Clinical presentation and extent of resection impacts progression-free survival in spinal ependymomas.

PURPOSE: Primary treatment of spinal ependymomas involves surgical resection, however recurrence ranges between 50 and 70%. While the association of survival outcomes with lesion extent of resection (EOR) has been studied, existing analyses are limited by small samples and archaic data resulting in an inhomogeneous population. We investigated the relationship between EOR and survival outcomes, chiefly overall survival (OS) and progression-free survival (PFS), in a large contemporary cohort of spinal ependymoma patients. METHODS: Adult patients diagnosed with a spinal ependymoma from 2006 to 2021 were identified from an institutional registry. Patients undergoing primary surgical resection at our institution, ≥ 1 routine follow-up MRI, and pathologic diagnosis of ependymoma were included. Records were reviewed for demographic information, EOR, lesion characteristics, and pre-/post-operative neurologic symptoms. EOR was divided into 2 classifications: gross total resection (GTR) and subtotal resection (STR). Log-rank test was used to compare OS and PFS between patient groups. RESULTS: Sixty-nine patients satisfied inclusion criteria, with 79.7% benefitting from GTR. The population was 56.2% male with average age of 45.7 years, and median follow-up duration of 58 months. Cox multivariate model demonstrated significant improvement in PFS when a GTR was attained (p <.001). Independently ambulatory patients prior to surgery had superior PFS (p <.001) and OS (p =.05). In univariate analyses, patients with a syrinx had improved PFS (p =.03) and were more likely to benefit from GTR (p =.01). Alternatively, OS was not affected by EOR (p =.78). CONCLUSIONS: In this large, contemporary series of adult spinal ependymoma patients, we demonstrated improvements in PFS when GTR was achieved.

Using standardized workflows and quantitative data-driven management to reduce time interval from simulation to treatment initiation.

PURPOSE: External beam radiotherapy is a complex process, involving timely coordination among multiple teams. The aim of this study is to report our experience of establishing a standardized workflow and using quantitative data and metrics to manage the time-to-treatment initiation (TTI). METHODS AND MATERIALS: Starting in 2014, we established a standard process in a radiation oncology-specific electronic medical record system (RO-EMR) for patients receiving external beam radiation therapy in our department, aiming to measure the time interval from simulation to treatment initiation, defined as TTI, for radiation oncology. TTI data were stratified according to the following treatment techniques: three-dimensional (3D) conformal therapy, intensity-modulated radiotherapy (IMRT), and stereotactic body radiotherapy (SBRT). Statistical analysis was performed with the Mann-Whitney test for the respective metrics of aggregate data for the initial period 2012- 2015 (PI) and the later period 2016-2019 (PII). RESULT: Over 8 years, the average annual number of treatments for PI and PII were 1760 and 2357 respectively, with 3D, IMRT, and SBRT treatments accounting for 53, 29, 18% and 44, 34, 22%, respectively, of the treatment techniques. The median TTI for 3D, IMRT, and SBRT for PI and PII were 1, 6, 7, and 1, 5, 7 days, respectively, while the 90th percentile TTI for the three techniques in both periods were 5, 9, 11 and 4, 9, 10 days, respectively. From the aggregate data, the TTI was significantly reduced (p = 0.0004, p < 0.0001, p < 0.0001) from PI to PII for the three treatment techniques. CONCLUSION: Establishing a standardized workflow and frequently measuring TTI resulted in shortening the TTI during the early years (in PI) and maintaining the established TTI in the subsequent years (in PII).

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Radiation necrosis or tumor progression? A review of the radiographic modalities used in the diagnosis of cerebral radiation necrosis.

PURPOSE: Cerebral radiation necrosis is a complication of radiation therapy that can be seen months to years following radiation treatment. Differentiating radiation necrosis from tumor progression on standard magnetic resonance imaging (MRI) is often difficult and advanced imaging techniques may be needed to make an accurate diagnosis. The purpose of this article is to review the imaging modalities used in differentiating radiation necrosis from tumor progression following radiation therapy for brain metastases. METHODS: We performed a review of the literature addressing the radiographic modalities used in the diagnosis of radiation necrosis. RESULTS: Differentiating radiation necrosis from tumor progression remains a diagnostic challenge and advanced imaging modalities are often required to make a definitive diagnosis. If diagnostic uncertainty remains following conventional imaging, a multi-modality diagnostic approach with perfusion MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission spectroscopy (SPECT), and radiomics may be used to improve diagnosis. CONCLUSION: Several imaging modalities exist to aid in the diagnosis of radiation necrosis. Future studies developing advanced imaging techniques are needed.

