K.J. Redmond

Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study

BACKGROUND Neurocognitive toxicity from radiation therapy (RT) for brain tumors may be related to damage to neural progenitor cells that reside in the subventricular zone and hippocampus. This prospective study examines the relationship between RT dose to neural progenitor cell niches, temporal lobes, and cerebrum and neurocognitive dysfunction following cranial irradiation. METHODS Standardized assessments of motor speed/dexterity, verbal memory, visual perception, vocabulary, and visuospatial working memory were conducted in 19 pediatric patients receiving cranial RT and 55 controls at baseline and 6, 15, and 27 months following completion of RT. Prescription doses ranged from 12 Gy to 59.4 Gy. Linear mixed effects regression model analyses were used to examine the relationships among neuropsychological performance, age, and radiation dose to the subventricular zone, hippocampus, temporal lobes, and cerebrum. RESULTS Performance on all neuropsychological tests, except vocabulary, was significantly reduced in patients relative to controls, particularly among younger children. Performance on motor speed/dexterity decreased with increasing dose to hippocampus (P < .05) and temporal lobes (P < .035). There was also a significant relationship between (i) reduced performance on verbal learning and increasing dose to the cerebrum (P = .022) and (ii) reduced performance on visual perception and increasing dose to the left temporal lobe (P = .038). There was no association between radiation dose to evaluated structures and performance on vocabulary or visuospatial working memory. CONCLUSIONS These prospective data demonstrate a significant association between increasing RT dose to hippocampus and temporal lobes and decline in neurocognitive skills following cranial irradiation. These findings have important implications for trials, including RTOG 0933 (hippocampal-sparing whole brain radiation therapy for brain metastases).

Increased Subventricular Zone Radiation Dose Correlates With Survival in Glioblastoma Patients After Gross Total Resection

PURPOSE Neural progenitor cells in the subventricular zone (SVZ) have a controversial role in glioblastoma multiforme (GBM) as potential tumor-initiating cells. The purpose of this study was to examine the relationship between radiation dose to the SVZ and survival in GBM patients. METHODS AND MATERIALS The study included 116 patients with primary GBM treated at the Johns Hopkins Hospital between 2006 and 2009. All patients underwent surgical resection followed by adjuvant radiation therapy with intensity modulated radiation therapy (60 Gy/30 fractions) and concomitant temozolomide. Ipsilateral, contralateral, and bilateral SVZs were contoured on treatment plans by use of coregistered magnetic resonance imaging and computed tomography. Multivariate Cox regression was used to examine the relationship between mean SVZ dose and progression-free survival (PFS), as well as overall survival (OS). Age, Karnofsky Performance Status score, and extent of resection were used as covariates. The median age was 58 years (range, 29-80 years). RESULTS Of the patients, 12% underwent biopsy, 53% had subtotal resection (STR), and 35% had gross total resection (GTR). The Karnofsky Performance Status score was less than 90 in 54 patients and was 90 or greater in 62 patients. The median ipsilateral, contralateral, and bilateral mean SVZ doses were 48.7 Gy, 34.4 Gy, and 41.5 Gy, respectively. Among patients who underwent GTR, a mean ipsilateral SVZ dose of 40 Gy or greater was associated with a significantly improved PFS compared with patients who received less than 40 Gy (15.1 months vs 10.3 months; P=.028; hazard ratio, 0.385 [95% confidence interval, 0.165-0.901]) but not in patients undergoing STR or biopsy. The subgroup of GTR patients who received an ipsilateral dose of 40 Gy or greater also had a significantly improved OS (17.5 months vs 15.6 months; P=.027; hazard ratio, 0.385 [95% confidence interval, 0.165-0.895]). No association was found between SVZ radiation dose and PFS and OS among patients who underwent STR or biopsy. CONCLUSION A mean radiation dose of 40 Gy or greater to the ipsilateral SVZ was associated with a significantly improved PFS and OS in patients with GBM after GTR.

