Frameless image-guided linear accelerator (LINAC) stereotactic radiosurgery for medically refractory trigeminal neuralgia: Clinical outcomes in 116 patients.

Background: Frameless image-guided radiosurgery (IGRS) is an effective and non-invasive method of treating patients who are unresponsive to medical management for trigeminal neuralgia (TN). This study evaluated the use of frameless IGRS to treat patients with medically refractory TN. Methods: We performed a retrospective review of records of 116 patients diagnosed with TN who underwent frameless IGRS using a linear accelerator (LINAC) over 10 years (March 2012-February 2023). All patients had failed medical management for TN. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. Each patient received a BNI score before frameless IGRS and following treatment. Failure was defined as a BNI score IV-V at the last follow-up and/or undergoing a salvage procedure following IGRS. Results: All patients had a BNI score of either IV or V before the frameless IGRS. The mean follow-up duration for all 116 patients following IGRS was 44.1 months. Most patients (81 [69.8%]) had not undergone surgery (microvascular decompression [MVD] or rhizotomy) or stereotactic radiosurgery (SRS) for TN before frameless IGRS. A total of 41 (35.3%) patients underwent a salvage procedure (MVD, rhizotomy, or an additional IGRS) following frameless IGRS. The mean duration between the initial frameless IGRS and salvage procedure was 20.1 months. At the last follow-up, a total of 110 (94.8%) patients had a BNI score of I-III. No complications were reported after the frameless IGRS. The BNI score at the last follow-up was lower compared to the initial BNI for patients regardless of prior intervention (P < 0.001). Patients who failed IGRS had a higher BNI score at the last follow-up compared to those who did not fail IGRS (2.8 vs. 2.5, P = 0.05). Patients with pain relief had a shorter follow-up compared to those with pain refractory to SRS (38.0 vs. 55.1, P = 0.005). Conclusion: In this large cohort of patients with medically refractory TN, frameless IGRS resulted in durable pain control in the majority of patients without any toxicity.

Impact of Reirradiation Utilizing Fractionated Stereotactic Radiotherapy for Recurrent Glioblastoma.

BACKGROUND: Patients with recurrent glioblastoma (GBM) have limited treatment options. This study determined whether patients with recurrent GBM treated with initial radiation/temozolomide (TMZ) and reirradiation using fractionated stereotactic radiotherapy (FSRT) had improved outcomes. MATERIALS AND METHODS: We identified 95 patients with recurrent GBM, 50 of whom underwent FSRT at recurrence and 45 who had systemic treatment only (control). The median total FSRT dose at the time of GBM recurrence was 30 Gy in five fractions of the gadolinium-enhanced tumor only. RESULTS: With a median follow-up of 18 months, the progression-free survival (PFS) and overall survival (OS) following initial GBM diagnosis were longer in the reirradiation group compared to the control group (13.5 vs. 7.5 months [p=0.001] and 24.6 vs. 12.6 months [p<0.001], respectively). For patients who underwent reirradiation, the median time interval between the end of the initial radiation and reirradiation was 15.2 months. The median OS after GBM recurrence was longer in the reirradiation group versus the control group (9.9 vs. 3.5 months [p<0.001]), with a one-year OS survival rate of 22%. The hazard ratio for death of patients in the reirradiation group was 0.31 [0.19-0.50]. The reirradiation group had a higher percentage of patients who received bevacizumab (BEV, 62.0% vs. 28.9%, p=0.002) and a lower percentage of patients whose TMZ was discontinued due to toxicity (8.0% vs. 28.9%, p=0.017) compared to the control group. CONCLUSIONS: Reirradiation utilizing FSRT was associated with improved PFS and OS after GBM recurrence compared to the control group who did not receive additional irradiation.

Stereotactic radiosurgery in the management of non-small cell lung cancer brain metastases: a prospective study using the NeuroPoint Alliance Stereotactic Radiosurgery Registry.

