Trifiletti, Daniel M.

Glioblastoma is a devastating primary brain tumor with a median overall survival of approximately 15 months despite the use of optimal modern therapy. While GBM has been studied for decades, modern therapies have allowed for a reduction in treatment-related toxicities, while the prognosis has largely been unchanged. Adjuvant stereotactic radiosurgery (SRS) was previously studied in GBM; however, the results were disappointing. SRS is a highly conformal radiation technique that permits the delivery of high doses of ionizing radiation in 1–5 sessions while largely sparing surrounding healthy tissues. Furthermore, studies have shown that the delivery of ablative doses of ionizing radiation within the central nervous system is associated with enhanced anti-tumor immunity. While SRS is commonly used in the definitive and adjuvant settings for other CNS malignancies, its role in the preoperative setting has become a topic of great interest due to the potential for reduced treatment volumes due to the treatment of an intact tumor, and a lower risk of nodular leptomeningeal disease and radiation necrosis. While early reports of SRS in the adjuvant setting for glioblastoma were disappointing, its role in the preoperative setting and its impact on the anti-tumor adaptive immune response is largely unknown. In this review, we provide an overview of GBM, discuss the potential role of preoperative SRS, and discuss the possible immunogenic effects of this therapy.

BACKGROUNDPatients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited.METHODSRN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN.RESULTSFifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow‐up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole‐brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06‐42.38 cm3); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27‐111.22 cm3). Any‐grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01‐1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99‐1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17‐2.30; P = .76), prior WBRT, and ICI agents were not statistically significant.CONCLUSIONSSymptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single‐fraction SRS.

AbstractPurposeTo reduce the likelihood of errors in organ delineations used for radiotherapy treatment planning, a knowledge‐based quality control (KBQC) system, which discriminates between valid and anomalous delineations is developed.Method and MaterialsThe KBQC is comprised of a group‐wise inference system and anomaly detection modules trained using historical priors from 296 locally advanced lung and prostate cancer patient computational tomographies (CTs). The inference system discriminates different organs based on shape, relational, and intensity features. For a given delineated image set, the inference system solves a combinatorial optimization problem that results in an organ group whose relational features follow those of the training set considering the posterior probabilities obtained from support vector machine (SVM), discriminant subspace ensemble (DSE), and artificial neural network (ANN) classifiers. These classifiers are trained on nonrelational features with a 10‐fold cross‐validation scheme. The anomaly detection module is a bank of ANN autoencoders, each corresponding with an organ, trained on nonrelational features. A heuristic rule detects anomalous organs that exceed predefined organ‐specific tolerances for the feature reconstruction error and the classifier's posterior probabilities. Independent data sets with anomalous delineations were used to test the overall performance of the KBQC system. The anomalous delineations were manually manipulated, computer‐generated, or propagated based on a transformation obtained by imperfect registrations. Both peer‐review–based scoring system and shape similarity coefficient (DSC) were used to label regions of interest (ROIs) as normal or anomalous in two independent test cohorts.ResultsThe accuracy of the classifiers was 99.8%, and the minimum per‐class F1‐scores were 0.99, 0.99, and 0.98 for SVM, DSE, and ANN, respectively. The group‐wise inference system reduced the miss‐classification likelihood for the test data set with anomalous delineations compared to each individual classifier and a fused classifier that used the average posterior probability of all classifiers. For 15 independent locally advanced lung patients, the system detected 79% of the anomalous ROIs. For 1320 auto‐segmented abdominopelvic organs, the anomaly detection system identified anomalous delineations, which also had low Dice similarity coefficient values with respect to manually delineated organs in the training data set.ConclusionThe KBQC system detected anomalous delineations with superior accuracy compared to classification methods that judge only based on posterior probabilities.