18F-fluciclovine PET/CT to distinguish radiation necrosis from tumor progression for brain metastases treated with radiosurgery: results of a prospective pilot study.

PURPOSE: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. METHODS: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. RESULTS: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). CONCLUSIONS: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance.

The dosimetric impact of titanium implants in spinal SBRT using four commercial treatment planning algorithms.

To evaluate the dosimetric impact of titanium implants in spine SBRT using four dose calculation algorithms. Twenty patients with titanium implants in the spine treated with SBRT without density override (DO) were selected. The clinical plan for each patient was created in Pinnacle and subsequently imported into Eclipse (AAA and AcurosXB) and Raystation (CC) for dose evaluation with and without DO to the titanium implant. We renormalized all plans such that 90% of the tumor volume received the prescription dose and subsequently evaluated the following dose metrics: (1) the maximum dose to 0.03 cc (Dmax), dose to 99% (D99%) and 90% (D90%) of the tumor volume; (2) Dmax and volumetric metrics of the spinal cord. For the same algorithm, plans with and without DO had similar dose distributions. Differences in Dmax, D99% and D90% of the tumor were on average <2% with slightly larger variations up to 5.58% in Dmax using AcurosXB. Dmax of the spinal cord for plans calculated with DO increased but the differences were clinically insignificant for all algorithms (mean: 0.36% ± 0.7%). Comparing to the clinical plans, the relative differences for all algorithms had an average of 1.73% (-10.36%-13.21%) for the tumor metrics and -0.93% (-9.87%-10.95%) for Dmax of the spinal cord. A few cases with small tumor and spinal cord volumes, dose differences of >10% in both D99% and Dmax of the tumor, and Dmax of the spinal cord were observed. For all algorithms, the presence of titanium implants in the spine for most patients had minimal impact on dose distributions with and without DO. For the same plan calculated with different algorithms, larger differences in volumetric metrics of >10% could be observed, impacted by dose gradient at the plan normalization volume, tumor volumes, plan complexity, and partial voxel volume interpolation.

Quality of life following concurrent temozolomide-based chemoradiation therapy or observation in low-grade glioma.

PURPOSE: Low-grade glioma (LGG) exhibits longer median survival than high-grade brain tumors, and thus impact of our therapies on patient quality of life remains a crucial consideration. This study evaluated the effects of concurrent temozolomide-based chemoradiation (RT + TMZ) or observation on quality of life (QOL) in patients with low-grade glioma. METHODS: We completed a retrospective cross-sectional study of adults with LGG who underwent surgery with known molecular classification from 1980 to 2018. Postoperatively, patients were either observed or received adjuvant concurrent temozolomide-based chemoradiation. EQ-5D and PHQ-9 depression screen were completed before outpatient visits every 2-3 months. Baseline score was defined as ± 30 days within initial operation. RESULTS: Of the 63 patients (mean age 44 ± 17 years, 51% female) with baseline EQ-5D or PHQ-9 depression screen data and at least one follow-up measure, 30 (48%) were observed and 33 (52%) received RT + TMZ. No significant decline was seen in EQ-5D or PHQ-9 scores at 3, 6, 9, 12, and 24 months compared to baseline scores for all patients. At each time point, there was no significant difference between those who were observed or received adjuvant therapy. The linear mixed model estimating PHQ-9 value or EQ-5D index demonstrated that there was no significant difference in PHQ-9 or EQ-5D index between treatment groups (p = 0.42 and p = 0.54, respectively) or time points (p = 0.24 and p = 0.99, respectively). CONCLUSION: Our study found no significant decline in patient QOL or depression scores as assessed by patient- reported outcome measures for patients with low-grade glioma up to 2 years following surgery. We found no difference between RT + TMZ compared to observation during this time frame. Additional follow-up can help identify the longer-term impact of treatment strategy on patient experience.

Cognitive function after concurrent temozolomide-based chemoradiation therapy in low-grade gliomas.