OBJECTIVE: The literature on non-small cell lung cancer (NSCLC) brain metastases (BMs) managed using stereotactic radiosurgery (SRS) relies mainly on single-institution studies or randomized controlled trials (RCTs). There is a literature gap on clinical and radiological outcomes of SRS for NSCLC metastases in real-world practice. The objective of this study was to benchmark mortality and progression outcomes in patients undergoing SRS for NSCLC BMs and identify risk factors for these outcomes using a national quality registry. METHODS: The SRS Registry of the NeuroPoint Alliance was used for this study. This registry included patients from 16 enrolling sites who underwent SRS from 2017 to 2022. Data are prospectively collected without a prespecified research purpose. The main outcomes of this analysis were overall survival (OS), out-of-field recurrence, local progression, and intracranial progression. All time-to-event investigations included Kaplan-Meier analyses and multivariable Cox regressions. RESULTS: Two hundred sixty-four patients were identified, with a mean age of 66.7 years and a female proportion of 48.5%. Most patients (84.5%) had a Karnofsky Performance Status (KPS) score of 80-100, and the mean baseline EQ-5D score was 0.539 quality-adjusted life years. A single lesion was present in 53.4% of the patients, and 29.1% of patients had 3 or more lesions. The median OS was 28.1 months, and independent predictors of mortality included no control of primary tumor (hazard ratio [HR] 2.1), KPS of 80 (HR 2.4) or lower (HR 2.4), coronary artery disease (HR 2.8), and 5 or more lesions present at the time of SRS treatment (HR 2.3). The median out-of-field progression-free survival (PFS) was 24.8 months, and the median local PFS was unreached. Intralesional hemorrhage was an independent risk factor of local progression, with an HR of 6.0. The median intracranial PFS was 14.0 months and was predicted by the number of lesions at the time of SRS (3-4 lesions, HR 2.2; 5-14 lesions, HR 2.5). CONCLUSIONS: In this real-world prospective study, the authors used a national quality registry and found favorable OS in patients with NSCLC BMs undergoing SRS compared with results from previously published RCTs. The intracranial PFS was mainly driven by the emergence of new lesions rather than local progression. A greater number of lesions at baseline was associated with out-of-field progression, while intralesional hemorrhage at baseline was associated with local progression.

Multifocal intradural extramedullary ependymoma, MYCN amplified: illustrative case.

BACKGROUND: Ependymomas are the most frequent tumors of the adult spinal cord, representing 1.9% of all central nervous system tumors and 60% of spinal cord tumors. Spinal ependymomas are usually solitary, intramedullary lesions. While intradural extramedullary (IDEM) ependymomas are infrequent, multifocal IDEM ependymomas are exceptionally rare. OBSERVATIONS: The authors reported the first case in the literature of a patient diagnosed with multifocal IDEM ependymomas who was treated with tumor resection and brain and spinal radiotherapy. The patient presented with a 10-day history of bilateral leg numbness extending to the umbilicus and gait instability. Magnetic resonance imaging (MRI) studies revealed multiple enhancing nodular nodules throughout the entire spinal canal. Brain MRI revealed no abnormal lesions. A World Health Organization grade II ependymoma was confirmed histologically. At 31 months postoperatively, the patient remained clinically asymptomatic. Although cervical and thoracic MRI revealed stable intradural nodules and several areas of leptomeningeal enhancement, no malignant cells were seen in the cerebrospinal fluid (CSF). He underwent genetic testing to determine the appropriate chemotherapeutic agent if activation of the tumor should arise. LESSONS: Because complete resection of multifocal IDEM ependymomas is not feasible, continued monitoring with brain and spine MRI is warranted to detect potential tumor dissemination in the CSF.

Single low-dose targeted bevacizumab infusion in adult patients with steroid-refractory radiation necrosis of the brain: a phase II open-label prospective clinical trial.

