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Stereotactic radiosurgery is increasingly used in patients with limited brain metastases and good baseline performance to avoid the toxicities of whole brain radiotherapy (WBRT). Patients with resected brain metastases are undergoing cavity-directed radiosurgery, withholding WBRT. Multiple institutions have published concerning incidences of leptomeningeal disease (LMD) when using this approach. We assess the risk of LMD in patients treated with this approach and identify risk factors for developing LMD. We identified 58 patients treated at our institution with cavity-directed SRS without WBRT for brain metastases between 2009 and 2015. Fifty-one (87.9%) had adequate follow-up for analysis, and 50 were treated to 30 Gy in 5 fractions to the resection cavity and are analyzed here. Patient demographics, tumor characteristics, and clinical outcomes were evaluated. With a median follow-up of 12.9 months (range, 1.9–63.2), the 1-year and 2-year incidences of LMD were 20 and 24%, respectively. The median time from SRS to the development of LMD was 6.0 months (range, 0.7–14.5). On multivariate analysis, ventricle violation during surgery (HR = 7.1, P = .030) and number of metastases (HR = 1.9, P = .034) were associated with an increased risk of LMD. One-year and 2-year leptomeningeal failure-free survival was 76 and 64%, and 1-year and 2-year survival of the entire cohort was 56 and 32%, respectively. LMD incidence is relatively high in patients receiving postoperative cavity-directed SRS. Ventricular violation during surgery causes a significantly higher risk of LMD, and consideration of WBRT, greater SRS target volumes, or preoperative treatment in these patients may be warranted.

Purpose The majority of oncologic care is provided in the outpatient setting, yet at many medical schools, the dominant means of exposure to oncology occurs during inpatient rotations. Given the multidisciplinary nature of the specialty, radiation oncology departments are well positioned to lead outpatient oncology rotations within medical schools. Since 1992, the University of Cincinnati’s Department of Radiation Oncology has administered a 2-week, third-year clinical oncology elective. This report characterizes the rotation and evaluates the impact of the rotation on students’ oncology exposure and career choices over the past 10 years. Methods and Materials A list of medical students who participated in the MS3 clinical oncology elective rotation from 2008 to 2018 was reviewed. A search engine was used to locate the physicians and identify their specialty choices. A survey of 7 questions was distributed to the oncologists to evaluate how the rotation influenced their oncology exposure and career choice. Results Two hundred sixty-eight medical students participated in the MS3 Clinical Oncology Specialty Clerkship from 2008 to 2018. Thirty-nine students (15%) ultimately pursued a career in oncology. Seventy-four percent of the oncologists are radiation oncologists. Eighty-eight percent of the physicians surveyed had a positive to very positive experience with the rotation. The rotation was the first clinical exposure to the field of oncology for 48% of the respondents and the first exposure to the field of radiation oncology for 69% of the physicians. Seventy-two percent of the oncologists attributed the MS3 rotation as providing a moderate or great deal of early exposure to the field of oncology. Conclusions Radiation oncology departments are well positioned to lead multidisciplinary, ambulatory oncology electives within US medical schools. A majority of participating oncologists viewed the rotation positively and attributed the rotation with their entrance into oncology.

Importance Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. Objective To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. Design, setting, and participants The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. Interventions Chemoradiation and consolidation chemotherapy with or without metformin. Main outcomes and measures The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. Results A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. Conclusions and relevance In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. Trial registration ClinicalTrials.gov Identifier: NCT02186847.

