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Background Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity. Methods A single-center, retrospective study was conducted of patients age ≥18 years from 1997–2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses. Results Fifty-nine patients met criteria, with median age of 25 years (range 18–62 y) and median follow-up of 6.5 years (range 0.7–23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05). Conclusions Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae.

PURPOSE To assess whether reirradiation (re-RT) and concurrent bevacizumab (BEV) improve overall survival (OS) and/or progression-free survival (PFS), compared with BEV alone in recurrent glioblastoma (GBM). The primary objective was OS, and secondary objectives included PFS, response rate, and treatment adverse events (AEs) including delayed CNS toxicities. METHODS NRG Oncology/RTOG1205 is a prospective, phase II, randomized trial of re-RT and BEV versus BEV alone. Stratification factors included age, resection, and Karnofsky performance status (KPS). Patients with recurrent GBM with imaging evidence of tumor progression ≥ 6 months from completion of prior chemo-RT were eligible. Patients were randomly assigned 1:1 to re-RT, 35 Gy in 10 fractions, with concurrent BEV IV 10 mg/kg once in every 2 weeks or BEV alone until progression. RESULTS From December 2012 to April 2016, 182 patients were randomly assigned, of whom 170 were eligible. Patient characteristics were well balanced between arms. The median follow-up for censored patients was 12.8 months. There was no improvement in OS for BEV + RT, hazard ratio, 0.98; 80% CI, 0.79 to 1.23; P = .46; the median survival time was 10.1 versus 9.7 months for BEV + RT versus BEV alone. The median PFS for BEV + RT was 7.1 versus 3.8 months for BEV, hazard ratio, 0.73; 95% CI, 0.53 to 1.0; P = .05. The 6-month PFS rate improved from 29.1% (95% CI, 19.1 to 39.1) for BEV to 54.3% (95% CI, 43.5 to 65.1) for BEV + RT, P = .001. Treatment was well tolerated. There were a 5% rate of acute grade 3+ treatment-related AEs and no delayed high-grade AEs. Most patients died of recurrent GBM. CONCLUSION To our knowledge, NRG Oncology/RTOG1205 is the first prospective, randomized multi-institutional study to evaluate the safety and efficacy of re-RT in recurrent GBM using modern RT techniques. Overall, re-RT was shown to be safe and well tolerated. BEV + RT demonstrated a clinically meaningful improvement in PFS, specifically the 6-month PFS rate but no difference in OS.

OBJECTIVE The effectiveness of starting systemic therapies after surgery for spinal metastases from renal cell carcinoma (RCC) has not been evaluated in randomized controlled trials. Agents that target tyrosine kinases, mammalian target of rapamycin signaling, and immune checkpoints are now commonly used. Variables like sarcopenia, nutritional status, and frailty may impact recovery from spine surgery and are considered when evaluating a patient’s candidacy for such treatments. A better understanding of the significance of these variables may help improve patient selection for available treatment options after surgery. The authors used comparative effectiveness methods to study the treatment effect of postoperative systemic therapies (PSTs) on survival. METHODS Univariable and multivariable Cox regression analyses were performed to determine factors associated with overall survival (OS) in a retrospective cohort of adult patients who underwent spine surgery for metastatic RCC between 2010 and 2019. Propensity score–matched (PSM) analysis and inverse probability weighting (IPW) were performed to determine the treatment effect of PST on OS. To address confounding and minimize bias in estimations, PSM and IPW were adjusted for covariates, including age, sex, frailty, sarcopenia, nutrition, visceral metastases, International Metastatic RCC Database Consortium (IMDC) risk score, and performance status. RESULTS In total, 88 patients (73.9% male; median age 62 years, range 29–84 years) were identified; 49 patients (55.7%) had an intermediate IMDC risk, and 29 (33.0%) had a poor IMDC risk. The median follow-up was 17 months (range 1–104 months) during which 57 patients (64.7%) died. Poor IMDC risk (HR 3.2 [95% CI 1.08–9.3]), baseline performance status (Eastern Cooperative Oncology Group score 3 or 4; HR 2.7 [95% CI 1.5–4.7]), and nutrition (prognostic nutritional index [PNI] first tertile, PNI < 40.74; HR 2.69 [95% CI 1.42–5.1]) were associated with worse OS. Sarcopenia and frailty were not significantly associated with poor survival. PST was associated with prolonged OS, demonstrated by similar effects from multivariable Cox analysis (HR 0.55 [95% CI 0.30–1.00]), PSM (HR 0.53 [95% CI 0.29–0.93]), IPW (HR 0.47 [95% CI 0.24–0.94]), and comparable confidence intervals. The median survival for those receiving PST was 28 (95% CI 19–43) months versus 12 (95% CI 4–37) months for those who only had surgery (log-rank p = 0.027). CONCLUSIONS This comparative analysis demonstrated that PST is associated with improved survival in specific cohorts with metastatic spinal RCC after adjusting for frailty, sarcopenia, and malnutrition. The marked differences in survival should be taken into consideration when planning for surgery.

Recent studies suggest that the cyclin-dependent kinase (CDK) pathway may be a therapeutic target for brain metastases (BM). Here, we present interim analysis of a basket trial evaluating the intracranial efficacy of the CDK inhibitor palbociclib in patients with progressive BM and CDK alterations. Our study met its primary endpoint and provides evidence for performing molecular testing of archival BM tissue, if available, to inform the choice of CNS-penetrant targeted therapy. Brastianos and colleagues report interim trial results on the intracranial clinical benefit of palbociclib for patients with progressive metastatic brain cancer carrying cyclin-dependent kinase pathway alterations.

PURPOSE The optimal timing of adjuvant radiation therapy (RT) in the management of atypical meningiomas remains controversial. We compared the outcomes of atypical meningiomas managed with upfront adjuvant RT versus postoperative surveillance. METHODS AND MATERIALS Patients with intracranial atypical meningiomas who underwent resection between 2000 and 2015 at a single institution were identified. Patients receiving adjuvant RT (n = 51), defined as RT within the first year of surgery before tumor progression/recurrence (P/R), were compared with those undergoing initial surveillance (n = 179). The primary endpoints were radiographic evidence of P/R and time to P/R from surgery. RESULTS A total of 230 patients were identified. Fifty-one (22%) patients received upfront adjuvant RT, and 179 (78%) underwent surveillance. Compared with the surveillance group, patients who received adjuvant RT had larger tumors (5.2 cm vs 4.6 cm; P = .04), were more likely to have undergone subtotal resection (65% vs 26%; P < . 01), and more often had bone invasion (18% vs 7%; P = .02). On multivariable analysis, receipt of adjuvant RT was associated with a lower risk of P/R compared with surveillance (hazard ratio, 0.21; 95% confidence interval, 0.11-0.41; P < .01). Patients who initially underwent surveillance and then received salvage RT at time of P/R had a shorter median time to local progression after RT compared with patients who developed local P/R after upfront adjuvant RT (19 vs 64 months, respectively; P < . 01). CONCLUSION Upfront adjuvant RT was associated with improved local control in atypical meningiomas irrespective of extent of initial resection compared with surveillance. Early adjuvant RT should be strongly considered after gross total resection of atypical meningiomas.