Background: Increased facility surgical treatment volume is sometimes associated with improved survival in patients with cancer; however, published studies evaluating volume are heterogeneous and disparate in their patient inclusion and definition of volume. The purpose of this work was to evaluate uniformly the impact of surgical facility volume on survival in patients with cancer. Methods: The National Cancer Database was searched for patients diagnosed in 2004 through 2013 with the 12 cancers most commonly treated surgically. Facilities were stratified by 4 categories using the overall population (low, intermediate, high, and very high), each including 25% of patients, and then stratified by each individual disease site. Five-year postsurgery survival was estimated using both the Kaplan-Meier method and corresponding log-rank tests for group comparisons. Cox proportional hazard models were used to evaluate the effects of facility volume on 5-year postsurgery survival further, adjusted for multiple covariates. Results: A total of 3,923,618 patients who underwent surgery were included from 1,139 facilities. Of these, 40.4% had breast cancer, 12.8% prostate cancer, and 10.0% colon cancer. Most patients were female (65.0%), White (86.4%), and privately insured (51.6%) with stage 0–III disease (64.8%). For all cancers, the risk of death for patients undergoing surgery at very high-volume facilities was 88% of that for those treated at low-volume facilities. Hazard ratios (HRs) were greatest (very high vs low volume) for cancer of the prostate (HR, 0.66; 95% CI, 0.63–0.69), pancreas (HR, 0.75; 95% CI, 0.71–0.78), and esophagus (HR, 0.78; 95% CI, 0.73–0.83), and for melanoma (HR, 0.81; 95% CI, 0.78–0.84); differences were smallest for uterine and non–small cell lung cancers. Overall survival differences were greatest for cancers of the brain, pancreas, and esophagus. Conclusions: Patients treated surgically at higher-volume facilities consistently had improved overall survival compared with those treated at low-volume centers, although the magnitude of difference was cancer-specific.

Abstract INTRODUCTION Multiple meningiomas (MM) occurs in up to 18% of meningioma patients and progression data are scarce. The objective of this study is to explore the influence of number of lesions and clinical characteristics on progression-free survival (PFS) and time to a second intervention (TTSI) in patients with WHO grade 1 meningiomas. METHODS We retrospectively reviewed records of all adults diagnosed with a meningioma at our three main sites from January 2009 to May 2020. Progression was considered as time from diagnosis until radiographic progression of the originally resected meningioma. A secondary analysis was carried to evaluate the time from diagnosis to time of a second intervention. Univariable and multivariable analyses were conducted to assess whether number of lesions or any associated variables (age, sex, race, radiation, location, and extent of resection) had a significant impact on PFS and TTSI. RESULTS 838 patients were included. Log-rank test evaluating PFS and TTSI between single and multiple lesions showed significantly shorter progression for MM (p< 0.001 and p< 0.001, respectively). Multivariable Cox regression showed significantly inferior PFS on MM vs. single lesion (HR 2.262 [CI 95%, 1.392-3.677], p=0.001) and a significantly inferior TTSI for patients with MM vs. single meningioma (HR 2.377 [CI 95%, 1.617 – 3.494], p=0.001). When input as a continuous variable, PFS was significantly inferior for each additional meningioma (HR 1.350 [CI 95% 1.074-1.698], p=0.010) and TTSI is significantly inferior as well (HR 1.428 [CI 95% 1.189 – 1.716], p< 0.001). African-Americans had an inferior PFS when compared to Non-Hispanic White patients (HR 3.472 [CI 95% 1.083-11.129], p=0.036). CONCLUSION The PFS of meningiomas is influenced by the number of lesions present. Patients with MM are more prone to undergo a second intervention for progressive disease. Hence, a closer follow-up may be warranted in patients who present with multiple lesions.

Abstract PURPOSE Vertebral compression fracture (VCF) is a potential adverse effect following stereotactic body radiation therapy (SBRT) for spinal metastases. In this analysis, we developed and internally validated a risk stratification model for VCF. METHODS From an initial set of 680 treatments, we excluded those with proton therapy, prior surgical intervention, or missing data. The final dataset had 464 treatments in 313 patients. Delineations of VCF and all radiographic components of the spinal instability neoplastic score (SINS) were determined by a radiologist. Recursive partitioning analysis (RPA) was conducted using separate training (70%), internal validation (15%), and test (15%) sets. The log-rank test was used as the criterion for node splitting. RESULTS With a median follow-up of 21 months, we identified 84 VCF (18%), including 65 (77%) de novo and 19 (23%) progressive fractures. There was a median 9 months (IQR: 3 – 21) to VCF. From an initial set of 15 candidate variables, six were identified using the backwards selection method, feature importance testing, and a correlation heatmap. Four were then selected in the highest-fidelity RPA models: epidural tumor extension, lumbar location, gross tumor volume > 10 cc, and SINS > 6. One point was assigned to each variable, and the resulting multivariate Cox model had a concordance of 0.760. Each one point increase in score was associated with increasing rates of VCF. Low-risk lesions (score: 0-1, n=273) had 2-year freedom from VCF of 92%, compared to 80% for intermediate-risk (score: 2, n=99) and 56% (score: 3-4, n=92) for high-risk lesions (p < 0.0001). Cumulative incidence curves with death as a competing risk showed increased VCF with higher scores via Gray’s test (p < 0.001). CONCLUSIONS Our internally-validated model identifies a subgroup of patients with high risk for VCF who may benefit from prophylactic surgical stabilization or vertebroplasty.