Radiosurgery of Glomus Jugulare Tumors: A Meta-analysis

PURPOSE During the past two decades, radiosurgery has arisen as a promising approach to the management of glomus jugulare. In the present study, we report on a systematic review and meta-analysis of the available published data on the radiosurgical management of glomus jugulare tumors. METHODS AND MATERIALS To identify eligible studies, systematic searches of all glomus jugulare tumors treated with radiosurgery were conducted in major scientific publication databases. The data search yielded 19 studies, which were included in the meta-analysis. The data from 335 glomus jugulare patients were extracted. The fixed effects pooled proportions were calculated from the data when Cochranes statistic was statistically insignificant and the inconsistency among studies was <25%. Bias was assessed using the Egger funnel plot test. RESULTS Across all studies, 97% of patients achieved tumor control, and 95% of patients achieved clinical control. Eight studies reported a mean or median follow-up time of >36 months. In these studies, 95% of patients achieved clinical control and 96% achieved tumor control. The gamma knife, linear accelerator, and CyberKnife technologies all exhibited high rates of tumor and clinical control. CONCLUSIONS The present study reports the results of a meta-analysis for the radiosurgical management of glomus jugulare. Because of its high effectiveness, we suggest considering radiosurgery for the primary management of glomus jugulare tumors.

Localized CT-Guided Irradiation Inhibits Neurogenesis in Specific Regions of the Adult Mouse Brain

Abstract Radiation is used in the study of neurogenesis in the adult mouse both as a model for patients undergoing radiation therapy for CNS malignancies and as a tool to interrupt neurogenesis. We describe the use of a dedicated CT-guided precision device to irradiate specific sub-regions of the adult mouse brain. Improved CT visualization was accomplished with intrathecal injection of iodinated contrast agent, which enhances the lateral ventricles. T2-weighted MRI images were also used for target localization. Visualization of delivered beams (10 Gy) in tissue was accomplished with immunohistochemical staining for the protein γ-H2AX, a marker of DNA double-strand breaks. γ-H2AX stains showed that the lateral ventricle wall could be targeted with an accuracy of 0.19 mm (n  =  10). In the hippocampus, γ-H2AX staining showed that the dentate gyrus can be irradiated unilaterally with a localized arc treatment. This resulted in a significant decrease of proliferative neural progenitor cells as measured by Ki-67 staining (P < 0.001) while leaving the contralateral side intact. Two months after localized irradiation, neurogenesis was significantly inhibited in the irradiated region as seen with EdU/NeuN double labeling (P < 0.001). Localized radiation in the rodent brain is a promising new tool for the study of neurogenesis.

Glioblastoma recurrence patterns near neural stem cell regions

PURPOSE Glioblastoma (GBM) cancer stem cells and their neural stem cell counterparts are hypothesized to contribute to tumor progression. We examined whether GBM contrast enhancement contact with neurogenic regions (NR) affect recurrence patterns, as contrast enhancement reflects regions of blood-brain barrier breakdown. METHODS 102 patients with primary GBM, treated at Johns Hopkins Hospital between 2006 and 2009, were included. All patients underwent surgical resection followed by adjuvant IMRT (60 Gy/30 fractions) and concomitant temozolomide. Initial and recurrent tumor distance from the subventricular zone (SVZ) or subgranular zone (SGZ) was measured. Tumors were categorized as NR contacting or non-contacting. The chi-square test was used to analyze the association between tumor contact and recurrence pattern. RESULTS 49 of 102 (48.0%, 95% CI: 0.386-0.576) tumors contacted NRs at initial presentation, and, of these tumors, 49/49 (100%) contacted NRs at recurrence. Of 53 tumors that were initially non-contacting, 37/53 (69.8%, 95% CI: 0.565-0.804) recurred contacting NRs. In total, 86/102 (84.3%, 95% CI: 0.760-0.901) recurrent GBM contacted NRs compared with 49/102 (48%, 95% CI: 0.386-0.576) at initial presentation. Of the recurrent tumors that did not contact NRs, 16/53 (30.1%, 95% CI: 0.195-0.435) recurred medially toward NRs with a significant decrease in distance between tumor contrast enhancement and NRs. 16/49 (32.6%, 95% CI: 0.212-0.466) initially NR-contacting GBMs recurred out-of field while 7/53 (13.2%, 95% CI: 0.0655-0.248) initially non-contacting recurred out of the radiation treatment field (p=0.0315, Odds ratio: 3.19, 95% CI: 1.18-8.62). CONCLUSIONS GBM contrast-enhancing recurrence is significantly associated with proximity to NRs. NR-contacting initial tumors were more likely to recur out of radiation treatment fields.

Consensus guidelines for postoperative stereotactic body radiation therapy for spinal metastases: results of an international survey.

