Recurrent Brain Metastases Research Articles

Salvage Resection and Intracranial Cesium-131 Brachytherapy for Brain Tumors

Management of progressive brain tumors following high dose radiotherapy is controversial. In select cases, surgical resection can provide rapid relief of regional mass effect and edema, and highly focal adjuvant re-irradiation can be administered in the form of brachytherapy. Permanent low-dose rate cesium-131 brachytherapy may offer dosimetric and radiobiologic advantages over other isotopes. The purpose of this study was to examine the safety and efficacy of intracranial cesium-131 brachytherapy after surgical resection in a heavily pre-treated patient cohort.A retrospective chart review was conducted of all patients treated with intraoperative intracranial cesium-131 brachytherapy from an institutional database. Treatment consisted of maximal safe resection followed by implantation of suture-stranded cesium-131 seeds, maintaining approximately 10mm spacing between seeds, with a planned target dose of 80 Gy to 5mm depth. Local failure was defined as recurrence in or contacting the resection cavity after salvage resection and brachytherapy. Regional failure was defined as recurrence within 10mm of the resection cavity. Recurrence was defined as a new lesion or growth of ≥25% in any axial dimension on interval MRI. Toxicity was collected based on CTCAE 4.0.A total of 35 patients with a median imaging follow up of 17.0 months (interquartile range [IQR] 9.7-25.9) underwent 41 consecutive cesium-131 implants between 2016 and 2020. 20 patients (59%; N = 22 implants) were treated for recurrent brain metastasis, 12 patients (34%; N = 16 implants) were treated for recurrent atypical (N = 8) or anaplastic meningioma (N = 4), and 3 patients (9%) were treated for recurrent glioma (N = 2) or hemangiopericytoma (N = 1). A majority of lesions had received prior surgery (N = 28, 66.7%, range 0-3 prior surgeries) and 34 patients had received prior high dose radiation. 34 of 41 (82.9%) tumors had received prior radiosurgery, and 12 (29.2%) had undergone prior external beam radiation (range 50-60 Gy). 17 of 41 lesions (41.5%) had radiologic evidence of adverse radiation/treatment effect (ARE) prior to salvage therapy. Median tumor size was 3.0cm (IQR 2.3-3.7). Overall actuarial local/loco-regional control at 1-year was 91.6%/84.7% (89.8%/88.9% for metastases and 100%/82.5% for meningiomas). Crude loco-regional control was 86.3% for metastases, 75% for meningiomas, and 66.7% for other lesions. Symptomatic ARE following treatment was observed in 9.8% (N = 4) resection cavities. The surgical complication rate was 14.6% (N = 6 total, N = 3 [7.3%] grade 3-5) including 1 peri-operative death.Cesium-131 brachytherapy in this heavily pre-treated cohort resulted in good local control and an acceptable rate of symptomatic adverse radiation effect and toxicity and may be a reasonable treatment option for this select population.W.C. Chen: None. M. Lafreniere: None. C. Phuong: None. M. Lometti: None. O. Morin: None. B.P. Ziemer: None. H. Vasudevan: Research Grant; Children's Tumor Foundation. Patent/License Fees/Copyright; Genentech, Eli Lilly. S. Hervey-Jumper: None. P.V. Theodosopoulos: None. S. Magill: None. S.E. Fogh: Independent Contractor; Accuray. J.L. Nakamura: None. L. Boreta: None. P.K. Sneed: None. M.W. McDermott: Chair; Miami Baptist. D. Raleigh: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.