OBJECTIVEAlthough several prognostic scores for spinal metastatic disease have been developed in the past 2 decades, the applicability and validity of these models to specific cancer types are not yet clear. Most of the data used for model formation are from small population sets and have not been updated or externally validated to assess their performance. Developing predictive models is clinically relevant as prognostic assessment is crucial to optimal decision-making, particularly the decision for or against spine surgery. In this study, the authors investigated the performance of various spinal metastatic disease risk models in predicting prognosis for spine surgery to treat metastatic renal cell carcinoma (RCC).METHODSData of patients who underwent surgery for RCC metastatic to the spine at 2 tertiary centers between 2010 and 2019 were retrospectively retrieved. The authors determined the prognostic value associated with the following scoring systems: the Tomita score, original and revised Tokuhashi scores, original and modified Bauer scores, Katagiri score, the Skeletal Oncology Research Group (SORG) classic algorithm and nomogram, and the New England Spinal Metastasis Score (NESMS). Regression analysis of patient variables in association with 1-year survival after surgery was assessed using Cox proportional hazard models. Calibration and time-dependent discrimination analysis were tested to quantify the accuracy of each scoring system at 3 months, 6 months, and 1 year.RESULTSA total of 86 metastatic RCC patients were included (median age 64 years [range 29–84 years]; 63 males [73.26%]). The 1-year survival rate was 72%. The 1-year survival group had a good performance status (Karnofsky Performance Scale [KPS] score 80%–100%) and an albumin level > 3.5 g/dL (p < 0.05). Multivariable-adjusted Cox regression analysis showed that poor performance status (KPS score < 70%), neurological deficit (Frankel grade A–D), and hypoalbuminemia (< 3.5 g/dL) were associated with a higher risk of death before 1 year (p < 0.05). The SORG nomogram, SORG classic, original Tokuhashi, and original Bauer demonstrated fair performance (0.7 < area under the curve < 0.8). The NESMS differentiates survival among the prognostic categories with the highest accuracy (area under the curve > 0.8).CONCLUSIONSThe present study shows that the most cited and commonly used scoring systems have a fair performance predicting survival for patients undergoing spine surgery for metastatic RCC. The NESMS had the best performance at predicting 1-year survival after surgery.

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1–3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients—17 with breast cancer, two with lung cancer and one with ovarian cancer—were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2–12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39–0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab. In a phase 2 clinical trial cohort of patients with leptomeningeal disease, anti-PD-1 monotherapy was safe and associated with a 3-month overall survival of 60%.

Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. A total of 32 patients (median age, 63.5 years, range 45.3–78.8 years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3 months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30 Gy with SIB to 37.5 Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p

Purpose The majority of patients with high‐risk lower grade gliomas (LGG) are treated with single‐agent temozolomide (TMZ) and radiotherapy despite three randomized trials showing a striking overall survival benefit with adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy and radiotherapy. This article aims to evaluate the evidence and rationale for the widespread use of TMZ instead of PCV for high‐risk LGG. Methods and Materials We conducted a literature search utilizing PubMed for articles investigating the combination of radiotherapy and chemotherapy for high‐risk LGG and analyzed the results of these studies. Results For patients with IDH mutant 1p/19q codeleted LGG tumors, there is limited evidence to support the use of TMZ. In medically fit patients with codeleted disease, existing data demonstrate a large survival benefit for PCV as compared to adjuvant radiation therapy alone. For patients with non‐1p/19q codeleted LGG, early data from the CATNON study supports inclusion of adjuvant TMZ for 12 months. Subset analyses of the RTOG 9402 and EORTC 26951 do not demonstrate a survival benefit for adjuvant PCV for non‐1p/19q codeleted gliomas, however secondary analyses of RTOG 9802 and RTOG 9402 demonstrated survival benefit in any IDH mutant lower grade gliomas, regardless of 1p/19q codeletion status. Conclusions At present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high‐risk LGG, and we instead recommend tailoring chemotherapy recommendation based on IDH status, favoring adjuvant PCV for patients with any IDH mutant tumors, both those that harbor 1p/19q codeletion and those non‐1p/19q codeleted. Given the critical role radiation plays in the treatment of LGG, radiation oncologists should be actively involved in discussions regarding chemotherapy choice in order to optimize treatment for their patients., Three randomized trials have shown a striking overall survival benefit with adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy and radiotherapy for the treatment of patients with high‐risk lower grade gliomas, however the majority of patients currently receive temozolomide (TMZ) instead of PCV chemotherapy. This review article examines the best available evidence to inform the choice of PCV or TMZ for the treatment of high‐risk lower grade gliomas.

Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of the present study was to determine the prognostic value of atypical histopathological features across all nonmalignant meningiomas (World Health Organization [WHO] grade I-II).The data from 334 patients with WHO grade I (n = 275) and grade II (n = 59) meningiomas who had undergone surgical resection from 2001 to 2015 at 2 academic centers were pooled. Progression/recurrence (P/R) was determined radiographically and measured from the date of surgery.The median follow-up was 52 months. The patients were stratified by the number of atypical features: 0 (n = 151), 1 (n = 71), 2 (n = 66), 3 (n = 22), and 4 or 5 (n = 24). The risk of P/R increased with an increasing number of atypical features (log-rank test, P = 0.001). The 5-year actuarial rates of P/R stratified by the number of atypical features were as follows: 0, 16.3% (95% confidence interval [CI], 10.7-24.4); 1, 21.7% (95% CI, 12.8-35.2); 2, 28.2% (95% CI, 18.4-41.7); 3, 30.4% (95% CI, 13.8-58.7); and 4 or 5, 51.4% (95% CI, 31.7-74.5). On univariate analysis, the presence of high nuclear/cytoplasmic ratio (P = 0.007), prominent nucleoli (P = 0.007), and necrosis (P0.00005) were associated with an increased risk of P/R. On multivariate analysis, the number of atypical features (hazard ratio [HR], 1.30; 95% CI, 1.03-1.63; P = 0.03), ≥4 mitoses per high-power fields (HR, 2.45; 95% CI, 1.17-5.15; P = 0.02), subtotal resection (HR, 3.9; 95% CI, 2.5-6.3; P0.0005), and the lack of adjuvant radiotherapy (HR, 2.40; 95% CI, 1.19-4.80; P = 0.01) were associated with an increased risk of P/R.An increased number of atypical features, ≥4 mitoses per 10 high-power fields, subtotal resection, and the lack of adjuvant radiotherapy were independently associated with P/R of WHO grade I-II meningiomas. Patients with these features might benefit from intensified therapy.

Background and purpose High-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. Materials and methods All patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. Results Of 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D50 = 57.7 Gy for intracranial tumors, D50 = 39.5 Gy for extracranial tumors, and γ50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. Conclusion In the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy.

INTRODUCTION High-grade meningiomas are associated with significant neuro-cognitive morbidity and a poor prognosis. Systemic therapies, to date, have demonstrated minimal efficacy. We recently found that high-grade meningiomas harbor an immunosuppressive tumor microenvironment and that programmed cell death-ligand 1 (PD-L1) expression may contribute to the aggressive phenotype of these tumors. Therefore, we conducted a single-arm, open-label phase II trial evaluating efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 24 patients with recurrent and progressive grade II and III meningiomas. METHODS The primary endpoint was the rate of progression-free survival at 6 months. The trial distinguished between 6-month PFS (PFS-6) rates of 26% vs. 52%. If at least 10 patients demonstrated a 6-month PFS, among the 24 patients, the agent would be considered worthy of further study. This design has at least 88% power using an exact binomial test with a one-sided significance level of 0.1. RESULTS Between November 2017 to December 2019, twenty-four patients were enrolled. The majority of the patients in our cohort were heavily pre-treated; prior to enrolling to the study, twenty patients underwent more than one surgical resection and twelve patients had received more than one round of radiotherapy. Our study met its primary endpoint and achieved a 6-month progression-free survival rate of 0.50 (90% exact CI: 0.32-0.68) and a median PFS of 8.3 months (90% CI: 4.1-12.9 months). For the twelve patients who achieved the PFS-6 primary endpoint, median PFS from the start of treatment was 17.3 months (90% CI: 9.7 – 24.3 months). Four patients had grade-3 or higher adverse events that were at least possibly treatment-related, including colitis, skin infection, encephalopathy and transaminitis. CONCLUSION Our study achieved its primary endpoint. These results suggest that pembrolizumab exerts promising activity on these tumors and results in prolonged PFS compared to historical controls.

Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results., Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.

Key Points Question Can cell-free DNA analysis of cerebrospinal fluid provide additional diagnostic utility beyond cytologic assessment? Findings In this diagnostic study of 43 cerebrospinal fluid samples from 22 patients with leptomeningeal disease confirmed by cytologic assessment who did not have parenchymal tumors abutting their cerebrospinal fluid, tumor-derived cell-free DNA was detected in the cerebrospinal fluid of 40 (93%) samples, whereas 31 (72%) of the samples were positive for malignant neoplasm as determined by cytologic analysis, a significant difference. Meaning These findings suggest that cerebrospinal fluid cell-free DNA analysis may be more sensitive than cytologic analysis for diagnosing leptomeningeal disease., Importance Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions. Objective To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis. Design, Setting, and Participants This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018. Main Outcomes and Measures The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection. Results In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients. Conclusions and Relevance This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted., This diagnostic study compares the sensitivity and accuracy for detecting leptomeningeal disease via genomic sequencing of cell-free DNA with that of cytologic assessment of cerebrospinal fluid obtained from patients with suspected or cytologically confirmed leptomeningeal disease.

Background Patients with low-grade gliomas (LGG) can survive years with their illness. Proton radiotherapy (PRT) can reduce off-target dose and decrease the risk of treatment-related morbidity. We examined long-term morbidity following proton therapy in this updated prospective cohort of patients with LGG. Methods Twenty patients with LGG were enrolled prospectively and received PRT to 54 Gy(RBE) in 30 fractions. Comprehensive baseline and longitudinal assessments of toxicity, neurocognitive and neuroendocrine function, quality of life, and survival outcomes were performed up to 5 years following treatment. Results Six patients died (all of disease) and six had progression of disease. Median follow-up was 6.8 years for the 14 patients alive at time of reporting. Median progression-free survival (PFS) was 4.5 years. Of tumors tested for molecular markers, 71% carried the IDH1-R132H mutation and 29% had 1p/19q co-deletion. There was no overall decline in neurocognitive function; however, a subset of five patients with reported cognitive symptoms after radiation therapy had progressively worse function by neurocognitive testing. Six patients developed neuroendocrine deficiencies, five of which received Dmax ≥20 Gy(RBE) to the hypothalamus–pituitary axis (HPA). Most long-term toxicities developed within 2 years after radiation therapy. Conclusions The majority of patients with LGG who received proton therapy retained stable cognitive and neuroendocrine function. The IDH1-R132H mutation was present in the majority, while 1p/19q loss was present in a minority. A subset of patients developed neuroendocrine deficiencies and was more common in those with higher dose to the HPA.

Purpose Proton treatment may be a useful radiation therapy modality for long-term surviving patients with glioma to reduce normal tissue toxicities. Photon studies demonstrate that most low-grade glioma (LGG) failures occur within the radiation field, supporting the use of more conformal treatment plans, yet it is unclear whether this can be translated to proton radiation therapy (PRT). Our objective is to examine our institutional experience to determine patterns of failure in patients with LGG with respect to the volume irradiated with PRT. Methods and materials Patients with World Health Organization 2007 grade I to II or isocitrate dehydrogenase 1–positive mutation grade III LGG treated with PRT between 2005 and 2015 were retrospectively reviewed. Patients with documented local recurrences on magnetic resonance imaging after receipt of PRT underwent a comparison with the initial treatment plan dosimetry to evaluate patterns of failure. A total of 141 patients were included in the final cohort. Results The median follow-up time was 46.7 months (range, 2.8-144 months), and 5-year overall survival was 84%. The median PRT dose delivered was 54 Gy (relative biological effectiveness) (range, 45-60 Gy). There were 42 failures after PRT (30%). The median time to progression after treatment was 32.7 months (range, 4.8-93.6 months). Thirty-one patients (74%) failed in-field (defined as within the 95% isodose volume), 5 patients (12%) failed out-of-field, and 5 patients (12%) had marginal failures (defined as within the 50%-95% isodose volume). The 5-year freedom from progression after PRT was 60.1% (95% confidence interval, 48.7-70.0). The 5-year cumulative incidence of overall survival was 33% among those with recurrence after PRT and 96% among those without recurrence after PRT (P Conclusions Of the patients with LGG who had documented failures after PRT, most recurred within the radiation field with few marginal failures, indicating that even with PRT, which often can have steeper dose gradients, coverage is adequate. Survival was poor for patients whose tumors recurred.

Patients undergoing cranial irradiation are at high risk for development of subsequent pituitary deficiencies. Patients with meningiomas can expect to live many years after treatment and are therefore particularly vulnerable to long-term sequalae of radiation therapy (RT). The purpose of this study was to determine the rates and timing of onset of pituitary dysfunction across each hypothalamic-pituitary axis in patients with meningiomas in the sellar region.Data from 74 patients with meningiomas in the sellar or perisellar region who underwent RT between 2001 and 2017 at a single academic center were analyzed. Dose-volume histograms were generated to determine the dose of radiation to the pituitary gland. Pituitary function tests were evaluated before and after completion of RT.There was a 20% risk for new hypopituitarism across any hypothalamic-pituitary axis after RT at a median follow-up of 43 months. Identified rates of dysfunction across each axis were 24% for thyroid and adrenal, 19% for growth hormone, and 10% for gonadal. Median time to develop deficiencies ranged from 11 months for growth hormone deficiency to 32 months for adrenal insufficiency. Deficiencies were likely to be correlated, with increased risk for thyroid dysfunction in patients with adrenal, gonadal, or prolactin deficiencies (P .05). On univariate analysis, mean dose to the pituitary gland and male sex were associated with increased risk for post-RT thyroid deficiency (P = .01 and P = .004, respectively). There was no difference in rates of hypothyroidism after protons compared with photons (P = .14).Cranial irradiation for sellar meningiomas carries a risk for subsequent hypopituitarism that appears to be dose dependent and may occur years after completion of RT. Growth hormone deficiency and gonadal dysfunction were likely underestimated here secondary to a lack of routine testing. Given the favorable tumor prognosis in this patient population, early and long-term endocrine follow-up is warranted.