2501 Background: MTX-based chemoradiotherapy is effective in PCNSL, but carries a risk of severe neurotoxicity (NT), especially in the elderly. In a phase II single arm study, R-MPV-A chemotherapy was combined with substantially reduced doses of radiotherapy (23.4 Gy), achieving prolonged progression free survival (PFS) and overall survival (OS) with acceptable NT. Because R-MPV-A had never been tested without radiotherapy, we conducted a randomized study to determine if the low doses of radiation played a role in the observed disease control, and to characterize NT as compared to chemotherapy alone. Methods: Patients were stratified by MSK RPA class and randomized to receive R-MPV-A with LD-WBRT (chemoRT arm) versus R-MPV-A alone (chemo arm). MTX dose was 3.5g/m2 infused over 2 hours. Filgrastim and pegfilgrastim support was given to all patients. LD-WBRT dose was 23.4 Gy (1.8 Gy X 13). The primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63, with one-sided alpha level of 0.15. Results: A total of 91 patients were randomized, of whom 4 were ineligible. Among eligible patients, 43 were enrolled in the chemoRT arm and 44 in the chemo arm. Median age was 66 (chemoRT) and 59 (chemo). Median KPS was 80 for both arms. Response rates following R-MPV were 81% (chemoRT) and 83% (chemo). In the chemoRT arm, 37 patients (86%) received LD-WBRT. After median follow-up of 55 months (m), the median ITT PFS was 25 m in the chemo arm and not reached in the chemoRT arm (HR 0.51; 95% CI [0.27, 0.95]; p = 0.015). The 2-year PFS was 54% (chemo) and 78% (chemoRT). Salvage radiotherapy has been given to 11 patients in the chemo arm. Median OS was not reached in either arm, with data still maturing. In both arms, most common grades 3 or 4 toxicities were anemia (27%), lymphopenia (41%), neutropenia (35%), thrombocytopenia (26%), ALT (23%) and AST (13%). One patient died from sepsis (chemo arm). As per investigators’ assessment, the rate of clinically defined moderate to severe NT was 11.4% (chemo) and 14% (chemoRT), p = 0.75. Conclusions: The study met the primary endpoint, demonstrating the addition of LD-WBRT to R-MPV-A improves PFS in newly diagnosed PCNSL. As per investigator’s assessment, NT rates were not statistically significantly increased, but further neuropsychological testing and neuroimaging analyses are ongoing to characterize cognitive decline and how it compares to other consolidation treatments. Clinical trial information: NCT01399372 .

Single-fraction stereotactic radiosurgery(SRS) for meningioma has high rates of symptomatic perilesional edema in some settings. Fractionated stereotactic radiosurgery(fSRS) could decrease edema rates while maintaining tumor control.Patients at an institution were retrospectively reviewed(2013-2017). Adults receiving definitive, linear accelerator(linac)-based fSRS (25-30Gy/5 fractions) were included. fSRS was recommended for tumors at high risk for perilesional edema with SRS due to large size, prior irradiation, or proximity to organs at risk. Endpoints included rates of symptomatic, radiographically-defined perilesional edema and local control(LC).12 Patients with 13 meningiomas met criteria. 24-month actuarial LC and overall survival were 87% and 100%. Symptomatic, post-treatment edema was identified on follow-up MRI in 31% of cases. No variables predicted edema, but affected lesions were larger(6.82 v. 2.46cc).Linac-based fSRS for meningioma has high local control and modest toxicity rates similar to SRS in the literature. Prospective studies comparing fSRS/SRS are warranted.

Neurofibromatosis (NF) types 1 and 2 are classified as phacomatoses with an autosomal-dominant inheritance pattern. They are important in the field of neuro-oncology as they predispose affected patients to a number of CNS tumors including acoustic schwannoma, meningioma, glioma, ependymoma, and malignant peripheral nerve sheath tumor (MPNST). Management of tumors in patients with NF can differ from that in the non-NF population owing to a natural history that may be more aggressive, a greater need to preserve function in patients with acoustic schwannoma, and the concern for increased risk of radiation-induced tumors in this population. The management of NF-related acoustic schwannoma, meningioma, and MPNST is discussed here, while management of glioma and ependymoma is presented in separate chapters.

8502 Background: Metformin, a diabetes agent that inhibits mitochondria complex I, enhances radiotherapy and chemotherapy responses in pre-clinical models of NSCLC. NRG-LU001 examined whether metformin can improve outcomes of curative CRT in locally advanced (LA)-NSCLC. Methods: The primary endpoint of this trial was 1-year progression free survival (PFS). Unresected, non-diabetic, stage IIIA/B NSCLC patients were randomized (1:1) to either carboplatin-paclitaxel chemotherapy concurrent with chest RT (60Gy), followed by consolidation carboplatin-paclitaxel chemotherapy (Control Arm) or the same and oral metformin (2000mg daily) during cytotoxic therapy (Experimental Arm). PFS and overall survival (OS) were estimated with the Kaplan-Meier method; time to local-regional progression (TTLRP), time to distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded with CTCAE v.4.0. Results: Between Aug.2014 and Dec.2016, 170 patients were accrued. Analysis was planned at 102 PFS events (Feb. 2019). There was no significant difference in rates or grade of toxicity between the two arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Metformin arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP or TTDM. Conclusions: NRG-LU001 center reported outcomes show that oral daily metformin was well-tolerated in combination with CRT treatment for LA-NSCLC. However, metformin did not improve PFS and OS and did not alter the rates of local-regional failure or distant metastasis. Acknowledgements: TT and HS are Co-Principal Investigators. This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). Clinical trial information: NCT02186847.