OBJECTIVE: There is an unmet need for safe and rapidly effective therapies for refractory brain radiation necrosis (RN). The aim of this prospective single-arm phase II trial was to evaluate the safety and efficacy of a single low-dose targeted bevacizumab infusion after blood-brain barrier disruption (BBBD) in adult patients with steroid-refractory brain RN. METHODS: Ten adults with steroid-refractory, imaging-confirmed brain RN were enrolled between November 2016 and January 2018 and followed for 12 months after treatment. Bevacizumab 2.5 mg/kg was administered as a one-time targeted intra-arterial infusion immediately after BBBD. Primary outcomes included safety and > 25% decrease in lesion volume. Images were analyzed by a board-certified neuroradiologist blinded to pretrial diagnosis and treatment status. Secondary outcomes included changes in headache, steroid use, and functional status and absence of neurocognitive sequelae. Comparisons were analyzed using the Fisher exact test, Mann-Whitney U-test, linear mixed models, Wilcoxon signed-rank test, and repeated-measures 1-way ANOVA. RESULTS: Ten adults (mean ± SD [range] age 35 ± 15 [22-62] years) participated in this study. No patients died or exhibited serious adverse effects of systemic bevacizumab. At 3 months, 80% (95% CI 44%-98%) and 90% (95% CI 56%-100%) of patients demonstrated > 25% decrease in RN and vasogenic edema volume, respectively. At 12 months, RN volume decreased by 74% (median [range] 76% [53%-96%], p = 0.012), edema volume decreased by 50% (median [range] 70% [-11% to 83%], p = 0.086), and headache decreased by 84% (median [range] 92% [58%-100%], p = 0.022) among the 8 patients without RN recurrence. Only 1 (10%) patient was steroid dependent at the end of the trial. Scores on 12 of 16 (75%) neurocognitive indices increased, thereby supporting a pattern of cerebral white matter recovery. Two (20%) patients exhibited RN recurrence that required further treatment at 10 and 11 months, respectively, after bevacizumab infusion. CONCLUSIONS: For the first time, to the authors' knowledge, the authors demonstrated that a single low-dose targeted bevacizumab infusion resulted in durable clinical and imaging improvements in 80% of patients at 12 months after treatment without adverse events attributed to bevacizumab alone. These findings highlight that targeted bevacizumab may be an efficient one-time treatment for adults with brain RN. Further confirmation with a randomized controlled trial is needed to compare the intra-arterial approach with the conventional multicycle intravenous regimen. Clinical trial registration no.: NCT02819479 (ClinicalTrials.gov).

Metastatic squamous cell carcinoma of the skin with clinical response to lapatinib.

BACKGROUND: Lapatinib is a tyrosine kinase inhibitor that blocks the HER2 receptor and is typically used in the setting of metastatic breast cancer. Both ERBB2 (HER2) and ERBB3 (HER3) belong to the same family of receptor tyrosine kinases. Dimerization of these receptors leads to activation of cell proliferation and survival pathways, granting oncogenic potential to dysregulated ERBB/HER receptors. Next generation sequencing (NGS) of tumors has ushered in a new era of personalized oncology therapy and has the ability to detect mutations in ERBB receptors. CASE PRESENTATION: We present a patient with metastatic cutaneous squamous cell carcinoma who failed surgery, radiation, and anti-PD1 therapy, but showed clinical response to a drug targeting an ERBB3 mutation identified with NGS. Following initiation of the drug lapatinib, this patient exhibited dramatic tumor regression in the skin, soft tissue, bone and nerves. CONCLUSIONS: Cutaneous squamous cell carcinoma is the 2nd most common skin cancer in humans and future investigation of ERBB2 targeted therapies may provide an effective treatment strategy for patients with mutations in the ERBB2/3 pathway.

A Regional Multicenter Retrospective Analysis of Patients with Primary Central Nervous System Lymphoma Diagnosed from 2000-2012: Treatment Patterns and Clinical Outcomes.

Introduction Primary central nervous system lymphoma (PCNSL) is a rare tumor without a well-defined standard of care. For immunocompetent patients, therapeutic regimens have largely evolved from treatment with whole-brain radiation therapy (WBRT) to treating initially with systemic chemotherapy regimens that include high-dose (HD) methotrexate (MTX) with or without WBRT. Looking at population-based treatment trends may help define which therapies are most effective. This study was conducted to determine treatment patterns and outcomes for patients with PCNSL in the Louisville, KY metropolitan area during the period 2000 to 2012. Methods Data were collected by retrospective chart reviews of patients identified using the International Classification of Diseases (ICD) code from three major oncology practices in the Louisville metropolitan area during the period 2000 to 2012. Patients were excluded if they were under age 18, positive for human immunodeficiency virus (HIV), had histology other than B-cell lymphoma, or had systemic lymphoma. Results A total of 21 patients were identified. The median age was 65 years (range: 30 to 90). All patients were Caucasian, and the median Karnofsky performance status (KPS) score was 80 (range: 50 to 100). The ratio of males to females was 1:1.3. Median overall survival (OS) for all patients was 22 months (range: 1 to 155 months). Of 21 patients, 11 (52 percent) received chemotherapy regimens that included systemic HD-MTX at their initial diagnosis with a median OS of 22 months (range: 1 to 155 months). Nine of 21 patients (42 patients) were offered other therapies, including WBRT or non-MTX-based chemotherapies; they had a median OS of 5 months (range: 2 to 150 months). The median OS for patients receiving at least four cycles of HD-MTX was 40 months (range: 4 to 155 months). Conclusions This population-based study shows that patients with PCNSL and the ability to undergo HD-MTX-based therapy had a superior survival rate compared to those receiving radiation alone or other non-HD-MTX-based therapies.