BACKGROUND: Recurrent atypical and malignant meningiomas have poor outcomes with surgical therapy alone. Neither adjuvant chemotherapy nor postoperative radiation therapy remedies this problem. OBJECTIVE: To evaluate our experience with the treatment of 15 patients treated with I-125 or Cs-131 brachytherapy radiation seeds as an adjuvant in these difficult cases. METHODS: Patients with high-grade recurrent meningioma who underwent resection and intraoperative placement of brachytherapy seeds at our institution from 2002 to 2014 were identified and studied by retrospective chart review. RESULTS: Fifteen patients with median age of 68.8 yr were treated with I-125 (n = 13) or Cs-131 (n = 2) brachytherapy seeds for cases of recurrent, grade II (n = 8), or grade III (n = 7) meningioma at our institution from 2002 to 2014. These lesions originated from a variety of locations including, convexity (3), falcine (3), frontal (2), occipital (1), parietal (2), 2 sphenoid wing (2), and temporal (2), based recurrent meningiomas. Patients had a median of 2 prior open surgical interventions and received local radiation therapy with a median dose of 55 Gy prior to brachytherapy. Survival at 2.5 yr was 56% for grade II and 17% for grade III lesions. Survival was significantly associated with patient age but not tumoral pathology. Forty percent of patients required reoperations for wound complications following brachytherapy. CONCLUSION: Brachytherapy with implantation of permanent radiation seeds provides a viable alternative treatment for recurrent meningioma while carrying a significant clinical risk of wound infection and need for reoperation.

Background Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy-induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy. Material and methods An institutional review board-approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS. Results The 2-year overall survival for patients treated with cytotoxic T-lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy-naive melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6-39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8-16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞; p = .12). On multivariate analysis, immunotherapy-naive brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00-2.99) compared with immunotherapy-naive brain metastases treated with surgery followed by immunotherapy. Conclusion In treatment-naive patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naive melanoma brain metastases is warranted. Implications for practice In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy-naive brain metastases. The benefit of surgical intervention was seen in immunotherapy-naive brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy-naive melanoma brain metastasis may provide a bridge toward immunotherapy-mediated systemic control.

Background Preoperative prognostication of short-term postoperative mortality in patients with spinal metastatic disease can improve shared decision making around end-of-life care. Objective To (1) develop machine learning algorithms for prediction of short-term mortality and (2) deploy these models in an open access web application. Methods The American College of Surgeons, National Surgical Quality Improvement Program was used to identify patients that underwent operative intervention for metastatic disease. Four machine learning algorithms were developed, and the algorithm with the best performance across discrimination, calibration, and overall performance was integrated into an open access web application. Results The 30-d mortality for the 1790 patients undergoing surgery for spinal metastatic disease was 8.49%. Preoperative factors used for prognostication were albumin, functional status, white blood cell count, hematocrit, alkaline phosphatase, spinal location (cervical, thoracic, lumbosacral), and severity of comorbid systemic disease (American Society of Anesthesiologist Class). In this population, machine learning algorithms developed to predict 30-d mortality performed well on discrimination (c-statistic), calibration (assessed by calibration slope and intercept), Brier score, and decision analysis. An open access web application was developed for the best performing model and this web application can be found here: https://sorg-apps.shinyapps.io/spinemets/. Conclusion Machine learning algorithms are promising for prediction of postoperative outcomes in spinal oncology and these algorithms can be integrated into clinically useful decision tools. As the volume of data in oncology continues to grow, creation of learning systems and deployment of these systems as accessible tools may significantly enhance prognostication and management.

Purpose This study aimed to evaluate the impact on spine growth in children with medulloblastoma using either photon or electron craniospinal irradiation (CSI). Methods and materials This was a single institution retrospective review of children who were treated with CSI for medulloblastoma. Spine growth was measured on magnetic resonance imaging scans at defined locations on the basis of a published predictive model of spine growth after CSI. Differences between spine growth in the anterior, middle, and posterior aspect of the designated vertebral segments were also assessed. Differences between the groups treated with photons or electrons were assessed with student’s t test. Results A total of 19 patients (10 patients treated with electrons and 9 with photons) with a median follow-up time of 45.5 months (confidence interval, 34.9-55.1 months) were evaluated. Patients treated with electrons were younger than those who received photons (5.1 years [range, 3.8-9.0 years] vs 9.6 years [range, 3.5-12.9 years]); however, there were no differences in other clinical characteristics, treatment, or follow-up between the groups. Spine growth rate for patients treated with electrons fit the predictive model (104% ± 5.2%), but patients treated with photons had growth that was faster than predicted by the model (150% ± 47%) and different from that observed with electrons. The differences between treatment the modalities were statistically significant (P = .03). For patients treated with photons, there were no statistical differences between the growth rate of the anterior vertebral body compared with the posterior aspect, but for patients treated with electrons, a faster spine growth in the anterior L1-L5 lumbar spine was observed compared with the posterior lumbar spine (3.90 vs 2.52 mm/year; P = .006) without differences in the cervical or thoracic spine. Conclusions The use of electrons to treat the craniospinal axis in children with medulloblastoma resulted in no significant difference in spine growth compared with the predicted spine growth on the basis of previously published models using photons, but with a clinically insignificant faster spine growth rate in the anterior lumbar spine.

PURPOSE/OBJECTIVE(S) Leptomeningeal disease (LMD) is a devastating diagnosis with limited treatment options and poor prognosis. With recent advances in treatment, women with breast cancer (BC) are living longer and the incidence of LMD in this population is increasing. There remains little data regarding the prognosis and optimal treatment of these patients. As such, we conducted a multi-institutional retrospective review of women with BC LMD and analyzed outcomes based on prognostic factors and treatments. MATERIALS/METHODS We analyzed the records of women diagnosed with BC LMD via MRIs of their brain and/or spine between 2000 and 2020 at two academic medical centers. Demographic and clinical characteristics were abstracted from electronic medical records and an in-depth radiographic review was performed by a neuro-radiologist for each case. Univariate and multivariate Cox proportional-hazards models were generated to identify factors associated with prolonged survival. Collection and analysis of the data was approved by institutional IRB. RESULTS We identified 227 women with BC LMD. Prior to developing LMD, most women initially presented with Stage I-III BC (62.1%) with ductal histology (67.0%) and biological subtypes including ER-positive/HER2-negative (56.8%), HER2-positive (17.6%), and triple-negative (22.0%). LMD was first diagnosed a median of 4.6 years (range: 0 to 34.1 years) after the initial diagnosis of BC, and the median age at LMD diagnosis was 54.6 years (range: 29.4 to 84.5 years). At time of LMD diagnosis, 146 (64.3%) women presented with a Karnofsky Performance Status (KPS) ≥ 70, 90 (39.6%) had a preceding parenchymal brain metastasis, and 23 (10.1%) had LMD as their only site of metastatic disease. Radiographically, classical LMD (61.7%) was observed more frequently than nodular-only LMD (13.2%). Brain-only LMD was present in 55.1% of patients, spine-only in 6.1% of patients, and both brain and spine in 38.8% of patients. Median survival from the time of LMD diagnosis was 4.5 months (95% CI: 3.4-7.8). Pre-treatment clinical factors associated with improved survival on univariate analysis included ER-positive/HER2-negative subtype (P = 0.010), KPS ≥ 70 (P < 0.001), LMD as the only site of metastasis (P = 0.004), stable or controlled extracranial metastases (P = 0.042), absence of leukopenia (P = 0.040) and the presence of nodular LMD (P < 0.001). After adjusting for these clinical factors, the receipt of radiation therapy (adjusted hazard ratio [AHR] 0.50, 95% CI: 0.37 - 0.68), systemic therapy (AHR 0.27, 95% CI: 0.19 - 0.38) and intrathecal chemotherapy (AHR 0.49, 95% CI: 0.33 - 0.75) were all associated with improved survival. CONCLUSION In one of the largest multi-institutional reviews to date, we found that several pre-treatment clinical factors were significantly associated with improved survival among women with breast cancer LMD. However, despite treatment overall survival remains poor, and there is a need for new, effective therapies. AUTHOR DISCLOSURE M.G. Milligan: None. A. Aitelli: None. W.A. Mehan: Consultant; Kura Oncology. D.D. Shi: None. D.N. Cagney: Research Grant; Viewray, NhTheraguix. K.S. Oh: None. N. Wang: None. P. Brastianos: Research Grant; Merck, Eli Lily, BMS. Honoraria; Merck, Genentech. Consultant; Angiochem, Dantari Pharmaceuticals, Elevatebio, Eli Lily, Genentech, Pfizer, SK Life Sciences, Tesaro. B. Moy: Research Grant; PUMA biotechnology. N.U. Lin: Research Grant; Genentech, Merck, Pfizer, Seattle Genetics. Consultant; PUMA Biotechnology, Seattle Genetics, Daiichi Sankyo, Astra Zeneca, Denali Therapeutics, California Institute for Regenerative Medicine, Prelude Therapeutics. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital.