PURPOSE: We sought to evaluate the effects of concurrent temozolomide-based chemoradiation therapy on neurocognitive function in patients with low-grade glioma (LGG). MATERIALS/METHODS: We included adult patients with LGG who were treated postoperatively with radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Patients were evaluated with comprehensive psychometric tests at baseline (prior to RT + TMZ) and at various time intervals following RT + TMZ. Baseline cognitive performance was analyzed by sex, age, education history, history of seizures, IDH mutation status, and 1p/19q codeletion status. Changes in neurocognitive performance were evaluated over time. RESULTS: Thirty-seven LGG patients (mean age 43.6, 59.5% male) had baseline neurocognitive evaluation. Patients with an age > 40 years old at diagnosis and those with an education > 16 years demonstrated superior baseline verbal memory as assessed by HVLT. No other cognitive domains showed differences when stratified by the variables mentioned above. A total of 22 LGG patients had baseline and post RT + TMZ neurocognitive evaluation. Overall, patients showed no statistical difference between group mean test scores prior to and following RT + TMZ on all psychometric measures (with the exception of HVLT Discrimination). CONCLUSION: Cognitive function remained stable following RT + TMZ in LGG patients evaluated prospectively up to 2 years. The anticipated analysis of RTOG 0424 will provide valuable neurocognitive outcomes specifically for high risk LGG patients treated with RT + TMZ.

A quantitative and comparative evaluation of stereotactic spine radiosurgery local control: proposing a consistent measurement methodology.

OBJECTIVE: Stereotactic body radiotherapy (SBRT) is a precise and conformal treatment modality used in the management of metastatic spine tumors. Multiple studies have demonstrated its safety and efficacy for pain and tumor control. However, no uniform quantitative imaging methodology exists to evaluate response to treatment in these patients. This study presents radiographic local control rates post-SBRT, systematically compares measurements acquired according to WHO and Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and explores the relationship to patient outcome. METHODS: The authors performed a retrospective review of prospectively obtained data from a cohort of 59 consecutive patients (81 metastatic isocenters) treated with SBRT and followed with serial MRI scans. Measurements were performed by a neuroradiologist blinded to the patients' clinical course. Local control status was determined according to both WHO and RECIST measurements, and agreement between the measuring methodologies was calculated and reported. RESULTS: Eighty-one isocenters (111 vertebral bodies) were treated with SBRT. The mean treatment dose was 13.96 Gy and the median follow-up duration was 10.8 months, during which 408 MRI scans were evaluated with both WHO and RECIST criteria for each scan point. Imaging demonstrated a mean unidimensional size decrease of 0.2 cm (p = 0.14) and a mean area size decrease of 0.99 cm2 (p = 0.03). Although 88% of the case classifications were concordant and the agreement was significant, WHO criteria were found to be more sensitive to tumor size change. The local control rates according to WHO and RECIST were 95% and 98%, respectively. CONCLUSIONS: Although WHO volumetric measurements are admittedly superior for tumor size measurement, RECIST is simpler, reproducible, and for the first time is shown here to be comparable to WHO criteria. Thus, the application of RECIST methodology appears to be a suitable standard for evaluating post-SBRT treatment response. Moreover, using comprehensive and consistent measuring approaches, this study substantiates the efficacy of SBRT in the treatment of spine metastases.

Outcomes of salvage radiation for recurrent world health organization grade II meningiomas: a retrospective cohort study.

PURPOSE: The optimal modality of radiation-intensity-modulated radiation therapy (IMRT) or stereotactic radiosurgery (SRS)-in patients with recurrent WHO grade II meningiomas is not well-established. The purpose of this study was to compare progression-free survival (PFS) in patients undergoing salvage IMRT vs SRS. We compared PFS in those with and without history of prior radiation. METHODS: Forty-two patients with 71 tumor recurrences treated with IMRT or SRS were retrospectively reviewed. Thirty-two salvage treatments were performed on recurrent tumors never treated with prior radiation ('radiation-naïve' cohort), whereas 39 salvage treatments were performed on recurrent tumors previously treated with radiation ('re-treatment cohort'). RESULTS: In the 'radiation-naïve' cohort, 3-year PFS for IMRT and SRS was 68.8% and 60.7%, respectively (p = 0.61). The median tumor volume for patients treated with IMRT was significantly larger than for patients treated with SRS (5.7 vs 2.2 cm3; p = 0.04). The 3-year PFS for salvage IMRT or SRS in the 're-treatment' cohort was 45.4% vs 65.8% in the 'radiation-naïve' cohort (p = 0.008). When analyzing the outcome of multiple re-treatments, median PFS was 47 months for 1st or 2nd salvage radiation (IMRT or SRS) compared to 16 months for the 3rd or greater salvage radiation treatment (p = 0.003). CONCLUSION: For salvage radiation of recurrent grade II tumors that are 'radiation-naïve', comparable 3-year PFS rates were found between IMRT and SRS, despite the IMRT group having significantly larger tumors. Salvage radiation overall was less successful in the 're-treatment' cohort compared with the 'radiation-naïve' cohort. Additionally, the effectiveness of radiation significantly declines with successive salvage radiation treatments.