Abstract IntroductionRadiotherapy is considered standard of care for adjuvant peri-operative treatment of many spinal tumors, including those with instrumented fusion. Unfortunately, radiation treatment has been linked to increased risk of pseudoarthrosis. Newerfocused radiotherapy strategies with enhanced conformalitycould offer improved fusion rates for these patients, but this has not been confirmed.MethodsWe performed a retrospective analysis of patients at three tertiary care academic institutions withprimary and secondary spinal malignancies that underwent resection, instrumented fusion, and peri-operative radiotherapy. Two board certified neuro-radiologists used theLenke fusion score to grade fusion status at6 and 12-months after surgery. Secondary outcomes includedclinical pseudoarthrosis, wound complications, and the effect of radiation timing, radiobiological dose delivered, the use of photons versus protons, tumor type, tumor location,and use of autograft on fusion outcomes.ResultsAfter reviewof 1252 spinal tumor patients, there were 60 patients with at least 6 months follow-up that were included in our analyses. Twenty-five of these patients received focused radiotherapy,20 patients received conventional radiotherapy, and 15 patients were treated with protons. There was no significant difference between the groups for covariates such assmoking status,obesity, diabetes, intraoperative use of autograft, and use of peri-operative chemotherapy. There was a significantly higher rate of fusion for patients treated with focused radiotherapy compared to those treated with conventional radiotherapy at 6-months (64.0% versus 30.0%, Odds ratio: 4.15, p=0.036) and 12-months (80.0% versus 42.1%, OR: 5.50, p=0.022). There was a significantly higher rate of clinical pseudoarthrosis in the conventional radiotherapy cohortcompared to patients in the focused radiotherapy cohort (19.1% versus 0%,p=0.037). There was no difference in fusion outcomes for any of the secondary outcomes except for use of autograft. The use ofintra-operative autograft was associated with an improved fusion at 12-months (66.7% versus 37.5%, OR: 3.33, p=0.043). ConclusionFocused radiotherapy may be associated withan improved rate of fusion and clinical pseudoarthrosis when compared to conventional radiation delivery strategiesin patients with spinal tumors.Use of autograft at the time of surgery may be associated with improved 12-month fusion rates.Further large-scale prospective and randomized controlled studies are needed to better stratify the effects of radiation delivery modality in these patients.

Objectives: Metastatic cancer has historically been considered fatal; however, there is a paucity of evidence characterizing the epidemiology of incidence, treatment, and outcomes in these patients. Materials and Methods: Incidence rates, annual percent change (APC), descriptive epidemiological statistics, and odds ratios for survival were calculated using registry data from the Surveillance, Epidemiology, and End Results (SEER) and the National Cancer Database (NCDB), 1998 to 2015. Results: There were a total of 1,055,860 patients with metastatic cancer. The most frequent primary cancers were lung (42.6%), colorectal (9.5%), and ovarian (5.5%). Metastatic lung and colorectal cancer incidence decreased, APC: −1.57 (P<0.001) and APC: −1.48 (P<0.001), respectively; metastatic pancreatic cancer incidence increased, APC: 0.62 (P=0.001). The use of local therapies decreased for almost all sites, and the use of systemic therapies increased across multiple sites: single-agent chemotherapy in kidney (2.54% increase/year), female breast (1.14% increase/year), and prostate cancer (1.08% increase/year); multiagent chemotherapy, most notably in pancreas (2.23% increase/year), uterus (1.81% increase/year), and colorectal cancer (1.54% increase/year). Increased utilization of immunotherapy was observed across the majority of sites, most notably in melanoma (2.14% increase/year). Patients diagnosed from 2006 to 2010 had 17.4% higher odds of surviving at least 60 months compared with 1998 to 2002. Conclusions: In this study, metastatic disease has been shown to have unique epidemiological patterns, and survival has improved. Continued research on metastatic disease is important in understanding and addressing the distinct health concerns of this population.

Radiotherapy (RT) is one of the cornerstones in the current treatment paradigm for glioblastoma (GBM). However, little has changed in the management of GBM since the establishment of the current protocol in 2005, and the prognosis remains grim. Radioresistance is one of the hallmarks for treatment failure, and different therapeutic strategies are aimed at overcoming it. Among these strategies, nanomedicine has advantages over conventional tumor therapeutics, including improvements in drug delivery and enhanced antitumor properties. Radiosensitizing strategies using nanoparticles (NP) are actively under study and hold promise to improve the treatment response. We aim to describe the basis of nanomedicine for GBM treatment, current evidence in radiosensitization efforts using nanoparticles, and novel strategies, such as preoperative radiation, that could be synergized with nanoradiosensitizers.