Brain metastases are the most common intracranial tumor in adults, with increasing incidence owing to prolonged survival times. Roughly half of patients diagnosed with new brain metastases have greater than 1 brain metastasis at the time of diagnosis, raising the question of how to optimize patient care with multiple brain metastases. The authors review studies relevant to the care of patients with brain metastasis, with emphasis on those relevant to the care of patients with multiple brain metastases. They discuss evolving strategies involving multiple modalities and the benefit of surgical management in patients with a large symptomatic brain metastasis.

The paradigm for post-operative cavity radiation therapy has shifted to more targeted, less morbid approaches. Single-fraction or hypofractionated radiation therapy is a common approach to treating the postoperative cavity but is associated with a local failure rate 20–40%. We employed an alternative treatment strategy involving fractionated partial brain radiation therapy to the surgical cavity. Patients with brain metastases who underwent radiation treatment 30–42 Gy in 3 Gy/fraction regimens to surgical cavity were retrospectively identified. The 6-month and 12-month freedom from local failure rates were 97.0% and 88.2%. Three patients (7%) experienced local failure at 4, 6, and 22 months. Of these, the histologies were colorectal adenocarcinoma (N = 1) and breast adenocarcinoma (N = 2). The 6-month and 12-month freedom from distant brain metastases rates were 74.1% and 68.8%, respectively, and the 6-month and 12-month overall survival rates were 84.9% and 64.3% respectively. The median overall survival was 39 months, and there were no events of late radionecrosis. Fractionated partial brain irradiation to the surgical cavity of resected brain metastases results in low rates of local failure. This strategy represents an alternative to SRS and WBRT.

Several sites of metastases near or within the brain require special consideration because of their neuroanatomical location, proximity to critical organs, or particularly poor prognosis. Many of these sites are not considered surgically accessible, nor easily treated with systemic therapy. Osseous skull base and brainstem metastases are challenging to treat due to the radiation dose tolerance and critically important function of the brainstem. Choroidal metastases present the competing goals of delivering sufficiently aggressive therapy for durable local control while sparing vision. Dural-based metastases and leptomeningeal disease are associated with a particularly dismal prognosis which obligates a delicate balance between offering effective therapy and prioritizing quality of life. This chapter reviews these special topics, describes their challenges in diagnosis and management, and reflects on future directions.

Purpose Response criteria of glioblastoma after chemoradiation do not account for metabolic changes that occur after treatment. The purpose of this study is to evaluate the utility of positron emission tomography (PET) imaging with C11 methionine (MET) (MET-PET) for detecting changes that occur after chemoradiation therapy and the value of molecular biomarkers for predicting the magnitude of metabolic response. Methods and Materials Patients with newly diagnosed glioblastoma undergoing standard chemoradiation treatment were enrolled in this prospective imaging study, with MET-PET scan performed within 3 days after surgical resection and again at 4 weeks after completion of chemoradiation. Near contemporaneous contrast-enhanced magnetic resonance imaging was performed within 2 weeks of each MET-PET scan. MET-PET imaging was analyzed for maximum standardized uptake value (SUV), SUVmean, and SUVvolume on a multimodality workstation. Results A total of 18 patients underwent baseline postoperative MET-PET imaging, 14 of whom underwent postchemoradiation MET-PET imaging. Among those who showed residual MET-avid disease on immediate postoperative MET-PET scans and underwent postchemoradiation MET-PET imaging (n = 10), mean ΔSUVmax was –40% (range –100% to 0%), mean ΔSUVmean was –35% (range –100% to 0%), and mean ΔSUV volume was –64% (range –100% to 0%). The Δtumor/brain reference was –40% (range –100% to 0%) using SUVmax and –35% (range –100% to 0%) using SUVmean. In contrast, none of the T2-weighted images on contrast-enhanced magnetic resonance imaging showed a >25% reduction in abnormal T2/fluid-attenuated inversion recovery signal on visual assessment. ΔSUVmax, ΔSUVmean, and ΔSUVvolume correlated with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status (P = .01), but not with epidermal growth factor receptor or c-MET amplification status. All patients were IDH-1 wildtype. Conclusions MET-PET scanning shows a significant decrease in metabolic signal at 1 month after chemoradiation compared with the immediate postoperative period, even when T2/fluid-attenuated inversion recovery changed little. MGMT promoter methylation status further predicts differential metabolic responses. MET-PET may be a useful tool for delineation of radiation targets and assessment of response.

Background In nongastric gastrointestinal (GI) cancers, HER2-positive (HER2+) disease is not common. In breast cancer, HER2 status is associated with increased risk of brain metastases and response to HER2-targeted therapy. The purpose of this project was to compare HER2 status in GI cancer brain metastases versus matched prior sites of disease in order to determine if HER2+ disease is more common intracranially. Materials and Methods We identified 28 patients with GI cancer who had craniotomy for brain metastases between 1999 and 2017 with intracranial metastatic tissue available at Massachusetts General Hospital. Twenty-four patients also had tissue from a prior site of disease. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for HER2 were performed on all samples. A tumor was defined as HER2+ if it had 3+ staining by IHC or amplification by FISH. Results A prior site of disease (including intracranial metastases) was HER2+ for 13% of evaluable patients: 3 of 11 patients with colorectal cancer and no patients with esophageal or pancreatic cancer. The most recent brain metastases were HER2+ for 32% of patients: 2 of 3 esophageal squamous cell carcinomas, 3 of 10 esophageal adenocarcinomas (ACs), 3 of 14 colorectal ACs, and 1 of 1 pancreatic AC. Only 37.5% of patients with HER2+ brain metastasis had concordant HER2+ prior tissue (κ = 0.38, p = .017). Conclusion In this cohort of patients with GI cancer with brain metastases, HER2+ status was more common intracranially compared with prior sites of disease. These findings suggest that testing HER2 in patients with GI cancer with brain metastases may lead to additional therapeutic options, regardless of HER2 status in previously examined tissue. Implications for Practice HER2 amplification is a well-known driver of oncogenesis in breast cancer, with associated increased risk of brain metastases and response to HER2-directed therapy. In nongastric gastrointestinal (GI) cancers, HER2 amplification is not common and consequently is infrequently tested. The current study shows that brain metastases in patients with GI primary malignancies have a relatively high likelihood of being HER2 positive despite HER2 amplification or overexpression being less commonly found in matched tissue from prior sites of disease. This suggests that regardless of prior molecular testing, patients with GI cancer with brain metastases who have tissue available are likely to benefit from HER2 assessment to identify potential novel therapeutic options.