Radiation Necrosis from Stereotactic Radiosurgery-How Do We Mitigate?

OPINION STATEMENT: Intracranial stereotactic radiosurgery (SRS) is an effective and convenient treatment for many brain conditions. Data regarding safety come mostly from retrospective single institutional studies and a small number of prospective studies. Variations in target delineation, treatment delivery, imaging follow-up protocols and dose prescription limit the interpretation of this data. There has been much clinical focus on radiation necrosis (RN) in particular, as it is being increasingly recognized on follow-up imaging. Symptomatic RN may be treated with medical therapy (such as corticosteroids and bevacizumab) with surgical resection being reserved for refractory patients. Nevertheless, RN remains a challenging condition to manage, and therefore upfront patient selection for SRS remains critical to provide complication-free control. Mitigation strategies need to be considered in situations where the baseline risk of RN is expected to be high-such as large target volume or re-irradiation. These may involve reduction in the prescribed dose or hypofractionated stereotactic radiation therapy (HSRT). Recently published guidelines and international meta-analysis report the benefit of HSRT in larger lesions, without compromising control rates. However, careful attention to planning parameters and SRS techniques still need to be adhered, even with HSRT. In cases where the risk is deemed to be high despite mitigation, a combination approach of surgery with or without post-operative radiation should be considered.

Factors associated with adjacent-level tumor progression in patients receiving surgery followed by radiosurgery for metastatic epidural spinal cord compression.

OBJECTIVE: Separation surgery followed by spine stereotactic radiosurgery (SSRS) has been shown to achieve favorable rates of local tumor control and patient-reported outcomes in patients with metastatic epidural spinal cord compression (MESCC). However, rates and factors associated with adjacent-level tumor progression (ALTP) in this population have not yet been characterized. The present study aimed to identify factors associated with ALTP and examine its association with overall survival (OS) in patients receiving surgery followed by radiosurgery for MESCC. METHODS: Thirty-nine patients who underwent separation surgery followed by SSRS for MESCC were identified using a prospectively collected database and were retrospectively reviewed. Radiological measurements were collected from preoperative, postoperative, and post-SSRS MRI. Statistical analysis was conducted using the Kaplan-Meier product-limit method and Cox proportional hazards test. Subgroup analysis was conducted for patients who experienced ALTP into the epidural space (ALTP-E). RESULTS: The authors' cohort included 39 patients with a median OS of 14.7 months (range 2.07-96.3 months). ALTP was observed in 16 patients (41.0%) at a mean of 6.1 ± 5.4 months postradiosurgery, of whom 4 patients (10.3%) experienced ALTP-E. Patients with ALTP had shorter OS (13.0 vs 17.1 months, p = 0.047) compared with those without ALTP. Factors associated with an increased likelihood of ALTP included the amount of bone marrow infiltrated by tumor at the index level, amount of residual epidural disease following separation surgery, and prior receipt of radiotherapy at the index level (p < 0.05). Subgroup analysis revealed that primary tumor type, amount of preoperative epidural disease, time elapsed between surgery and radiosurgery, and prior receipt of radiotherapy at the index level were significantly associated with ALTP-E (p < 0.05). CONCLUSIONS: To the authors' knowledge, this study is the first to identify possible risk factors for ALTP, and they suggest that it may be associated with shorter OS in patients receiving surgery followed by radiosurgery for MESCC. Future studies with higher power should be conducted to further characterize factors associated with ALTP in this population.