Frameless image-guided radiosurgery for trigeminal neuralgia.

BACKGROUND: Frameless image-guided radiosurgery (IGRS) is a safe and effective noninvasive treatment for trigeminal neuralgia (TN). This study evaluates the use of frameless IGRS to treat patients with refractory TN. METHODS: We reviewed the records of 20 patients diagnosed with TN who underwent frameless IGRS treatments between March 2012 and December 2013. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. The initial setup uncertainty from simulation to treatment and the patient intrafraction uncertainty were measured. The median follow-up was 32 months. RESULTS: All patients' pain was BNI Grade IV or V before the frameless IGRS treatment. The mean intrafraction shift was 0.43 mm (0.28-0.76 mm), and the maximum intrafraction shift was 0.95 mm (0.53-1.99 mm). At last follow-up, 8 (40%) patients no longer required medications (BNI 1 or 2), 11 (55%) patients were pain free but required medication (BNI 3), and 1 (5%) patient had no pain relief (BNI 5). Patients who did not have prior surgery had a higher odds ratio for pain relief compared to patients who had prior surgery (14.9, P = 0.0408). CONCLUSIONS: Frameless IGRS provides comparable dosimetric and clinical outcomes to frame-based SRS in a noninvasive fashion for patients with medically refractory TN.

Practical considerations of linear accelerator-based frameless extracranial radiosurgery for treatment of occipital neuralgia for nonsurgical candidates.

Occipital neuralgia generally responds to medical or invasive procedures. Repeated invasive procedures generate increasing complications and are often contraindicated. Stereotactic radiosurgery (SRS) has not been reported as a treatment option largely due to the extracranial nature of the target as opposed to the similar, more established trigeminal neuralgia. A dedicated phantom study was conducted to determine the optimum imaging studies, fusion matrices, and treatment planning parameters to target the C2 dorsal root ganglion which forms the occipital nerve. The conditions created from the phantom were applied to a patient with medically and surgically refractory occipital neuralgia. A dose of 80 Gy in one fraction was prescribed to the C2 occipital dorsal root ganglion. The phantom study resulted in a treatment achieved with an average translational magnitude of correction of 1.35 mm with an acceptable tolerance of 0.5 mm and an average rotational magnitude of correction of 0.4° with an acceptable tolerance of 1.0°. For the patient, the spinal cord was 12.0 mm at its closest distance to the isocenter and received a maximum dose of 3.36 Gy, a dose to 0.35 cc of 1.84 Gy, and a dose to 1.2 cc of 0.79 Gy. The brain maximum dose was 2.20 Gy. Treatment time was 59 min for 18, 323 MUs. Imaging was performed prior to each arc delivery resulting in 21 imaging sessions. The average deviation magnitude requiring a positional or rotational correction was 0.96 ± 0.25 mm, 0.8 ± 0.41°, whereas the average deviation magnitude deemed within tolerance was 0.41 ± 0.12 mm, 0.57 ± 0.28°. Dedicated quality assurance of the treatment planning and delivery is necessary for safe and accurate SRS to the cervical spine dorsal root ganglion. With additional prospective study, linear accelerator-based frameless radiosurgery can provide an accurate, noninvasive alternative for treating occipital neuralgia where an invasive procedure is contraindicated.

Neoadjuvant chemotherapy for atypical teratoid rhabdoid tumors: case report.