Purpose Despite the emerging role of programmed cell death-1 (PD-1) pathway inhibitors for patients with advanced lung cancer, a paucity of data are available on the activity of these agents among patients with brain metastases. We investigated the outcomes of PD-1 pathway inhibitors and stereotactic radiosurgery (SRS) for the treatment of patients with brain metastases from lung cancer. Methods and Materials We retrospectively reviewed the medical records of non-small-cell lung cancer patients with brain metastases consecutively treated with PD-1 pathway inhibitors and SRS at our institution from 2012 to 2017. Overall survival (OS), distant brain failure (DBF), and local control (LC) were assessed using Kaplan-Meier estimates and Cox regression models. Results We identified 37 patients treated with SRS to 85 lesions (90.6% intact and 9.4% resected) and a median total of 7 doses of PD-1 pathway inhibitors (83.8% nivolumab, 10.8% atezolizumab, 5.4% pembrolizumab). Most lesions were treated with 18 Gy in a single fraction (n = 61; 71.8%). Patients treated with concurrent SRS and PD-1 pathway inhibitors had longer OS and reduced rates of DBF compared with patients treated with SRS before or after PD-1 pathway inhibitor therapy (1-year OS, 87.3% vs 70.0% vs 0%, P = .008; 1-year DBF, 38.5% vs 65.8% vs 100%, P = .042). LC was favorable among lesions treated with SRS concurrent with or after PD-1 pathway inhibitor therapy compared with before PD-1 pathway inhibitor therapy (1-year LC, 100% vs 72.3%, P = .016). Three lesions transiently enlarged after SRS and then had partially or completely resolved on follow-up imaging. Four patients required steroids for SRS-associated toxicity. No patient experienced grade ≥ 4 toxicity. Conclusions Concurrent treatment with SRS and PD-1 pathway inhibitors was associated with favorable OS and locoregional disease control. This combination of therapy was well tolerated and merits further evaluation in larger cohorts in a prospective setting.

Purpose To report the first series of proton stereotactic radiosurgery (SRS) for the treatment of patients with single or multiple brain metastases, including failure patterns, survival outcomes, and toxicity analysis. Methods and Materials This was a single-institution, retrospective study of 815 metastases from 370 patients treated with proton SRS between April 1991 and November 2016. Cumulative incidence estimates of local failure, distant brain failure, and pathologically confirmed radionecrosis and Kaplan-Meier estimates of overall survival were calculated. Fine and Gray and Cox regressions were performed to ascertain whether clinical and treatment factors were associated with the described endpoints. Results The median follow-up from proton SRS was 9.2 months. The 6- and 12-month estimates of local failure, distant brain failure, and overall survival were 4.3% (95% confidence interval [CI] 3.0%-5.9%) and 8.5% (95% CI 6.7%-10.6%), 39.1% (95% CI 34.1%-44.0%) and 48.2% (95% CI 43.0%-53.2%), and 76.0% (95% CI 71.3%-80.0%) and 51.5% (95% CI 46.3%-56.5%), respectively. The median survival was 12.4 months (95% CI 10.8-14.0 months) after proton SRS. The most common symptoms were low-grade fatigue (12.5%), headache (10.0%), motor weakness (6.2%), seizure (5.8%), and dizziness (5.4%). The rate of pathologically confirmed radionecrosis at 12 months was 3.6% (95% CI 2.0%-5.8%), and only target volume was associated on multivariate analysis (subdistribution hazard ratio 1.13, 95% CI 1.0-1.20). Conclusions To the best of our knowledge, this is the first reported series of proton SRS for the management of brain metastases. Moderate-dose proton SRS is well tolerated and can achieve good local control outcomes, comparable to those obtained with conventional photon SRS strategies. Although proton SRS remains resource-intensive, future strategies evaluating its selective utility in patients who would benefit most from integral dose reduction should be explored.

Purpose This study aimed to develop a linac-mounted kilovoltage (kV) projection streaming-based tracking method for vertebral targets during spine stereotactic radiation surgery and evaluate the clinical feasibility of the proposed spine tracking method. Methods and materials Using real-time kV projection streaming within XVI (Elekta XVI), kV–projection-based tracking was applied to the target vertebral bodies. Two-dimensional in-plane patient translation was calculated via an image registration between digitally reconstructed radiographs (DRRs) and kV projections. DRR was generated from the cone beam computed tomography (CBCT) scan, which was obtained immediately before the tracking session. During a tracking session, each kV projection was streamed for an intensity gradient-based image with similar metric-based registration to the offset DRR. The ground truth displacement for each kV beam angle was calculated at the beam isocenter using the 6 degrees-of-freedom transformation that was obtained by a CBCT-CBCT rigid registration. The resulting translation by the DRR-projection registration was compared with the ground truth displacement. The proposed tracking method was evaluated retrospectively and online, using 7 and 5 spine patients, respectively. Results The accuracy and precision of spine tracking for in-plane patient motion were 0.5 ± 0.2 and 0.2 ± 0.1 mm. The magnitude of patient motion that was estimated using the CBCT-CBCT rigid registration was (0.5 ± 0.4, 0.4 ± 0.3, 0.3 ± 0.3) mm and (0.3 ± 0.4, 0.2 ± 0.2, 0.5 ± 0.6) mm for all tracking sessions. The intrafraction motion was within 2 mm for all CBCT scans considered. Conclusions This study demonstrated that the proposed spine tracking method can track intrafraction motion with sub-millimeter accuracy and precision, and sub-second latency.

Introduction Intracranial metastases are a common cause of morbidity and mortality in patients with advanced NSCLC, and are frequently managed with radiation therapy (RT). The safety of cranial RT in the setting of treatment with immune checkpoint inhibitors (ICIs) has not been established. Methods We identified patients with advanced NSCLC with brain metastases who received cranial RT and were treated with or without programmed cell death 1/programmed death ligand 1 inhibitors between August 2013 and September 2016. RT-related adverse events (AEs) were retrospectively evaluated and analyzed according to ICI treatment status, cranial RT type, and timing of RT with respect to ICI. Results Of 163 patients, 50 (31%) received ICIs, whereas 113 (69%) were ICI naive. Overall, 94 (58%), 28 (17%), and 101 (62%) patients received stereotactic radiosurgery, partial brain irradiation, and/or whole brain RT, respectively. Fifty percent of patients received more than one radiation course. We observed no significant difference in rates of all-grade AEs and grade 3 or higher AEs between the ICI-naive and ICI-treated patients across different cranial RT types (grade ≥3 AEs in 8% of ICI-naive patients versus in 9% of ICI-treated patients for stereotactic radiosurgery [ p = 1.00] and in 8% of ICI-naive patients versus in 10% of ICI-treated patients for whole brain RT [ p = 0.71]). Additionally, there was no difference in AE rates on the basis of timing of ICI administration with respect to RT. Conclusions Treatment with an ICI and cranial RT was not associated with a significant increase in RT-related AEs, suggesting that use of programmed cell death 1/programmed death ligand 1 inhibitors in patients receiving cranial RT may have an acceptable safety profile. Nonetheless, additional studies are needed to validate this approach.