NEIM-02. TRIAL IN PROGRESS: A MULTICENTER PHASE 3 STUDY TO ESTABLISH THE DIAGNOSTIC PERFORMANCE OF 18F-FLUCICLOVINE PET IN DETECTING RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (REVELATE)

Abstract BACKGROUND Brain metastases occur in up to 40% of patients with cancer and are associated with poor prognosis and considerable levels of recurrence. Consequently, close follow-up with serial brain MRI is performed post-treatment to monitor for recurrent disease. Although conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) is the recommended follow-up modality, it has poor specificity with limited ability to differentiate between true disease recurrence and treatment-related changes such as radiation necrosis. Therefore, alternative imaging options are sought in order to help physicians confidently diagnose treatment-related changes and thus reliably stratify the risk of continuation of a therapeutic regimen, especially given the morbidity associated with current treatments. Amino acid PET imaging agent, 18F-fluciclovine, has increased uptake in brain tumors relative to normal tissue and may be useful for detecting recurrent brain metastases. METHODS NCT04410133 is a prospective, open-label, single-arm, single-dose (185 MBq ±20%) study with a primary objective to confirm the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for detection of recurrent brain metastases where MRI is equivocal. Approximately 150 subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled in this multicenter trial (~18 US sites) if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures such as biopsy/neurosurgical intervention or clinical follow-up. Subjects will undergo 18F-fluciclovine PET <42 days after the equivocal MRI and 1–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is open at the time of submission.

CLRM-02. TRIAL IN PROGRESS: A PROSPECTIVE, MULTICENTER PHASE 2B STUDY TO ESTABLISH IMAGE INTERPRETATION CRITERIA FOR 18F-FLUCICLOVINE PET IN DETECTING RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (PURSUE)

BACKGROUNDBrain metastases represent the most common intracranial tumor in adults, occurring in 10-40% of cancer patients. Most patients undergo multimodal treatment approaches and post-treatment follow-up with conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) of the brain is performed to monitor for disease recurrence. However, owing to the similar appearance of treatment-related changes like radiation necrosis with that of true recurrence, conventional MRI alone suffers from low specificity. Given the high mortality of patients with brain metastases and the considerable treatment-associated morbidity, a need remains for an imaging modality that accurately differentiates recurrence from treatment-related changes. Accurate imaging is key to preventing unnecessary surgery or changes in effective therapy in patients mistaken for disease progression as well as prevent continuation of ineffective therapy if radiation necrosis is incorrectly diagnosed. To this end, 18F-fluciclovine is a synthetic amino acid-based PET imaging agent that has potential to evaluate primary and metastatic brain cancers owing to its low normal background uptake in the brain and increased uptake in brain tumors.METHODSNCT04410367 is a prospective, open-label, single-arm, single-dose (185 MBq ± 20%) study with a primary objective to establish visual image interpretation criteria for 18F-fluciclovine PET studies of recurrent brain metastases. Forty subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled across ~8 US sites if they have a reference lesion considered equivocal on MRI for recurrent disease and are planned for craniotomy. Subjects will undergo 18F-fluciclovine PET <42 days after the MRI and 1–21 days before planned craniotomy. Outcome measures comprise the diagnostic performance of 18F-fluciclovine PET at different thresholds of 18F-fluciclovine uptake compared with histopathology, subject- and lesion-level diagnostic performance based on established image interpretation criteria, and safety evaluations. Enrolment began in August 2020 and the trial is open at the time of submission.

Investigating diffusion patterns of brain metastases pre- and post-stereotactic radiosurgery: a feasibility study