Atypical teratoid rhabdoid tumors (ATRTs) are a rare pediatric brain tumor with high mortality rate. Several large series have reported achieving gross-total resection (GTR) in less than 50% of patients due to the lesions' large size, vascularity, and limited blood volume in young patients. While neoadjuvant chemotherapy for choroid plexus carcinomas in pediatric patients has become widely accepted, it has not been used as widely for other pediatric brain tumors. To the best of the authors' knowledge, there are only 3 published cases of neoadjuvant chemotherapy for ATRTs. In the present report, the authors present a fourth case of neoadjuvant chemotherapy for ATRT and review the available literature on this strategy. A 17-month-old child presented with a left ventricular ATRT for which imaging raised concern for a highly vascularized tumor. The authors undertook neoadjuvant chemotherapy with 2 cycles of Head Start II therapy, which reduced the size of the ventricular tumor by 35% and decreased the vascularity of the lesion on imaging. The estimated blood loss during resection was 425 ml and GTR was achieved. The patient continued with postoperative chemotherapy but suffered an on-therapy recurrence. While higher-quality data are necessary, available evidence suggests that neoadjuvant chemotherapy can reduce the size and vascularity of ATRTs and facilitate a surgical avenue for large or "inoperable" tumors.

Pathology concordance levels for meningioma classification and grading in NRG Oncology RTOG Trial 0539.

BACKGROUND: With advances in the understanding of histopathology on outcome, accurate meningioma grading becomes critical and drives treatment selection. The 2000 and 2007 WHO schema greatly increased the proportion of grade II meningiomas. Although associations with progression-free survival (PFS) and overall survival (OS) have been independently validated, interobserver concordance has not been formally assessed. METHODS: Once mature, NRG Oncology RTOG-0539 will report PFS and OS in variably treated low-, intermediate-, and high-risk cohorts. We address concordance of histopathologic assessment between enrolling institutions and central review, performed by a single pathologist (AP), who is also involved in developing current WHO criteria. RESULTS: The trial included 170 evaluable patients, 2 of whom had 2 eligible pathology reviews from different surgeries, resulting in 172 cases for analysis. Upon central review, 76 cases were categorized as WHO grade I, 71 as grade II, and 25 as grade III. Concordance for tumor grade was 87.2%. Among patients with WHO grades I, II, and III meningioma, respective concordance rates were 93.0%, 87.8%, and 93.6% (P values < .0001). Moderate to substantial agreement was encountered for individual grading criteria and were highest for brain invasion, ≥20 mitoses/10 high-powered field [HPF], and spontaneous necrosis, and lowest for small cells, sheeting, and ≥4 mitoses/10 HPF. In comparison, published concordance for gliomas in clinical trials have ranged from 8%-74%. CONCLUSION: Our data suggest that current meningioma classification and grading are at least as objective and reproducible as for gliomas. Nevertheless, reproducibility remains suboptimal. Further improvements may be anticipated with education and clarification of subjective criteria, although development of biomarkers may be the most promising strategy.

Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients.

BACKGROUND: Dexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration. METHODS: We reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m(2)). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV. RESULTS: With a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p <0.0001). DXM did not reduce OS in patients who received TMZ and BEV concurrently with RT (22.9 vs 22.8 months, p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045). CONCLUSIONS: Our results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered.

Heterogeneity correction for intensity-modulated frameless SRS in pituitary and cavernous sinus tumors: a retrospective study.