Background Modern medical management of metastatic renal cell carcinoma (RCC) includes therapies targeting tyrosine kinases, growth pathways (mammalian target of rapamycin (mTOR)), and immune checkpoints. Objective To test our hypothesis that patients with spinal metastases would benefit from postoperative systemic therapy despite presenting with disease that, in many cases, was resistant to prior systemic therapy. Methods This is an Institutional Review Board-approved clinical retrospective cohort analysis. A sample of adult patients with RCC metastatic to the spine who underwent operative intervention between January 2010 and December 2017 at 2 large academic medical centers was used in this study. Results We identified 78 patients with metastatic RCC in whom instrumented stabilization was performed in 79% and postoperative stereotactic radiosurgery was performed in 41% of patients. Of patients presenting with weakness or myelopathy, 93% noted postoperative improvement and 78% reported improvement in radicular and axial paraspinal pain severity. Increased overall survival (OS) (913 d (95% CI: 633-1975 d, n = 49) vs 222 d (95% CI: 143-1005 d, n = 29), P = .003) following surgery was noted in patients who received postoperative systemic therapy a median of 80 d (interquartile range 48-227 d) following the surgical intervention. Conclusion Postoperative outcomes and palliation of symptoms for metastatic RCC without targeted therapies in this cohort are similar to those reported in earlier series prior to the adoption of these systemic therapies. We observed a significantly longer OS among patients who received modern systemic therapies postoperatively. These findings have implications for the preoperative evaluation of patients with systemic disease who may have been deemed poor surgical candidates prior to the availability of these systemic therapies.

Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.

Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.

Purpose Stereotactic radiation therapy (SRT) enables focused, short course, high dose per fraction radiation delivery to brain tumors that are less ideal for single fraction treatment because of size, shape, or close proximity to sensitive structures. We sought to identify optimal SRT treatment regimens for maximizing local control while minimizing morbidity. Methods and materials We performed a retrospective review of patients treated with SRT for solid brain metastases using variable dose schedules between 2001 and 2011 at 3 academic hospitals. Endpoints included (1) local control, (2) acute toxicity (Common Toxicity Criteria for Adverse Events v3.0), and (3) symptomatic radionecrosis. Kaplan-Meier and a competing risks methodology were used to estimate the actuarial rate of local failure and assess the association of clinical and treatment covariates with time to local failure. Results A total of 156 patients was identified. Common tumor histologies included breast (21%), non-small cell lung (32%), melanoma (22%), small cell lung (9%), and renal cell carcinoma (6%). The majority of lesions were supratentorial (57%). Median target volume was 3.99 mL (range, 0.04-58.42). Median total SRT dose was 25 Gy (range, 12-36), median fractional dose was 5 Gy (range, 2.5-11), and median number of fractions was 5 (range, 2-10). Cumulative incidence of local progression at 3, 6, 12, 18, and 24 months was 11%, 22%, 29%, 34%, and 36%. Total prescription dose was the only factor significantly associated with time to local progression on univariate ( P = .02) and multivariable analysis ( P = .01, adjusted hazards ratio, 0.87). Five patients experienced seizures within 10 days of SRT and 5 patients developed radionecrosis. All patients with documented radionecrosis received prior radiation to the index lesion. Conclusions Our series of SRT for brain metastases found total prescription dose to be the only factor associated with local control. Both acute and long-term toxicity events from SRT were modest.

Introduction: Historically, brain metastases are considered to be uncommon in HR+/HER2- breast cancer compared to triple-negative or HER2+ breast cancer. However, improved systemic therapy and prolonged overall survival in patients with metastatic HR+/HER2- breast cancer may result in increased incidence of brain metastases as most currently available therapeutic agents do not penetrate blood-brain barrier giving the brain a sanctuary site status. Although certain tumor cells may also exhibit brain-specific tropism or may have selective growth advantage in the brain microenvironment, biological factors that govern metastases to brain, including role of PIK3CA mutations, are poorly understood. In this study, we review our clinical experience with the brain metastases among patients with metastatic ER+/HER2- breast cancer, including their association with PIK3CA genotype. Methods: Since 2008, at our institution, a multiplexed tumor genotyping assay (SNaPshot), has been utilized to assess for presence of potentially actionable oncogenic driver mutations, including PIK3CA, using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. We identified patients with metastatic HR+/HER2- breast cancer who had tumor genotyping performed at any point during their care and who had at least 6 months of follow-up in our clinic. Relevant clinical information, including development of brain metastases, was gathered from chart reviews. Results: From a total of 251 patients with HR+/HER2- metastatic breast cancer, 23.5% (N=59) developed brain metastases. Approximately 1/3rd of patients (31.7%, N = 20) had brain metastases seen on imaging as an incidental finding, while others presented with 1-2 symptoms that could be associated with CNS disease, including ataxia/weakness (34.9%), visual/speech difficulties (26.9%), headaches (23.8%), altered mental status (14.3%), seizures (14.3%), and nausea (9.5%). PIK3CA mutations were identified in 45.2% of all patients, including mutations in both helical (exon 9) and kinase (exon 20) domains. Patients with tumors harboring PIK3CA mutations had significantly higher incidence of brain metastases, as compared to those without PIK3CA mutations (30.7%, versus 18.7%; p = 0.034). The median time between diagnosis of metastatic disease and diagnosis of brain metastasis was longer among those patients with PIK3CA mutation (32 months) as compared to those without PIK3CA mutation (18 months). Conclusion: Brain metastases are common among patients with HR+/HER2- breast cancer, particularly HR+/HER2- breast cancer harboring PIK3CA mutations where it approaches the incidence historically seen in HER2+ breast cancer. Early recognition and appropriate diagnostic work-up of any symptoms potentially associated with presence of CNS disease is necessary in PIK3CA-mutant HR+/HER2- breast cancer. Further studies are needed to explain the mechanistic link between the PIK3CA mutant phenotype, phosphatidylinositol 3-kinase (PI3K) pathway activation and CNS disease. Citation Format: Fitzgerald DM, Henderson LE, Isakoff SJ, Moy B, Oh K, Shih HA, Dias-Santagata D, Borger DR, Iafrate AJ, Brastianos PK, Bardia A, Juric D. Association between tumor genotype and development of brain metastases in patients with hormone receptor positive (HR+)/HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-03.

Brain metastases (BM) are the most common tumors to affect the central nervous system (CNS). Treatment options have recently evolved with the use of new targeted therapies, immune checkpoint inhibitors, and increased access to clinical trials. We describe our institutional experience with a weekly tumor board dedicated to BM. METHODS We conducted a single-institution cohort study at an academic hospital. Attendance at tumor board included representatives from neuro-oncology, medical oncology, radiation oncology, neurosurgery, neuropsychology, and neuroradiology. We prospectively gathered data on patient demographics, clinical history, and tumor board recommendations. Patients were followed to assess treatment course and survival. The Kaplan Meier method was used to calculate time to progression. RESULTS A total of 49 patients were presented over 2 months. The median age at presentation was 63 yrs with a median ECOG of 1. The primary malignancy was 35% melanoma, 29% lung, 23% breast, the remainder other. Most patients had advanced, heavily pretreated disease: 69% had Stage IV disease with a median of 2 prior lines of systemic therapy, 73% had multiple BM, 39% had prior surgical resection of BM, and 57% had prior CNS radiation. Change in management was recommended in 26/53 case presentations, with active BM-directed therapy (surgery, radiation, systemic therapy) recommended in 25/26 patients. The median time to start active therapy was 7 days. Only 3 patients have died at a median follow-up of 62 days. 9 patients have progressed, with a median time to progression of 57 days. CONCLUSIONS Multidisciplinary BM tumor board provides unique opportunities in the management of complex BM patients in an era of rapidly evolving therapeutic options. Additional follow-up is needed to assess long-term outcomes.

Neurologic complications are common in patients with melanoma and are often associated with a poor prognosis. In an era with new, effective treatments, patients are living longer, and this has resulted in an increase in complications of both the disease and the therapy. A multidisciplinary approach to neurologic complications in patients with melanoma, with involvement from medical oncology, neuro-oncology, radiation oncology, and often neurosurgery, is necessary. In this review, neurologic complications of melanoma, including clinical implications and treatment strategies, are described.