Purpose. Metastatic complications are responsible for 90% of cancer-associated mortality. Magnetic resonance imaging (MRI) can be used to observe the brain’s microstructure and potentially correlate changes with metastasis occurrence. Diffusion weighted imaging (DWI) is an MRI technique that utilizes the kinetics of water molecules within the body. The aim of this study is to use DWI to characterize diffusion changes within brain metastases in cancer patients pre- and post-stereotactic radiosurgery (SRS). Methods. We retrospectively analyzed 113 metastases from 13 patients who underwent SRS for brain metastasis recurrence. Longitudinal apparent diffusion coefficient (ADC) maps were registered to Gd-T1 images and CT, and clinical metastasis ROIs from all SRS treatments were retrospectively transferred onto these ADC maps for analysis. Metastases were characterized based on pre-SRS diffusion pattern, primary cancer site, and post-SRS outcome. ADC values were calculated pre- and post-SRS. Results.ADC values were significantly elevated (980.2 × 10−6 mm2 s−1 and 1040.3 × 10−6 mm2 s−1 pre- and post-SRS, respectively) when compared to healthy brain tissue (826.8 × 10−6 mm2 s−1) for all metastases. Three identified pre-SRS patterns were significantly different before SRS and within 6 months post-SRS. No significant differences were observed between different primaries pre-SRS. Post-SRS, Lung metastases ADC decreased by 86.2 × 10−6 mm2 s−1, breast metastases increased by 116.7 × 10−6 mm2 s−1, and genitourinary metastases showed no significant ADC change. SRS outcomes showed ADC variability pre-treatment but no significant differences pre- and post-SRS, except at 6–9 months post-SRS where progressing metastases were elevated when compared to other response groups. Conclusion. This study provided a unique opportunity to characterize diffusion changes in brain metastases before their manifestation on standard Gd-T1 images and post-SRS. Identified patterns may improve early detection of brain metastases as well as predict their response to treatment.

BSCI-13. MTH1 expression is upregulated in brain metastases of malignant melanoma

ObjectiveMuT Homolog1 (MTH1) is an enzyme involved in DNA repair in normal cells and is often up- regulated in cancer cells. The enzyme catalyses the hydrolysis of oxidised dNTPs, to prevent their incorporation into DNA or RNA, resulting in mutations or cell damage/death. Cancer cells can have a high concentration of ROS, due to defective redox regulation. This results in the damage of DNA and oxidises free dNTPS, which in turn leads to mutations in DNA replication or cell death. Identifying MTH1 in brain metastases could present a target for treatment with MTH1-Inhibitors.MethodsThe quantification of MTH1 expression was shown using Western Blot analysis. 16 tumours were obtained during neurosurgery, 8 metastatic and 8 recurrent tumours of the same patient, and immediately frozen using liquid nitrogen. The proteins were extracted using RIPA lysis buffer. Western Blot was performed and detection followed via peroxidase linked secondary antibodies.ResultsMTH1 expression was shown to be up-regulated in brain metastases (1,442+/-0,6374) versus normal brain tissue (0,4133+/-0,277). However, in the recurrent tumour of the brain metastases, MTH1 was not expressed in a significantly higher amount compared the controll tissue and less than in the brain metastases (0,6941+/-0,4146).ConclusionThe high expression of MTH1 in cerebral metastases is not uncommon for many cancers and thus presents a therapeutic target for MTH1-inhibitors, provided these are able to cross the blood brain barrier. Comparison to the primary melanoma tumour would be useful in showing significant differences of the metastases. Lower levels of MTH1 in recurrent brain metastases may suggest dedifferentiation from the original metastases. It may present a target for specific treatment of brain metastases of melanoma.

TRLS-01. Trial in Progress: A Prospective, Multicenter Phase 2b Study to Establish Image Interpretation Criteria for 18F-Fluciclovine PET in Detecting Recurrent Brain Metastases after Radiation Therapy (PURSUE)