BACKGROUND: Frameless immobilization allows for planning and quality assurance of intensity-modulated radiosurgery (IM-SRS) plans. We tested the hypothesis that IM-SRS planning with uniform tissue density corrections results in dose inaccuracy compared to heterogeneity-corrected algorithms. METHODS: Fifteen patients with tumors of the pituitary or cavernous sinus underwent frameless IM-SRS. Treatment planning CT and MRI scans were obtained and fused to delineate the tumor, optic nerves, chiasm, and brainstem. The plan was developed with static gantry IM-SRS fields using a pencil beam (PB), analytical anisotropic (AAA), and Acuros XB (AXB) algorithms. We evaluated measures of target coverage as well as doses to organs at risk (OAR) for each algorithm. We compared the results of each algorithm in the cases where PTV overlapped OAR (n = 10) to cases without overlapping OAR with PTV (n = 5). Utilizing film dosimetry, we measured the dose distribution for each algorithm through a uniform density target to a rando phantom with non-uniform density of air, tissue, and bone. RESULTS: There was no difference in target coverage measured by DMaxPTV, DMinPTV, D95%PTV, or the isodose surface (IDS) covering 95% of the PTV regardless of algorithm. However, there were differences in dose to OAR. PB predicted higher (p < 0.05) Dmax for the brainstem, chiasm, right optic nerve, and left optic nerve. In cases of PTV overlapping an optic nerve (n = 7), PB was unable to limit dose to 8 Gy while achieving PTV coverage (PB 855 cGy vs. AAA 769 cGy, p = 0.05 vs. AXB 658 cGy, p = 0.03). Within the rando phantom, the PB and AAA algorithms over-estimated the dose delivered in the bone-tissue-air interface of the sinus (+17%), while the AXB algorithm closely predicted the actual dose delivered through the inhomogeneous tissue (+/- 1 % max, p < 0.05). CONCLUSIONS: Patients undergoing frameless SRS benefit from heterogeneity corrected dose plans when the lesion lies in areas of widely varying tissue density and near critical normal structures such as the skull base. Film dosimetry confirms that the AXB dose calculation algorithm more accurately predicts actual dose delivered though tissues of varying densities than PB or AAA dose calculation algorithms.

Quantifying isocenter measurements to establish clinically meaningful thresholds.

A dataset range of isocenter congruency verification tests have been examined from a statistical perspective for the purpose of establishing tolerance levels that are meaningful, based on the fundamental limitation of linear accelerator isocentricity and the demands of a high-precision stereotactic radiosurgery program. Using a laser-defined isocenter, a total of 149 individual isocenter congruency tests were examined with recorded values for ideal spatial corrections to the isocenter test tool. These spatial corrections were determined from radiation exposures recorded on an electronic portal imaging device (EPID) at various gantry, collimator, and treatment couch combinations. The limitations of establishing an ideal isocenter were quantified from each variable which contributed to uncertainty in isocenter definition. Individual contributors to uncertainty, specifically, daily positioning setup errors, gantry sag, multileaf collimator (MLC) offset, and couch walkout, were isolated from isocenter congruency measurements to determine a clinically meaningful isocenter measurement. Variations in positioning of the test tool constituted, on average, 0.38 mm magnitude of correction. Gantry sag and MLC offset contributed 0.4 and 0.16 mm, respectively. Couch walkout had an average degrading effect to isocenter of 0.72 mm. Considering the magnitude of uncertainty contributed by each uncertainty variable and the nature of their combination, an appropriate schedule action and immediate action level were determined for use in analyzing daily isocenter congruency test results in a stereotactic radiosurgery (SRS) program. The recommendations of this study for this linear accelerator include a schedule action level of 1.25 mm and an immediate action level of 1.50mm, requiring prompt correction response from clinical medical physicists before SRS or stereotactic body radiosurgery (SBRT) is administered. These absolute values were derived from considering relative data from a specific linear accelerator and, therefore, represent a means by which a numerical quantity can be used as a test threshold with relative specificity to a particular linear accelerator.

Guidelines for treatment naming in radiation oncology.

Safety concerns may arise from a lack of standardization and ambiguity during the treatment planning and delivery process in radiation therapy. A standardized target and organ-at-risk naming convention in radiation therapy was developed by a task force comprised of several Radiation Oncology Societies. We present a nested-survey approach in a community setting to determine the methodology for radiation oncology departments to standardize their practice. Our Institution's continuous quality improvement (CQI) committee recognized that, due to growth from one to three centers, significant variability existed within plan parameters specific to patients' treatment. A multidiscipline, multiclinical site consortium was established to create a guideline for standard naming. Input was gathered using anonymous, electronic surveys from physicians, physicists, dosimetrists, chief therapists, and nurse managers. Surveys consisted of several primary areas of interest: anatomical sites, course naming, treatment plan naming, and treatment field naming. Additional concepts included capitalization, specification of laterality, course naming in the event of multiple sites being treated within the same course of treatment, primary versus boost planning, the use of bolus, revisions for plans, image-guidance field naming, forbidden characters, and standard units for commonly used physical quantities in radiation oncology practice. Guidelines for standard treatment naming were developed that could be readily adopted. This multidisciplinary study provides a clear, straightforward, and easily implemented protocol for the radiotherapy treatment process. Standard nomenclature facilitates the safe means of communication between team members in radiation oncology. The guidelines presented in this work serve as a model for radiation oncology clinics to standardize their practices.