Background Increasing prevalence of metastatic disease has been accompanied by increasing rates of surgical intervention. Current tools have poor to fair predictive performance for intermediate (90-d) and long-term (1-yr) mortality. Objective To develop predictive algorithms for spinal metastatic disease at these time points and to provide patient-specific explanations of the predictions generated by these algorithms. Methods Retrospective review was conducted at 2 large academic medical centers to identify patients undergoing initial operative management for spinal metastatic disease between January 2000 and December 2016. Five models (penalized logistic regression, random forest, stochastic gradient boosting, neural network, and support vector machine) were developed to predict 90-d and 1-yr mortality. Results Overall, 732 patients were identified with 90-d and 1-yr mortality rates of 181 (25.1%) and 385 (54.3%), respectively. The stochastic gradient boosting algorithm had the best performance for 90-d mortality and 1-yr mortality. On global variable importance assessment, albumin, primary tumor histology, and performance status were the 3 most important predictors of 90-d mortality. The final models were incorporated into an open access web application able to provide predictions as well as patient-specific explanations of the results generated by the algorithms. The application can be found at https://sorg-apps.shinyapps.io/spinemetssurvival/. Conclusion Preoperative estimation of 90-d and 1-yr mortality was achieved with assessment of more flexible modeling techniques such as machine learning. Integration of these models into applications and patient-centered explanations of predictions represent opportunities for incorporation into healthcare systems as decision tools in the future.

3059 Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) in melanoma and lung cancer. Several studies demonstrate that 20-50% of BM patients respond to ICI. The reasons behind this wide variability in treatment response is not clear. Therefore, using physiologic imaging, we seek to identify the longitudinal biological changes exerted on BM as a result of ICI administration. Methods: Given the importance of aberrant tumor vasculature in cancer proliferation, we have focused on assessing changes in vascular physiology. We analyzed standard post-contrast and dynamic susceptibility contrast (DSC) MRI to identify characteristic vascular signatures as part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology. Tumor volume measurements were calculated by summating all enhancing voxels. As per modified RECIST and RANO criteria for immunotherapy, volumetric increase of > 40% was defined as progressive disease (PD), a decrease of > 60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 35 patients, out of the total cohort of 60, have undergone DSC-MRI analysis. Histologies include 15 with breast cancer, 6 with non-small cell lung cancer, 4 with melanoma, and 10 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 35 evaluable patients include 4 PR, 12 SD, and 19 PD. Thus far, we found that ICI-resistant BM had a 50% increase in cerebral blood flow (CBF), 105% increase in cerebral blood volume (CBV), a 15% increase in mean transit time (MTT), and an 80% increase in vessel caliber at 6 weeks post-treatment. On the other hand, ICI-responsive BM had no change in CBF, a 33% increase in CBV, a 10% decrease in MTT, and no change in vessel caliber. Ongoing analysis to uncover additional vascular changes (e.g. tumor oxygenation, vessel size index) within BM to ICI are pending. Conclusions: Our data provides evidence that effective ICI for BM is associated with unique intra-tumoral vascular physiology. With final analysis, we will uncover other facets of vascular physiology that correlate with ICI response, and may reveal mechanisms of response/resistance within tumors to ICI.

OBJECTIVE This study is a multi-institutional pooled analysis specific to imaging-based local control of spinal metastases in patients previously treated with conventional external beam radiation therapy (cEBRT) and then treated with re-irradiation stereotactic body radiotherapy (SBRT) to the spine as salvage therapy, the largest such study to date. METHODS The authors reviewed cases involving 215 patients with 247 spinal target volumes treated at 7 institutions. Overall survival was calculated on a patient basis, while local control was calculated based on the spinal target volume treated, both using the Kaplan-Meier method. Local control was defined as imaging-based progression within the SBRT target volume. Equivalent dose in 2-Gy fractions (EQD2) was calculated for the cEBRT and SBRT course using an α/β of 10 for tumor and 2 for both spinal cord and cauda equina. RESULTS The median total dose/number of fractions of the initial cEBRT was 30 Gy/10. The median SBRT total dose and number of fractions were 18 Gy and 1, respectively. Sixty percent of spinal target volumes were treated with single-fraction SBRT (median, 16.6 Gy and EQD2/10 = 36.8 Gy), and 40% with multiple-fraction SBRT (median 24 Gy in 3 fractions, EQD2/10 = 36 Gy). The median time interval from cEBRT to re-irradiation SBRT was 13.5 months, and the median duration of patient follow-up was 8.1 months. Kaplan-Meier estimates of 6- and 12-month overall survival rates were 64% and 48%, respectively; 13% of patients suffered a local failure, and the 6- and 12-month local control rates were 93% and 83%, respectively. Multivariate analysis identified Karnofsky Performance Status (KPS) < 70 as a significant prognostic factor for worse overall survival, and single-fraction SBRT as a significant predictive factor for better local control. There were no cases of radiation myelopathy, and the vertebral compression fracture rate was 4.5%. CONCLUSIONS Re-irradiation spine SBRT is effective in yielding imaging-based local control with a clinically acceptable safety profile. A randomized trial would be required to determine the optimal fractionation.

OBJECTIVE The purpose of this study was to identify factors contributing to an increased risk for vertebral compression fracture (VCF) following stereotactic body radiation therapy (SBRT) for spinal tumors. METHODS A total of 594 tumors were treated with spinal SBRT as primary treatment or re-irradiation at 8 different institutions as part of a multi-institutional research consortium. Patients underwent LINAC-based, image-guided SBRT to a median dose of 20 Gy (range 8–40 Gy) in a median of 1 fraction (range 1–5 fractions). Median patient age was 62 years. Seventy-one percent of tumors were osteolytic, and a preexisting vertebral compression fracture (VCF) was present in 24% of cases. Toxicity was assessed following treatment. Univariate and multivariate analyses were performed using a logistic regression method to determine parameters predictive for post-SBRT VCF. RESULTS At a median follow-up of 10.1 months (range 0.03–57 months), 80% of patients had local tumor control. At the time of last imaging follow-up, at a median of 8.8 months after SBRT, 3% had a new VCF, and 2.7% had a progressive VCF. For development of any (new or progressive) VCF following SBRT, the following factors were predictive for VCF on univariate analysis: short interval from primary diagnosis to SBRT (less than 36.8 days), solitary metastasis, no additional bone metastases, no prior chemotherapy, preexisting VCF, no MRI used for target delineation, tumor volume of 37.3 cm3 or larger, equivalent 2-Gy-dose (EQD2) tumor of 41.8 Gy or more, and EQD2 spinal cord Dmax of 46.1 Gy or more. Preexisting VCF, solitary metastasis, and prescription dose of 38.4 Gy or more were predictive on multivariate analysis. The following factors were predictive of a new VCF on univariate analysis: solitary metastasis, no additional bone metastases, and no MRI used for target delineation. Presence of a solitary metastasis and lack of MRI for target delineation remained significant on multivariate analysis. CONCLUSIONS A VCF following SBRT is more likely to occur following treatment for a solitary spinal metastasis, reflecting a more aggressive treatment approach in patients with adequately controlled systemic disease. Higher prescription dose and a preexisting VCF also put patients at increased risk for post-SBRT VCF. In these patients, pre-SBRT cement augmentation could be considered to decrease the risk of subsequent VCF.