BackgroundBrain metastases are the most common intracranial tumor in adults, occurring in 10–40% of patients with cancer. Despite multimodal treatment approaches, the prognosis remains poor and post-treatment follow-up with conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) of the brain is recommended to monitor for disease recurrence. However, owing to the similar appearance of treatment-related changes like radiation necrosis with that of true recurrence, conventional MRI has low specificity.Given the high mortality of patients with brain metastases and the considerable treatment-associated morbidity, a need remains for an imaging modality that accurately differentiates recurrence from treatment-related changes. Accurate imaging could help physicians identify patients for whom non-effective or unneeded treatments can be ceased in order to minimize treatment-associated morbidity, and to avoid erroneous premature cessation of potentially effective therapy.18F-Fluciclovine is a synthetic amino acid-based PET imaging agent that has potential to evaluate primary and metastatic brain cancers owing to its low normal background uptake in the brain and increased uptake in brain tumors.MethodsNCT04410367 is a prospective, open-label, single-arm, single-dose (185 MBq ± 20%) study with a primary objective to establish visual image interpretation criteria for 18F-fluciclovine PET studies of recurrent brain metastases. Forty subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled across 8 US sites if they have a reference lesion considered equivocal on MRI for recurrent brain metastasis and are planned for craniotomy. Subjects will undergo 18F-fluciclovine PET <28 days after the equivocal MRI and 2–21 days before planned craniotomy. Outcome measures comprise diagnostic performance of 18F-fluciclovine PET at different thresholds of 18F-fluciclovine uptake compared with histopathology, subject- and lesion-level diagnostic performance based on application of the established image interpretation criteria, and safety evaluations. Enrolment began in August 2020 and the trial is open at the time of submission.

PO-1040 Brain metastasis recurrence for SRS in non-previously radiated patients

PO-1040 Brain metastasis recurrence for SRS in non-previously radiated patients

PO-1112 Repeated courses of RT in breast cancer patients as salvage therapy for recurrent brain metastases

PO-1112 Repeated courses of RT in breast cancer patients as salvage therapy for recurrent brain metastases

Neurosurgical resection for locally recurrent brain metastasis.

In patients with locally recurrent brain metastases (LRBMs), the role of (repeat) craniotomy is controversial. This study aimed to analyze long-term oncological outcomes in this heterogeneous population. Craniotomies for LRBM were identified from a tertiary neuro-oncological institution. First, we assessed overall survival (OS) and intracranial control (ICC) stratified by molecular profile, prognostic indices, and multimodality treatment. Second, we compared LRBMs to propensity score-matched patients who underwent craniotomy for newly diagnosed brain metastases (NDBM). Across 180 patients, median survival after LRBM resection was 13.8 months and varied by molecular profile, with >24 months survival in ALK/EGFR+ lung adenocarcinoma and HER2+ breast cancer. Furthermore, 102 patients (56.7%) experienced intracranial recurrence; median time to recurrence was 5.6 months. Compared to NDBMs (n = 898), LRBM patients were younger, more likely to harbor a targetable mutation and less likely to receive adjuvant radiation (P < 0.05). After 1:3 propensity matching stratified by molecular profile, LRBM patients generally experienced shorter OS (hazard ratio 1.67 and 1.36 for patients with or without a mutation, P < 0.05) but similar ICC (hazard ratio 1.11 in both groups, P > 0.20) compared to NDBM patients with similar baseline. Results across specific molecular subgroups suggested comparable effect directions of varying sizes. In our data, patients with LRBMs undergoing craniotomy comprised a subgroup of brain metastasis patients with relatively favorable clinical characteristics and good survival outcomes. Recurrent status predicted shorter OS but did not impact ICC. Craniotomy could be considered in selected, prognostically favorable patients.

Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (Korean Radiation Oncology Group 1612).

e14008 Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM &gt; 4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p = 0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p &lt; 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM &gt; 4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p = 0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 &gt; 37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS.

A Liquid Biopsy to Assess Brain Tumor Recurrence: Presence of Circulating Mo-MDSC and CD14+ VNN2+ Myeloid Cells as Biomarkers That Distinguish Brain Metastasis From Radiation Necrosis Following Stereotactic Radiosurgery.

