Lehrer, Eric J.

Abstract INTRODUCTION Optic nerve sheath meningiomas (ONSMs) are often managed with radiotherapy (RT) with the goal of achieving radiographic local control (LC) to prevent further decline in visual acuity (VA); however, reports on outcomes are limited to small retrospective series. Thus, we aimed to perform a systematic review and meta-analysis of outcomes for patients with ONSM treated with RT. METHODS A PICOS/PRISMA/MOOSE selection criteria was utilized to identify studies for inclusion. Primary outcomes were stable or improved VA and radiographic LC at last follow-up. The secondary outcome was incidence of radiation-induced retinopathy. Weighted random effects meta-analyses using the DerSimonian and Laird methods were conducted to characterize effect sizes. Mixed effects regression models were used to examine potential correlations between gross tumor volume (GTV) and outcomes. RESULTS In total, 381 patients with ONSM across 18 published studies were included. Of these, 332 and 386 treated ONSMs had information on VA or LC, respectively. Median age was 46.75 (range: 9-87), median/mean GTV was 2.905cc (range: 0.28-26.3), and median follow-up was 51.15 months (range: 1-248.4 months). The estimated LC rate at last follow-up was 100% (95% CI: 98-100%), and the estimated proportion of patients with stable or improved VA at last follow-up was 89% (95% CI: 84-93%). The rate of chronic radiation retinopathy was estimated to be 7% (95% CI: 5-11%). GTV was significantly associated with VA (p=0.014) with estimated VA rates of 96.4%, 91.4%, and 80.5% for GTVs of 2.0, 3.0, and 4.0ccs, respectively. CONCLUSIONS RT was well-tolerated in the treatment of ONSM with excellent LC achieved. Nearly 90% of patients noted either stability or improvement in VA. Larger ONSMs were found to be associated with poorer VA. Incidences of radiation-induced retinopathy were limited and estimated to be less than 10%.

Abstract Background The objectives of this study were to characterize (1) epidemiology of brain metastases at the time of primary cancer diagnosis, (2) incidence and trends of synchronous brain metastases from 2010 to 2015, and (3) overall survival (OS) of patients with synchronous brain metastases. Methods A total of 42 047 patients with synchronous brain metastases from 2010 to 2015 were identified from the Surveillance, Epidemiology, and End Results database. Descriptive analysis was utilized to analyze demographics and incidence. The Kaplan–Meier method and a Cox proportional hazards model were utilized to evaluate potential prognostic factors for OS. Results The majority of patients were diagnosed from age older than 50 (91.9%). Common primary sites included lung (80%), melanoma (3.8%), breast (3.7%), and kidney/renal pelvis (3.0%). Among pediatric patients, common primaries included kidney/renal pelvis and melanomas. The incidence was roughly 7.3 persons/100 000. Synchronous brain metastases were associated with significantly poorer OS compared to extracranial metastases alone (hazard ratio [HR] =1.56; 95% CI: 1.54–1.58; P < .001). Among patients with brain metastases, male gender (HR = 1.60 vs 1.52), age older than 65 years (HR = 1.60 vs 1.46), synchronous liver, bone, or lung metastases (HR = 1.61 vs 1.49), and earlier year of diagnosis (HR = 0.98 for each year following 2010) were associated with significantly poorer OS. Conclusions The vast majority of brain metastases are from lung primaries. Synchronous brain metastases are associated with poorer OS compared to extracranial metastases alone.