Treatment planning of VMAT and step-and-shoot IMRT delivery techniques for single fraction spine SBRT: An intercomparative dosimetric analysis and phantom-based quality assurance measurements.

PURPOSE: To retrospectively compare clinically treated step-and-shoot intensity modulated radiotherapy (ssIMRT) and volumetric modulated arc therapy (VMAT) spine stereotactic body radiotherapy (SBRT) plans in dosimetric endpoints and pretreatment quality assurance (QA) measurements. METHODS: Five single fraction spine SBRT (18 Gy) cases - including one cervical, two thoracic, and two lumbar spines - clinically treated with ssIMRT were replanned with VMAT, and all plans were delivered to a phantom for comparing plan quality and delivery accuracy. Furthermore, we analyzed 98 clinically treated plans (18 Gy single fraction), including 34 ssIMRT and 29 VMAT for cervical/thoracic spine, and 19 ssIMRT and 16 VMAT for lumbar spine. The conformality index (CI) and homogeneity index (HI) were calculated, and QA measurement records were compared. For the spinal cord/cauda equina, the maximum dose to 0.03 cc (D0.03cc ) and volume receiving 10 or 12 Gy (V10Gy /V12Gy ) were recorded. Statistical significance was tested with the Mann-Whitney U test. RESULTS: Compared to ssIMRT, replanned VMAT plans had lower V10Gy /V12Gy and D0.03cc to the spinal cord/cauda equina in all five cases, and better CI in three out of five cases. The VMAT replans were slightly less homogeneous than those of ssIMRT plans. Both modalities passed IMRT QA with >95% passing rate with (3%, 3 mm) gamma criteria. With the 98 clinical cases, for cervical/thoracic ssIMRT and VMAT plans, the median V10Gy of spinal cord was 4.15% and 1.85% (P = 0.004); the median D0.03cc of spinal cord was 10.85 Gy and 10.10 Gy (P = 0.032); the median CI was 1.28 and 1.08 (P = 0.009); the median HI were 1.34 and 1.33 (P = 0.697), respectively. For lumbar spine, no significant dosimetric endpoint differences were observed. The two modalities were comparable in delivery accuracy. CONCLUSION: From our clinically treated plans, we found that VMAT plans provided better dosimetric quality and comparable delivery accuracy when compared to ssIMRT for single fraction spine SBRT.

Fractionated Gamma Knife radiosurgery for skull base meningiomas: a single-institution experience.

OBJECTIVEGamma Knife radiosurgery (GKRS) has been successfully used for the treatment of intracranial meningiomas given its steep dose gradients and high-dose conformality. However, treatment of skull base meningiomas (SBMs) may pose significant risk to adjacent radiation-sensitive structures such as the cranial nerves. Fractionated GKRS (fGKRS) may decrease this risk, but until recently it has not been practical with traditional pin-based systems. This study reports the authors' experience in treating SBMs with fGKRS, using a relocatable, noninvasive immobilization system.METHODSThe authors performed a retrospective review of all patients who underwent fGKRS for SBMs between 2013 and 2018 delivered using the Extend relocatable frame system or the Icon system. Patient demographics, pre- and post-GKRS tumor characteristics, perilesional edema, prior treatment details, and clinical symptoms were evaluated. Volumetric analysis of pre-GKRS, post-GKRS, and subsequent follow-up visits was performed.RESULTSTwenty-five patients met inclusion criteria. Nineteen patients were treated with the Icon system, and 6 patients were treated with the Extend system. The mean pre-fGKRS tumor volume was 7.62 cm3 (range 4.57-13.07 cm3). The median margin dose was 25 Gy delivered in 4 (8%) or 5 (92%) fractions. The median follow-up time was 12.4 months (range 4.7-17.4 months). Two patients (9%) experienced new-onset cranial neuropathy at the first follow-up. The mean postoperative tumor volume reduction was 15.9% with 6 patients (27%) experiencing improvement of cranial neuropathy at the first follow-up. Median first follow-up scans were obtained at 3.4 months (range 2.8-4.3 months). Three patients (12%) developed asymptomatic, mild perilesional edema by the first follow-up, which remained stable subsequently.CONCLUSIONSfGKRS with relocatable, noninvasive immobilization systems is well tolerated in patients with SBMs and demonstrated satisfactory tumor control as well as limited radiation toxicity. Future prospective studies with long-term follow-up and comparison to single-session GKRS or fractionated stereotactic radiotherapy are necessary to validate these findings and determine the efficacy of this approach in the management of SBMs.