Brain metastases (BM) are the most common type of brain tumor malignancy in the US. They are also the most common indication for stereotactic radiosurgery (SRS). However, the incidence of both local recurrence and radiation necrosis (RN) is increasing as treatments improve. MRI imagery often fails to differentiate BM from RN; thus, patients must often undergo surgical biopsy or resection to obtain a definitive diagnosis. To hypothesize that a marker of immunosuppression might serve as a surrogate marker to differentiate patients with active vs inactive cancer-including RN. We thus purified and quantified Monocytic Myeloid-Derived Suppressor Cells (Mo-MDSC) by flow cytometry in patients proven by biopsy to represent BM or RN. We report the utility of the previously reported HLA-Dr-Vnn2 Index or DVI to discriminate recurrent BM from RN using peripheral blood. The presence of CD14+ HLA-DRneg/low Mo-MDSC is significantly increased in the peripheral blood of patients with brain metastasis recurrence compared to RN (Average 61.5%vs 7%, n=10 and n=12, respectively, P<.0001). In contrast, expression of VNN2 on circulating CD14+ monocytes is decreased in BM patients compared to patients with RN (5.5%vs 26.5%, n=10 and n=12, respectively, P=.0008). In patients with biopsy confirmed recurrence of brain metastasis, the average DVI was 11.65, whereas the average DVI for RN patients was consistently <1 (Avg. of 0.17). These results suggest that DVI could be a useful diagnostic tool to differentiate recurrent BM from RN using a minimally invasive blood sample.

Resection and Surgically Targeted Radiation Therapy for the Treatment of Larger Recurrent or Newly Diagnosed Brain Metastasis: Results From a Prospective Trial.

IntroductionAchieving durable local control (LC) for larger (e.g., >2-3 cm) brain metastasis whether newly diagnosed or recurrent remains problematic. Resection (R) alone is typically insufficient and adding radiation therapy (RT) still results in a 12-month recurrence rate of 20% or more in many series. Hypothesizing that R plus immediate radiation utilizing brachytherapy may improve outcomes for this cohort of patients, we designed and prospectively evaluated a permanently implanted surgically targeted radiation therapy (STaRT) device consisting of cesium-131 (Cs-131) seeds positioned within a collagen carrier (GammaTile, GT Medical Technologies, Tempe, AZ). The device was designed to prevent direct source-to-brain contact and maintain inter-source spacing after closure.MethodsThis was a subgroup analysis of a cohort of patients with either recurrent or previously untreated brain metastases enrolled in a prospective, multi-histology single-arm trial (ClinicalTrials.gov, NCT#03088579), conducted between February 2013 and February 2018, of resection and tumor bed brachytherapy with Cs-131 containing permanently implanted collagen tiles to deliver 60 Gray (Gy) at .5 cm depth. No additional local therapy was given without progression.ResultsA total of 16 metastases in 11 patients were treated; 12 tumors were recurrent and four were previously untreated. The median preoperative maximum diameter was 3.2 cm (range: 1.9-5.1 cm). Histology was seven breasts, six lungs, and three sarcomas. The median age was 60 years (range: 41-80 years); the Karnofsky Performance Status (KPS) was 70 (range: 70-90). The cohort consisted of seven females and four males. The mean time for implantation completion was five minutes. The median overall survival (OS) was 9.3 months. At a median radiographic follow-up of 9.5 months' treatment, site progression was found in 1/16 (6%) at 10.9 months, and the median treatment site time-to-progression (TTP) has not been reached [95% confidence interval (CI): >10.9 months]. At 12 months, the Kaplan-Meier (K-M) estimates for LC after R+STaRT for all tumors was 83%; for previously untreated tumors, LC at 12 months was 100% and for recurrent tumors, it was 80%. Two tumor beds (12.5%) experienced radiation brain changes: one had grade two and the other grade three. No surgical adverse events occurred.ConclusionIn this single-arm precommercial study, R+STaRT demonstrated excellent safety and LC in this cohort. The device has recently received FDA clearance for use in newly diagnosed and recurrent brain metastasis, and randomized clinical trials vs. standard of care treatments in both settings are scheduled to open in 2020.

IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p &amp;lt; 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values &amp;lt; 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

RTID-01. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS FOR BRAIN METASTASES (1-10) FROM NSCLC IN THE PHASE 3 METIS TRIAL

Abstract BACKGROUND Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The objective of the METIS study [NCT02831959] is evaluation of the efficacy and safety of TTFields in NSCLC patients with brain metastases. METHODS NSCLC patients (N=270) with 1-10 brain metastases were randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &amp;gt; 18 hours/day) within 7 days of SRS or supportive care. The portable device delivered TTFields to the brain using 4 transducer arrays, while patients received the best standard-of-care for systemic disease. Patients were followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT, surgical resection of metastases, or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. On September, 2019, an independent Data Monitoring Committee (DMC) reviewed METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.

SURG-04. SALVAGE RESECTION OF RECURRENT PREVIOUSLY-IRRADIATED BRAIN METASTASES: CLINICAL AND RADIOGRAPHIC OUTCOMES

Abstract BACKGROUND The management of brain metastasis (BrM) recurrence after stereotactic body radiotherapy (SBRT) poses a clinical challenge. The efficacy of salvage resection is undefined, and the role of adjuvant resection cavity reirradiation is unclear given the compounded risk of radiation injury. METHODS Retrospective analysis of previously-irradiated BrM that underwent resection between March 2003 and February 2020 at Memorial Sloan Kettering Cancer Center was performed. Only cases with histopathologic evidence of viable malignancy were included, and specimens were classified by the gross proportion of viable tumor versus treatment effect. Clinical and radiographic parameters were collected. Post-operative recurrence and radiation necrosis were based on RANO-BM criteria and distinguished by histopathologic, radiographic and clinical characteristics. Equivocal cases were adjudicated by a blinded neuroradiologist. RESULTS One-hundred fifty-five resected recurrent BrM following SBRT in 135 patients were evaluated. Seventeen received additional prior whole-brain radiation. Metastases derived from non-small-cell lung (36.8%), melanoma (27.1%), breast (21.3%), renal (3.9%), colorectal (1.9%) and other (9.0%) primary malignancies. Forty-eight (31.0%) had only microscopic malignant disease with extensive necrosis, 44 (28.4%) had mixed or unspecified tumor with treatment effect, and 63 (40.6%) were reported as purely viable tumor by histopathologic report. Thirty-nine (25.2%) post-operative cavities underwent adjuvant reirradiation within 60 days. At 6 and 12 months, local tumor recurrence occurred in 31.6% (95% CI: 24.4%-39.1%) and 40.4% (95% CI: 32.5%-48.2%), respectively, with a proportion of these lesions displaying mixed tumor plus treatment effect. Median overall survival was 13.4 months (95% CI: 10.5-17.7) from salvage resection. CONCLUSIONS Salvage of previously-irradiated BrM remains challenging. This represents the largest known series correlating salvage resection and histopathologically-confirmed viable recurrent BrM with long-term outcomes. Tumor recurrence risk remains high at one year. Further exploration will stratify local progression and radiation necrosis rates by features including extent of resection, degree of viable tumor and adjuvant reirradiation use.

SURG-03. COMBINATION LASER INTERSTITIAL THERMAL THERAPY PLUS SRS INCREASES TIME TO PROGRESSION FOR RECURRENT SRS-TREATED BRAIN METASTASES