Background The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. Methods This retrospective, population‐based study used the Surveillance, Epidemiology, and End Results database (1980‐2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. Results There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person‐years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100‐50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87‐76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28‐181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82‐620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89‐102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51‐57.09). Conclusions The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Background The goal of this study was to characterize the efficacy and safety of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy with concurrent chemotherapy (CFRT) for the definitive treatment of locally advanced pancreatic cancer. The primary outcome measure was efficacy, defined by 2‐year overall survival (OS). Secondary outcomes were incidence of any grade 3/4 toxicity and 1‐year OS. Methods A PICOS/PRISMA/MOOSE selection protocol was used to identify eligible studies. Inclusion criteria were: 1) patients diagnosed with locally advanced N0‐1 M0 pancreatic cancer; 2) CFRT 1.8 to 2.0 Gy/fraction with chemotherapy per protocol or SBRT ≥5 Gy/fraction in ≤5 fractions; 3) either no control group or another definitive chemotherapy or radiation therapy arm; 4) at least 1 of the outcome measures reported; and 5) single or multi‐arm phase 2/3 prospective study for CFRT and/or phase 1/2 or retrospective study for SBRT. Neoadjuvant and/or adjuvant chemotherapy was prescribed per protocol specifications. Weighted random effects meta‐analyses were conducted using the DerSimonian and Laird method to characterize summary effect sizes for each outcome. Results A total of 470 studies were initially screened; of these, 9 studies assessed SBRT and 11 studies assessed CFRT. For SBRT, the median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. For CFRT, doses ranged from 45 to 54 Gy in 1.8‐ to 2.0‐Gy fractions, with the majority of studies delivering 50.4 Gy in 28 fractions with concurrent gemcitabine. The random effects estimate for 2‐year OS was 26.9% (95% CI, 20.6%‐33.6%) for SBRT versus 13.7% (95% CI, 8.9%‐19.3%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for 1‐year OS was 53.7% (95% CI, 39.3%‐67.9%) for SBRT versus 49.3% (95% CI, 39.3%‐59.4%) for CFRT, and was not statistically significant. The random effects estimate for acute grade 3/4 toxicity was 5.6% (95% CI, 0.0%‐20.0%) for SBRT versus 37.7% (95% CI, 24.0%‐52.5%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for late grade 3/4 toxicity was 9.0% for SBRT (95% CI, 3.3%‐17.1%) versus 10.1% (95% CI, 1.8%‐23.8%) for CFRT, which was not statistically significant. Conclusion These results suggest that SBRT for LAPC may result in a modest improvement in 2‐year OS with decreased rates of acute grade 3/4 toxicity and no change in 1‐year‐OS or late toxicity. Further study into the use of stereotactic body radiation therapy for these patients is needed.

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

Purpose: We aim to systematically review and analyze the available literature on “exceptional responders” in oncology. We hypothesize that survival or patients with an exceptional response may be predicted based on clinical factors. Materials and Methods: A PICOS/PRISMA/MOOSE selection protocol was used to find studies that reported oncology patients with an exceptional response. A total of 333 initial articles were screened, and 76 articles were included, accounting for 85 patients. The primary outcome was survival after exceptional response therapy (ERT). The secondary outcome was survival since diagnosis. Univariate and multivariate analyses were conducted for both outcomes with 17 covariates. Results: The median age was 52 years (interquartile range, 35-66 y), 51.8% were male individuals, 18 (21.2%) had lung cancer, and 1 patient (1%) met all National Cancer Institute criteria for exceptional response. The most common treatment resulting in exceptional response was a form of chemotherapy (49.2%) followed by targeted therapy (26.8%) and radiation therapy (7.7%). The median time from diagnosis to initiation of ERT was 7.92 months (interquartile range, 0-24.72 mo). On multivariate analysis of survival after initiation of ERT, there were no predictors of exceptional response. On multivariate analysis of survival since diagnosis, predictors of prolonged survival included time between diagnosis and ERT initiation (hazard ratio, 0.52; 95% confidence interval, 0.32-0.87; P=0.0124) and single prior surgery versus none (0.08; 95% confidence interval, 0.01-0.98; P=0.04853). Conclusions: There were no clinically apparent patient or treatment factors that predicted favorable survival following ERT; instead, reporting of exceptional response appears to be biased.

Brain metastases traditionally carried a poor prognosis with an overall survival of weeks to months in the absence of treatment. Radiation therapy modalities include whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). WBRT delivers a relatively low dose of radiation, has neurocognitive sequelae, and has not been investigated for its immunostimulatory effects. Furthermore, WBRT exposes the entire intracranial tumor immune microenvironment to radiation. SRS delivers a high dose of conformal radiation with image guidance to minimize dose to surrounding normal brain tissue, and appears to promote anti-tumor immunity. In parallel with many of these discoveries, immune checkpoint inhibitors (ICIs) have demonstrated a survival advantage in multiple malignancies commonly associated with brain metastases (e.g., melanoma). Combination SRS and ICI are theorized to be synergistic in anti-tumor immunity directed to brain metastases. The purpose of this review is to explore the synergy of SRS and ICIs, including pre-clinical data, existing clinical data, and ongoing prospective trials.