁄4 0.02). The frequencies of BMG for time intervals between dMRI and FFSRS of ,7, 7-13, 14-20, 21-27, and ≥ 28 days were 11%, 12%, 32%, 36% and 38% respectively (p 1⁄4 0.02, chi square). Melanoma patients more commonly had BMG (p 1⁄4 0.03), but chemotherapy, neurologic symptoms, and dMRI slice thickness were not associated with BMG. Patients with BMG at FFSRS had similar LFFP compared to patients without growth (82% versus 88% at 6 months, p 1⁄4 0.71), and OS did notdiffer (p 1⁄4 0.47). CONCLUSION: Timebetween diagnosticMRI and SRS is associated with BMG, but LFFP is not compromised when patients receive FFSRS. Over a third of patients have clear BMG at SRS delivered 14 days afterdMRI.For framelessSRS, BMGafterplanningMRI may lead tomarginal miss. Neuro-Oncology 17:v195–v200, 2015. doi:10.1093/neuonc/nov231.6 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Stereotactic radiosurgery for large brain metastases

We evaluated patient outcomes following stereotactic radiosurgery (SRS)-treatment of large brain metastasis (⩾3cm) at our institution. SRS is an established treatment for limited brain metastases. However, large tumors pose a challenge for this approach. For this study, 343 patients with 754 total brain metastases were treated with SRS, of which 93 had large tumors. The tumor size was 3–3.5, 3.5–4, and ⩾4cm in 29%, 32%, and 39% of these patients. Surgical resection was performed prior to SRS in 68% of patients, and 53% achieved a gross total resection. The local control of large metastases was inferior compared to smaller tumors, with 1year local control of 68 versus 86%, respectively (p<0.001). Among the patients with large metastases, no correlation between local control and surgical resection (p=0.747), or extent of surgery (gross total versus subtotal resection; p=0.120), was identified. Histology (p=0.939), tumor size (3–4 versus >4cm; p=0.551), and SRS dose (⩽16 versus >16Gy; p=0.539) also showed no correlation with local failure. The overall survival at 1, 2, and 5years was 46%, 29% and 5%, respectively. Prolonged survival was seen in patients with age <65years (p=0.009), primary treatment compared with salvage (p=0.077), and controlled primary tumors (p=0.022). Radiation necrosis developed in 10 patients (11.8%). For patients with large brain metastases, SRS is well tolerated and can achieve local central nervous system disease control in the majority of patients, and extended survival in some, though the local control rate is suboptimal. Further strategies to improve the outcomes in this subgroup of patients are needed.

Abstract P4-04-04: Estrogen signaling through astrocytes promotes migration and invasion of ER-negative brain metastatic breast cancer cells

Abstract Approximately 16% of patients with breast cancer develop symptomatic brain metastases (BMs) and the majority [∼80%] will die subsequently. Symptomatic BMs are more prevalent in breast tumors overexpressing Human Epidermal Growth Factor Receptors (HER1, EGFR) or 2 (HER2) and triple-negative (TN) tumors (lacking estrogen receptor (ER), progesterone receptor (PR) and HER2). Although the majority of breast cancer cells colonizing the brain lack ER, central nervous system (CNS) metastases are more frequent in pre-menopausal women with high levels of circulating estrogens. Since astrocytes are ER+ cells that surround and infiltrate brain metastases, we hypothesize that estrogens act in a paracrine manner on reactive astrocytes to promote BMs. Results: To determine the effect of estrogen in brain colonization, a brain-seeking sub-line of human MDA-MB-231 TN breast carcinoma cells (231Br) cells were injected intracardially in ovariectomized female nude mice supplemented with placebo (n=5) or 1mg 17-βestradiol (E2) pellets (n=5), and metastases were detected by gadolinium-enhanced magnetic resonance imaging (MRI) 5 weeks later. 100% (5/5) of mice from E2 group showed large and multiple BM when compared to 3/5 (60%) of placebo mice. Further, E2-treated mice showed decreased survival (41.6%, n=12) by 3 weeks following IC injection of 231Br cells compared to E2-depleted mice (84%, n=12) (P=0.03). Since astrocytes are the most abundant brain cell type expressing ERs, we focused on their interaction with 231BR cells. Using global gene expression arrays and RT-PCR we found that E2 upregulated Egf and Tgf-a in primary mouse astrocytes and human astrocytes (derived from neural stem cells), and that anti-estrogens blocked this effect. Concentrated conditioned media (CM) from E2-treated astrocytes increased P-EGFR levels in 231Br cells compared to vehicle (EtOH), or E2+ICI astrocytic CM. Moreover, CM from E2-treated astrocytes significantly increased migration and invasion of 231Br cells as compared to EtOH-treated CM, and ERs inhibitors abolish this effect. Treatment of 231Br cells with lapatinib abolished EGFR activation in response to E2-astrocytic CM, and decreased migration and invasion of 231BR cells. These data suggest that EGFR-ligands upregulated by E2 in astrocytes activated brain metastatic cells-EGFR resulting in increased migration and invasion. To identify the mechanisms of increased migration and invasion we performed global gene expression profiling of 231Br cells co-cultured with E2- or EtOH-stimulated-astrocytes. Co-culture with E2-treated astrocytes significantly increased expression of metastatic mediators Matrix-metalloproteinase-9 (MMP9) and S100 Calcium-binding protein A4 (S100A4) in 231Br cells, and treatment of astrocytes with ER inhibitors abolished this effect. Furthermore, MMP9 or S100A4 knockdown in 231Br cells significantly decreased migration and/or invasion in response to E2-astrocytic CM, suggesting that MMP9 and S100A4 are functional mediators of the paracrine effect of E2. Conclusion: These studies suggest that EGFR activation by astrocytic ligands is at least one mechanism by which E2 contributes to the promotion of BM of ER- breast cancer cells and suggests a novel role for ER in breast cancer BM. Citation Format: Diana M Cittelly, Hazel Cruz, Natalie J Serkova, Borges F Virginia, Kabos Peter, Steeg S Patricia, Sartorius A Carol. Estrogen signaling through astrocytes promotes migration and invasion of ER-negative brain metastatic breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-04.

Fractionated Stereotactic Radiosurgery for Large Brain Metastases

Large brain metastases (>3 cm) present a therapeutic dilemma, as the dose delivered by stereotactic radiosurgery (SRS) in a single fraction is limited by toxicity to adjacent tissues, resulting in suboptimal local control. This study assessed the efficacy and safety of fractionated SRS for the treatment of large brain metastases. We identified 36 patients with 37 brain metastases treated with fractionated SRS. The median SRS dose was 24 Gy (range, 12 to 27 Gy) in 2 to 5 fractions and the median treatment volume was 15.6 mL (range, 10 to 82.7 mL). Kaplan-Meier analysis was used to estimate local control and overall survival rates. Of the 21 lesions with available radiographic follow-up, 6 lesions (29%) had a documented local failure, yielding an actuarial progression-free survival at 6 and 12 months of 73% and 63%, respectively. The actuarial 6-month and 1-year overall survival rates were 22% and 13%, respectively. No patients in this cohort experienced acute or late complications secondary to SRS. Fractionated SRS is feasible and safe in patients with large brain metastases. Local control rates appear to be improved when compared with that of single fraction SRS with a relative paucity of treatment-related toxicity.