Abstract INTRODUCTION Laser interstitial thermal therapy (LITT) has evolved as an effective treatment for brain metastases (BM) failing stereotactic radiosurgery (SRS), and an alternative to open resection/repeat SRS. We sought to evaluate the efficacy of LITT+SRS in recurrent SRS-treated BM, and compare outcomes to LITT alone vs. repeat SRS. METHODS A multicenter, retrospective study was performed of patients with biopsy-proven BM recurrence after SRS. Patients were stratified by planned LITT+SRS vs. LITT alone vs. repeat SRS. Index lesion progression was determined by RANO criteria. RESULTS Forty-five patients fit inclusion, with a median follow-up of 7.3 months (range:1.1-30.5), age of 60 (range:37-86), KPS of 80 (range:60-100), and contrasted tumor volume (CTV) of 6.1cc (range:1.4-19.4). Histologies included NSCLC (44%), breast (24%), SCLC, melanoma, colon, and oroesophageal (&amp;lt; 10% each). Sixty-three percent of patients underwent LITT alone, 18% had repeat SRS, while 27% had LITT+SRS (post-LITT SRS). Median time to index lesion progression was greatest in the LITT+SRS group compared to LITT alone or repeat SRS (&amp;gt;23, 7.5, and 3.6 months, respectively [p=0.018]), as was overall survival (23.7, 5.9, and 7.0 months, respectively [p=0.023]). Age, sex, primary histology, CTV, and treatment strategy were univariate predictors of tumor progression; patients not treated with LITT+SRS were more likely to have index lesion progression (p=0.016). When controlling for histology and CTV in a multivariate model, patients not treated with LITT+SRS were significantly more likely to have progression (p=0.001). All LITT+SRS patients who experienced subsequent radiographic progression were diagnosed with recurrent tumor, while radiation necrosis incidence in the repeat SRS arm was 25%. CONCLUSION LITT+SRS appears superior to LITT alone or repeat SRS for treatment of biopsy-proven BM recurrence after SRS when controlling for other variables known to be predictive of progression. Prospective trials should be designed to validate the utility of combination LITT+SRS after SRS failure.

Magnetic resonance-guided laser interstitial thermal therapy for brain tumors in geriatric patients.

There is a paucity of studies assessing the use of MR-guided laser interstitial thermal therapy (LITT), specifically in the elderly population. The aim of this study was to evaluate the safety of LITT for brain tumors in geriatric patients. Geriatric patients (≥ 65 years of age) treated with LITT for intracranial tumors at a single institution between January 2011 and November 2019 were retrospectively identified. The authors grouped patients into two distinct age cohorts: 65-74 years (group 1) and 75 years or older (group 2). Baseline characteristics, operative parameters, postoperative course, and morbidity were recorded for each patient. Fifty-five geriatric patients underwent 64 distinct LITT procedures for brain tumors. The majority of lesions (40 [62.5%]) treated were recurrent brain metastases or radiation necrosis. The median modified frailty index was 0.1 (low frailty; range 0-0.4) for patients in group 1 and 0.2 (intermediate frailty; range 0-0.4) for patients in group 2 (p > 0.05). The median hospital length of stay (LOS) was 1 day (IQR 1-2 days); there was no significant difference in LOS between the age groups. The hospital stay was significantly longer in patients who presented with a neurological symptom and in those who experienced a postoperative complication. The majority of patients (43 [68.3%] of 63 cases) were fit for discharge to their preoperative accommodation following LITT. The rate of discharge to home was not significantly different between the age groups. Those discharged to rehabilitation facilities were more likely to have presented with a neurological symptom. Nine patients (14.1% of cases) were found to have acute neurological complications following LITT, with nearly all patients showing complete or partial recovery at follow-up. The 30-day postoperative mortality rate was 1.6% (1 case). The complication and 30-day postoperative mortality rates were not significantly different between the two age groups. LITT can be considered a minimally invasive and safe neurosurgical procedure for the treatment of intracranial tumors in geriatric patients. Careful preoperative preparation and postoperative care is essential as LITT is not without risk. Appropriate patient selection for cranial surgery is essential, because neurosurgeons are treating an increasing number of elderly patients, but advanced age alone should not exclude patients from LITT without considering frailty and comorbidities.