Targeted intraarterial anti-VEGF therapy for medically refractory radiation necrosis in the brain.

Radiation necrosis (RN) is a serious complication that can occur in up to 10% of brain radiotherapy cases, with the incidence dependent on both dose and brain location. Available medical treatment for RN includes steroids, vitamin E, pentoxifylline, and hyperbaric oxygen. In a significant number of patients, however, RN is medically refractory and the patients experience progressive neurological decline, disabling headaches, and decreased quality of life. Vascular endothelial growth factor (VEGF) is a known mediator of cerebral edema in RN. Recent reports have shown successful treatment of RN with intravenous bevacizumab, a monoclonal antibody for VEGF. Bevacizumab, however, is associated with significant systemic complications including sinus thrombosis, pulmonary embolus, gastrointestinal tract perforation, wound dehiscence, and severe hypertension. Using lower drug doses may decrease systemic exposure and reduce complication rates. By using an intraarterial route for drug administration following blood-brain barrier disruption (BBBD), the authors aim to lower the bevacizumab dose while increasing target delivery. In the present report, the authors present the cases of 2 pediatric patients with cerebral arteriovenous malformations, who presented with medically intractable RN following stereotactic radiosurgery. They received a single intraarterial infusion of 2.5 mg/kg bevacizumab after hyperosmotic BBBD. At mean follow-up duration of 8.5 months, the patients had significant and durable clinical and radiographic response. Both patients experienced resolution of their previously intractable headaches and reversal of cushingoid features as they were successfully weaned off steroids. One of the patients regained significant motor strength. There was an associated greater than 70% reduction in cerebral edema. Intraarterial administration of a single low dose of bevacizumab after BBBD was safe and resulted in durable clinical and radiographic improvements at concentrations well below those required for the typical systemic intravenous route. Advantages over the intravenous route may include higher concentration of drug delivery to the affected brain, decreased systemic toxicity, and a significantly lower cost.

Improvement of therapeutic index for brain tumors with daily image guidance.

BACKGROUND: Image-guidance maximizes the therapeutic index of brain irradiation by decreasing setup uncertainty. As dose-volume data emerge defining the tolerance of critical normal structures responsible for neuroendocrine function and neurocognition, minimizing clinical target volume (CTV) to planning target volume (PTV) expansion of targets near these structures potentially lessens long-term toxicity. METHODS: We reviewed the treatment records of 29 patients with brain tumors, with a total of 517 fractions analyzed. The CTV was uniformly expanded by 3 mm to create the PTV for all cases. We determined the effect of patient specific factors (prescribed medications, weight gain, tumor location) and image-guidance technique on setup uncertainty and plotted the mean +/- standard deviation for each factor. ANOVA was used to determine significance between these factors on setup uncertainty. We determined the impact of applying the initial three fraction variation as custom PTV-expansion on dose to normal structures. RESULTS: The initial 3 mm margin encompassed 88% of all measured shifts from daily imaging for all fractions. There was no difference (p = n.s.) in average setup uncertainty between CBCT or kV imaging for all patients. Vertical, lateral, longitudinal, and 3D shifts were similar (p = n.s.) between days 1, 2, and 3 imaging and later fractions. Patients prescribed sedatives experienced increased setup uncertainty (p < 0.05), while weight gain, corticosteroid administration, and anti-seizure medication did not associate with increased setup uncertainty. Patients with targets near OAR with individualized margins led to decreased OAR dose. No reductions to targets occurred with individualized PTVs. CONCLUSIONS: Daily imaging allows application of individualized CTV expansion to reduce dose to OAR responsible for neurocognition, learning, and neuroendocrine function below doses shown to correlate with long-term morbidity. The demonstrated reduction in dose to OAR in this study has implications for quality of life and provides the motivation to pursue custom PTV expansion.

The effect of radiation timing on patients with high-risk features of parameningeal rhabdomyosarcoma: an analysis of IRS-IV and D9803.