Recursive partitioning analysis is predictive of overall survival for patients undergoing spine stereotactic radiosurgery.

Spine stereotactic radiosurgery (SRS) offers excellent radiographic and pain control for patients with spine metastases. We created a prognostic index using recursive partitioning analysis (RPA) to allow better patient selection for spine SRS. Patients who underwent single-fraction spine SRS for spine metastases were included. Primary histologies were divided into favorable (breast/prostate), radioresistant (renal cell/sarcoma/melanoma) and other. Cox proportional hazards regression was done to identify factors associated with overall survival (OS). RPA was performed to identify factors to classify patients into distinct risk groups with respect to OS. A total of 444 patients were eligible. Median dose was 16 Gy (range 8-18) in 1 fraction and median follow-up was 11.7 months. At time of analysis, 103 (23.1%) patients were alive. Median OS was 12.9 months. RPA identified three distinct classes. Class 1 was defined as KPS > 70 with controlled systemic disease (n = 142); class 3 was defined as KPS ≤ 70 and age < 54 years or KPS ≤ 70 age ≥ 54 years and presence of visceral metastases (n = 95); all remaining patients comprise class 2 (n = 207). Median overall survival was 26.7 months for class 1, 13.4 months for class 2, and 4.5 months for class 3 (p < 0.01). Our analysis demonstrates that there is considerably variability in survival among patients undergoing spine SRS. We created an objective risk stratification via RPA for spine SRS. Given the safety and efficacy of spine SRS and good survival in class 1 and 2 patients, this RPA can help clinicians identify patients who may benefit from upfront spine SRS.

Expression of LC3B and FIP200/Atg17 in brain metastases of breast cancer.

BACKGROUND: Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated with metastatic disease and poor outcome. FIP200/Atg17, a multi-functional pro-survival molecule required for autophagy, has been implicated in brain metastases in experimental models. However, expression of these proteins has not been examined in brain metastases from patients with breast cancer. METHODS: In this retrospective study, specimens from 44 patients with brain metastases of infiltrating ductal carcinoma of the breast (IDC), unpaired samples from 52 patients with primary IDC (primary-BC) and 16 matched-paired samples were analyzed for LC3 puncta, expression of FIP200/Atg17, and p62 staining. RESULTS: LC3-puncta+ tumor cells and FIP200/Atg17 expression were detected in greater than 90% of brain metastases but there were considerable intra- and inter-tumor differences in expression levels. High numbers of LC3-puncta+ tumor cells in brain metastases correlated with a significantly shorter survival time in triple-negative breast cancer. FIP200/Atg17 protein levels were significantly higher in metastases that subsequently recurred following therapy. The percentages of LC3 puncta+ tumor cells and FIP200/Atg17 protein expression levels, but not mRNA levels, were significantly higher in metastases than primary-BC. Meta-analysis of gene expression datasets revealed a significant correlation between higher FIP200(RB1CC1)/Atg17 mRNA levels in primary-BC tumors and shorter disease-free survival. CONCLUSIONS: These results support assessments of precision medicine-guided targeting of autophagy in treatment of brain metastases in breast cancer patients.

Overall survival and the response to radiotherapy among molecular subtypes of breast cancer brain metastases treated with targeted therapies.