Efficacy of Lung Autotransplantation for Central Non-small Cell Lung Cancer

背景与目的全肺切除术和袖状切除术是治疗中央型非小细胞肺癌的常规术式, 但存在肺功能差不能耐受全肺切除或因为肿瘤广泛侵犯支气管和肺动脉而不能进行袖状切除的情况。本研究旨在探讨自体肺移植治疗中央型非小细胞肺癌的可行性。方法回顾性分析2016年12月-2018年12月3例行自体肺移植的中央型非小细胞肺癌患者的诊疗资料。1例双袖状切除左肺上叶, 吻合支气管, 因肺动脉切除过长, 肺动脉吻合口张力大, 遂切断下肺静脉, 将下肺上移后再吻合肺动脉, 最后将下肺静脉与上肺静脉残端吻合。2例行左全肺切除, 体外切除左肺上叶, 将修剪、灌洗后的左肺下叶重置胸腔, 依次吻合支气管、肺动脉、肺静脉。结果平均手术时间333 min, 平均血流阻断65 min, 平均出血量450 mL, 平均住院日18.7 d; 围手术期出现痰栓堵塞支气管1例, 经支纤镜吸痰后好转; 平均随访时间20个月, 癌症死亡1例, 术后吻合口复发及脑转移1例, 4R淋巴结转移1例(经化疗后病情稳定), 无复发生存1例。结论对于肿瘤侵犯广泛, 不能进行袖状切除或无法耐受全肺切除的中央型非小细胞肺癌患者, 自体肺移植可在彻底切除肿瘤基础上最大限度保留肺功能, 提高术后生存质量。

36. A PROSPECTIVE TRIAL OF RESECTION PLUS SURGICALLY TARGETED RADIATION THERAPY FOR BRAIN METASTASIS

INTRODUCTIONAchieving durable local control for larger brain metastases remains problematic. Resection (R) alone is typically insufficient. Even with the addition of stereotactic radiation the 12-month recurrence rate for larger lesions (i.e., >2.5–3 cm) is 20% or more in many series. To improve outcomes we designed and prospectively evaluated a permanently implanted radiation device consisting of Cs-131 seeds positioned within a collagen tile (GammaTile, GT Medical Technologies, Tempe AZ). We combined maximum safe resection and collagen tile brachytherapy (CTBT) with the hypothesis that immediate radiation initiation and/or dose intensification could improve outcomes.MATERIALS/METHODSFrom 2013–2018 patients undergoing resection with either previously untreated or recurrent brain metastasis were enrolled on a single arm, multi-histology study (ClinicalTrials.gov, NCT#03088579). At resection completion the tumor bed was lined with collagen tiles imbedded with Cs-131, delivering 60–80 Gy at 5 mm depth. The device was designed to prevent direct source-to-brain contact and to maintain inter-source spacing after closure. No additional local therapy was given unless progression occurred.RESULTS16 metastases (12 recurrent/4 previously untreated) in 11 patients were treated. Median diameter 3.1 cm, range 1.9–5.1. Histology was 7 breast, 6 lung, and 3 sarcoma. Median age 60 years; 7 females/4 males. Average time for implantation was 5 minutes. At median radiographic follow-up of 9.5 months (range 0.1–25.2) treatment site progression occurred 1/16 (6%) at 10.9 months. Median treatment site time-to-progression (TTP) has not been reached (95% CI, >10.9 months). Median overall survival (OS) 9.3 months. No surgical adverse events occurred. One patient (6.2%) experienced radiation brain changes and was treated medically.CONCLUSIONR+CTBT demonstrated excellent safety and local control outcomes in this single-arm pre-commercial study. The device recently received FDA clearance for use in newly diagnosed and recurrent brain metastasis. Randomized clinical trials vs standard of care treatments are expected to open in 2020.

30. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL

BACKGROUNDTumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The objective of the METIS study [NCT02831959] is evaluation of the efficacy and safety of TTFields in NSCLC patients with brain metastases.METHODSNSCLC patients (N=270) with 1–10 brain metastases were randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The portable device delivered TTFields to the brain using 4 transducer arrays, while patients received the best standard-of-care for systemic disease. Patients were followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT, surgical resection of metastases, or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. On September, 2019, an independent Data Monitoring Committee (DMC) reviewed METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.