PURPOSE: Radiation therapy remains an essential treatment for patients with parameningeal rhabdomyosarcoma (PMRMS), and early radiation therapy may improve local control for patients with intracranial extension (ICE). METHODS AND MATERIALS: To address the role of radiation therapy timing in PMRMS in the current era, we reviewed the outcome from 2 recent clinical trials for intermediate-risk RMS: Intergroup Rhabdomyosarcoma Study (IRS)-IV and Children's Oncology Group (COG) D9803. The PMRMS patients on IRS-IV with any high-risk features (cranial nerve palsy [CNP], cranial base bony erosion [CBBE], or ICE) were treated immediately at day 0, and PMRMS patients without any of these 3 features received week 6-9 radiation therapy. The D9803 PMRMS patients with ICE received day 0 X-Ray Therapy (XRT) as well; however, those with either CNP or CBBE had XRT at week 12. RESULTS: Compared with the 198 PMRMS patients from IRS-IV, the 192 PMRMS patients from D9803 had no difference (P<.05) in 5-year local failure (19% vs 19%), failure-free-survival (70% vs 67%), or overall survival (75% vs 73%) in aggregate. The 5-year local failure rates by subset did not differ when patients were classified as having no risk features (None, 15% vs 19%, P=.25), cranial nerve palsy/cranial base of skull erosion (CNP/CBBE, 15% vs 28%, P=.22), or intracranial extension (ICE, 21% vs 15%, P=.27). The D9083 patients were more likely to have received initial staging by magnetic resonance imaging (71% vs 53%). CONCLUSIONS: These data support that a delay in radiation therapy for high-risk PMRMS features of CNP/CBBE does not compromise clinical outcomes.

Concurrent bevacizumab and temozolomide alter the patterns of failure in radiation treatment of glioblastoma multiforme.

BACKGROUND: We investigated the pattern of failure in glioblastoma multiforma (GBM) patients treated with concurrent radiation, bevacizumab (BEV), and temozolomide (TMZ). Previous studies demonstrated a predominantly in-field pattern of failure for GBM patients not treated with concurrent BEV. METHODS: We reviewed the treatment of 23 patients with GBM who received 30 fractions of simultaneous integrated boost IMRT. PTV60 received 2 Gy daily to the tumor bed or residual tumor while PTV54 received 1.8 Gy daily to the surrounding edema. Concurrent TMZ (75 mg/m^2) daily and BEV (10 mg/kg every 2 weeks) were given during radiation therapy. One month after RT completion, adjuvant TMZ (150 mg/m^2 × 5 days) and BEV were delivered monthly until progression or 12 months total. RESULTS: With a median follow-up of 12 months, the median disease-free and overall survival were not reached. Four patients discontinued therapy due to toxicity for the following reasons: bone marrow suppression (2), craniotomy wound infection (1), and pulmonary embolus (1). Five patients had grade 2 or 3 hypertension managed by oral medications. Of the 12 patients with tumor recurrence, 7 suffered distant failure with either subependymal (5/12; 41%) or deep white matter (2/12; 17%) spread detected on T2 FLAIR sequences. Five of 12 patients (41%) with a recurrence demonstrated evidence of GAD enhancement. The patterns of failure did not correlate with extent of resection or number of adjuvant cycles. CONCLUSIONS: Treatment of GBM patients with concurrent radiation, BEV, and TMZ was well tolerated in the current study. The majority of patients experienced an out-of-field pattern of failure with radiation, BEV, and TMZ which has not been previously reported. Further investigation is warranted to determine whether BEV alters the underlying tumor biology to improve survival. These data may indicate that the currently used clinical target volume thought to represent microscopic disease for radiation may not be appropriate in combination with TMZ and BEV.

Glycogen Synthase Kinase 3ß in Pancreatic Cancer and its Implications in Chemotherapy and Radiation Therapy.

Pancreatic cancer is a highly lethal disease with a poor prognosis characterized by local and systemic disease progression. Both radiation and chemotherapy play important roles in the management of this disease. However, in order to improve standard therapy many molecularly targeted agents are being developed. Glycogen synthase kinase 3ß (GSK3ß) participates in a multitude of cellular processes and is a newly proposed therapeutic target in pancreatic cancer. This review will discuss both the oncogenic and tumor suppressor functions of GSK3ß in pancreatic cancer with an emphasis on the roles of GSK3ß in tumor cell survival and sensitivity to radiation and chemotherapy.