OBJECTIVE Although postoperative stereotactic body radiation therapy (SBRT) for spinal metastases is increasingly performed, few guidelines exist for this application. The purpose of this study is to develop consensus guidelines to promote safe and effective treatment for patients with spinal metastases. METHODS Fifteen radiation oncologists and 5 neurosurgeons, representing 19 centers in 4 countries and having a collective experience of more than 1300 postoperative spine SBRT cases, completed a 19-question survey about postoperative spine SBRT practice. Responses were defined as follows: 1) consensus: selected by ≥ 75% of respondents; 2) predominant: selected by 50% of respondents or more; and 3) controversial: no single response selected by a majority of respondents. RESULTS Consensus treatment indications included: radioresistant primary, 1-2 levels of adjacent disease, and previous radiation therapy. Contraindications included: involvement of more than 3 contiguous vertebral bodies, ASIA Grade A status (complete spinal cord injury without preservation of motor or sensory function), and postoperative Bilsky Grade 3 residual (cord compression without any CSF around the cord). For treatment planning, co-registration of the preoperative MRI and postoperative T1-weighted MRI (with or without gadolinium) and delineation of the cord on the T2-weighted MRI (and/or CT myelogram in cases of significant hardware artifact) were predominant. Consensus GTV (gross tumor volume) was the postoperative residual tumor based on MRI. Predominant CTV (clinical tumor volume) practice was to include the postoperative bed defined as the entire extent of preoperative tumor, the relevant anatomical compartment and any residual disease. Consensus was achieved with respect to not including the surgical hardware and incision in the CTV. PTV (planning tumor volume) expansion was controversial, ranging from 0 to 2 mm. The spinal cord avoidance structure was predominantly the true cord. Circumferential treatment of the epidural space and margin for paraspinal extension was controversial. Prescription doses and spinal cord tolerances based on clinical scenario, neurological compromise, and prior overlapping treatments were controversial, but reasonable ranges are presented. Fifty percent of those surveyed practiced an integrated boost to areas of residual tumor and density override for hardware within the beam path. Acceptable PTV coverage was controversial, but consensus was achieved with respect to compromising coverage to meet cord constraint and fractionation to improve coverage while meeting cord constraint. CONCLUSIONS The consensus by spinal radiosurgery experts suggests that postoperative SBRT is indicated for radioresistant primary lesions, disease confined to 1-2 vertebral levels, and/or prior overlapping radiotherapy. The GTV is the postoperative residual tumor, and the CTV is the postoperative bed defined as the entire extent of preoperative tumor and anatomical compartment plus residual disease. Hardware and scar do not need to be included in CTV. While predominant agreement was reached about treatment planning and definition of organs at risk, future investigation will be critical in better understanding areas of controversy, including whether circumferential treatment of the epidural space is necessary, management of paraspinal extension, and the optimal dose fractionation schedules.

Postoperative Stereotactic Body Radiation Therapy (SBRT) for Spine Metastases: A Critical Review to Guide Practice

Postoperative stereotactic body radiation therapy (SBRT) for metastatic spinal tumors is increasingly being performed in clinical practice. Whereas the fundamentals of SBRT practice for intact spinal metastases are established, there are as yet no comprehensive practice guidelines for the postoperative indications. In particular, there are unique considerations for patient selection and treatment planning specific to postoperative spine SBRT that are critical for safe and effective management. The purpose of this critical review is to discuss the rationale for treatment, describe those factors affecting surgical decision making, introduce modern surgical trends, and summarize treatment outcomes for both conventional postoperative external beam radiation therapy and postoperative spine SBRT. Lastly, an in-depth practical discussion with respect to treatment planning and delivery considerations is provided to help guide optimal practice.