BACKGROUND: The current study was conducted to investigate survival and the response to radiotherapy among patients with molecular subtypes of breast cancer brain metastases treated with or without targeted therapies. METHODS: Patients diagnosed with breast cancer brain metastases at a single tertiary care institution were included. The primary outcome was overall survival, whereas secondary outcomes included the cumulative incidences of distant intracranial failure, local failure, and radiation necrosis. Competing risks regression was used to model secondary outcomes. RESULTS: Within the study period, 547 patients presented with 3224 brain metastases and met inclusion criteria. Among patients with human epidermal growth factor receptor 2 (HER2)-amplified disease, 80% received HER2 antibodies and 38% received HER2/epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The median survival was significantly shorter in the basal cohort (8.4 months), and progressively increased in the luminal A (12.3 months), HER2-positive (15.4 months), and luminal B (18.8 months) cohorts (P<.001). Among patients with HER2-amplified disease, the median survival was extended with the use of both HER2 antibodies (17.9 months vs 15.1 months; P = .04) and TKIs (21.1 months vs 15.4 months; P = .03). The 12-month cumulative incidences of local failure among molecular subtypes were 6.0% in the luminal A cohort, 10.3% in the luminal B cohort, 15.4% in the HER2-positive cohort, and 9.9% in the basal cohort (P = .01). Concurrent HER2/epidermal growth factor receptor TKIs with stereotactic radiosurgery significantly decreased the 12-month cumulative incidence of local failure from 15.1% to 5.7% (P<.001). CONCLUSIONS: Molecular subtypes appear to be prognostic for survival and predictive of the response to radiotherapy. TKIs were found to improve survival and local control, and may decrease the rate of distant failure. To preserve neurocognition, these results support a paradigm of upfront radiosurgery and HER2-directed therapy in the HER2-amplified population, reserving whole-brain radiotherapy for salvage. Cancer 2017;123:2283-2293. © 2017 American Cancer Society.

Longitudinal experience with WHO Grade III (anaplastic) meningiomas at a single institution.

To retrospectively analyze and assess the outcomes and prognostic factors in patients with anaplastic meningioma (AM) (WHO Grade III). Clinical data and outcome [overall (OS) and progression-free (PFS) survival] from 18 patients with Grade III meningioma (AM, based on World Health Organization 2016 definition) initially treated between March 2000 and June 2015 were analyzed. Eleven patients (61%) were male, median age at diagnosis was 63 (range 48-86), and 55% (10/18 patients) had good performance status (KPS ≥ 80). Eight patients (45%) had lower grade disease (Grade I-n = 2; Grade II-n = 6) prior to being upgraded to AM. Ten patients had fractionated radiation after primary surgery, eight patients had salvage fractionated RT, stereotactic radiosurgery (SRS) boost along with primary RT in 1 patient, and salvage SRS to 18 separate areas in 14 patients. Salvage chemotherapy was mainly considered in third or fourth recurrences. 13 (72%) patients recurred and 10 (56%) have died. Median PFS was 14.5 months (95% CI 6.9-22.2). The 5-year survival rate was 40 ± 15% and median OS was 55.8 months (95% CI 27.7-80.3). Of all factors examined, only Karnofsky performance status (KPS) affected outcome (PFS p = 0.0003; OS p = 0.0003). With median OS of 55 months (4.6 years) our results are consistent with existing reports of the poor outcomes for AM patients. From the available data, surgical resection followed by RT and salvage radiosurgery and/or chemotherapy can lead to extended survival; however the benefit may decrease with successive treatments.

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies.

To investigate late toxicity among patients with newly-diagnosed brain metastases undergoing stereotactic radiosurgery (SRS) with concurrent systemic therapies with or without whole-brain radiation therapy (WBRT). Patients with newly-diagnosed brain metastasis who underwent SRS at a single tertiary-care institution from 1997 to 2015 were eligible for inclusion. The class and timing of all systemic therapies were collected for each patient. The primary outcome was the cumulative incidence of radiographic radiation necrosis (RN). Multivariable competing risks regression was used to adjust for confounding. During the study period, 1650 patients presented with 2843 intracranial metastases. Among these, 445 patients (27%) were treated with SRS and concurrent systemic therapy. Radiographic RN developed following treatment of 222 (8%) lesions, 120 (54%) of which were symptomatic. The 12-month cumulative incidences of RN among lesions treated with and without concurrent therapies were 6.6 and 5.3%, respectively (p = 0.14). Concurrent systemic therapy was associated with a significantly increased rate of RN among lesions treated with upfront SRS and WBRT (8.7 vs. 3.7%, p = 0.04). In particular, concurrent targeted therapies significantly increased the 12-month cumulative incidence of RN (8.8 vs. 5.3%, p < 0.01). Among these therapies, significantly increased rates of RN were observed with VEGFR tyrosine kinase inhibitors (TKIs) (14.3 vs. 6.6%, p = 0.04) and EGFR TKIs (15.6 vs. 6.0%, p = 0.04). Most classes of systemic therapies may be safely delivered concurrently with SRS in the management of newly-diagnosed brain metastases. However, the rate of radiographic RN is significantly increased with the addition of concurrent systemic therapies to SRS and WBRT.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.