Prognostic factors associated with pain palliation after spine stereotactic body radiation therapy

OBJECT The number of patients with spinal tumors is rapidly increasing; spinal metastases develop in more than 30% of cancer patients during the course of their illness. Such lesions can significantly decrease quality of life, often necessitating treatment. Stereotactic radiosurgery has effectively achieved local control and symptomatic relief for these patients. The authors determined prognostic factors that predicted pain palliation and report overall institutional outcomes after spine stereotactic body radiation therapy (SBRT). METHODS Records of patients who had undergone treatment with SBRT for either primary spinal tumors or spinal metastases from June 2008 through June 2013 were retrospectively reviewed. Data were collected at the initial visit just before treatment and at 1-, 3-, 6-, and 12-month follow-up visits. Collected clinical data included Karnofsky Performance Scale scores, pain status, presence of neurological deficits, and prior radiation exposure at the level of interest. Radiation treatment plan parameters (dose, fractionation, and target coverage) were recorded. To determine the initial extent of epidural spinal cord compression (ESCC), the authors retrospectively reviewed MR images, assessed spinal instability according to the Bilsky scale, and evaluated lesion progression after treatment. RESULTS The study included 99 patients (mean age 60.4 years). The median survival time was 9.1 months (95% CI 6.9-17.2 months). Significant decreases in the proportion of patients reporting pain were observed at 3 months (p < 0.0001), 6 months (p = 0.0002), and 12 months (p = 0.0019) after treatment. Significant decreases in the number of patients reporting pain were also observed at the last follow-up visit (p = 0.00020) (median follow-up time 6.1 months, range 1.0-56.6 months). Univariate analyses revealed that significant predictors of persistent pain after intervention were initial ESCC grade, stratified by a Bilsky grade of 1c (p = 0.0058); initial American Spinal Injury Association grade of D (p = 0.011); initial Karnofsky Performance Scale score, stratified by a score of 80 (p = 0.002); the presence of multiple treated lesions (p = 0.044); and prior radiation at the site of interest (p < 0.0001). However, when multivariate analyses were performed on all variables with p values less than 0.05, the only predictor of pain at last follow-up visit was a prior history of radiation at the site of interest (p = 0.0038), although initial ESCC grade trended toward significance (p = 0.073). Using pain outcomes at 3 months, at this follow-up time point, pain could be predicted by receipt of radiation above a threshold biologically effective dose of 66.7 Gy. CONCLUSIONS Pain palliation occurs as early as 3 months after treatment; significant differences in pain reporting are also observed at 6 and 12 months. Pain palliation is limited for patients with spinal tumors with epidural extension that deforms the cord and for patients who have previously received radiation to the same site. Further investigation into the optimal dose and fractionation schedule are needed, but improved outcomes were observed in patients who received radiation at a biologically effective dose (with an a/b of 3.0) of 66.7 Gy or higher.

A multi-national report on stereotactic body radiotherapy for oligometastases: Patient selection and follow-up*

Abstract Aims Stereotactic body radiotherapy (SBRT) for oligometastases is increasingly used with few evidenced-based guidelines. We conducted a survey to determine patient selection and follow-up practice patterns. Materials and methods Seven institutions from US, Canada, Europe, and Australia that recommend SBRT for oligometastases participated in a 72-item survey. Levels of agreement were categorized as strong (6–7 common responses), moderate (4–5), low (2–3), or no agreement. Results There was strong agreement for recommending SBRT for eradication of all detectable oligometastases with most members limiting the number of metastases to five (range 2–5) and three within a single organ (range 2–5). There was moderate agreement for recommending SBRT as consolidative therapy after systemic therapy. There was strong agreement for requiring adequate performance status and no concurrent chemotherapy. Additional areas of strong agreement included staging evaluations, primary diagnosis, target sites, and follow-up recommendations. Several differences emerged, including the use of SBRT for sarcoma oligometastases, treatment response evaluation, and which imaging should be performed during follow-up. Conclusion Significant commonalities and variations exist for patient selection and follow-up recommendations for SBRT for oligometastases. Information from this survey may serve to help clarify the current landscape.

New Considerations in Radiation Treatment Planning for Brain Tumors: Neural Progenitor Cell–Containing Niches

The purpose of this critical review is to explore the controversy regarding the relationship between radiation dose to the neural progenitor cell (NPC) niches and patient outcomes, in terms of both toxicity and tumor control. NPCs in the subventricular zone (SVZ) and hippocampus are paradoxically associated with long-term neurocognitive sequelae of brain irradiation, as well as resistance to therapy and tumor recurrence. The reconciliation of these somewhat opposing functions is challenging. Current literature suggests that radiation and other treatments against the NPC in the hippocampus and the SVZ may influence patient outcome. As a result, both the SVZ and the hippocampus could have important implications on radiation treatment planning strategies, and future laboratory and clinical evaluations will be critical in designing studies to optimize treatment outcome, effectiveness, and safety.