Publications by authors named "Igor Barani"

74 Publications

Small-field beam data acquisition, detector dependency, and film-based validation for a novel self-shielded stereotactic radiosurgery system.

Med Phys 2021 Jul 14. Epub 2021 Jul 14.

Department of Radiation Oncology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.

Purpose: This study reports a single-institution experience with beam data acquisition and film-based validation for a novel self-shielded sterotactic radiosurgery unit and investigates detector dependency on field output factors (OFs), off-axis ratios (OARs), and percent depth dose (PDD) measurements within the context of small-field dosimetry.

Methods: The delivery platform for this unit consists of a 2.7-MV S-band linear accelerator mounted on coupled gimbals that rotate around a common isocenter (source-to-axis distance [SAD] = 450 mm), allowing for more than 260 noncoplanar beam angles. Beam collimation is achieved via a tungsten collimator wheel with eight circular apertures ranging from 4 mm to 25 mm in diameter. Three diodes (PTW 60012 Diode E, PTW 60018 SRS Diode, and Sun Nuclear EDGE) and a synthetic diamond detector (PTW 60019 micro Diamond [µD] detector) were used for OAR, PDD, and OF measurements. OFs were also acquired with a PTW 31022 PinPoint ionization chamber. Beam scanning was performed using a 3D water tank at depths of 7, 50, 100, 200, and 250 mm with a source-to-surface distance of 450 mm. OFs were measured at the depth of maximum dose (d  = 7 mm) with the SAD at 450 mm. Gafchromic EBT3 film was used to validate OF and profile measurements and as a reference detector for estimating correction factors for active detector OFs. Deviations in field size, penumbra, and PDDs across the different detectors were quantified.

Results: Relative OFs (ROFs) for the diodes were within 1.4% for all collimators except for 5 and 7.5 mm, for which SRS Diode measurements were higher by 1.6% and 2.6% versus Diode E. The µD ROFs were within 1.4% of the diode measurements. PinPoint ROFs were lower by >10% for the 4-mm and 5-mm collimators versus the Diode E and µD. Corrections to OFs using EBT3 film as a reference were within 1.2% for all diodes and the µD detector for collimators 10 mm and greater and within 2.0%, 2.8%, and 1.1% for the 7.5-, 5-, and 4-mm collimators, respectively. The maximum difference in full width at half maximum (FWHM) between the Diode E and the other active detectors was for the 25-mm collimator and was 0.09 mm (µD), 0.16 mm (SRS Diode), and 0.65 mm (EDGE). Differences seen in PDDs beyond the depth of d were <1% across the three diodes and the µD. FWHM and penumbra measurements made using EBT3 film were within 1.34% and 3.26%, respectively, of the processed profile data entered into the treatment planning system.

Conclusions: Minimal differences were seen in OAR and PDD measurements acquired with the diodes and the µD. ROFs measured with the three diodes were within 2.6% and within 1.4% versus the µD. Gafchromic Film measurements provided independent verification of the OAR and OF measurements. Estimated corrections to OFs using film as a reference were <1.6% for the Diode E, EDGE, and µD detector.
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http://dx.doi.org/10.1002/mp.15091DOI Listing
July 2021

Treatment planning system and beam data validation for the ZAP-X: A novel self-shielded stereotactic radiosurgery system.

Med Phys 2021 May 1;48(5):2494-2510. Epub 2021 Apr 1.

Department of Radiation Oncology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.

Purpose: To evaluate the treatment planning system (TPS) performance of the ZAP-X stereotactic radiosurgery (SRS) system through nondosimetric, dosimetric, and end-to-end (E2E) tests.

Methods: A comprehensive set of TPS commissioning and validation tests was developed using published guidelines. Nondosimetric validation tests included information transfer, computed tomography-magnetic resonance (CT-MR) image registration, structure/contouring, geometry, dose tools, and CT density. Dosimetric validation included comparisons between TPS and water tank/Solid Water measurements for various geometries and beam arrangements and end-to-end (E2E) tests. Patient-specific quality assurance was performed with an ion chamber in the Lucy phantom and with Gafchromic EBT3 film in the CyberKnife head phantom. RadCalc was used for independent verification of monitor units. Additional E2E tests were performed using the RPC Gamma Knife thermoluminescent dosimeter (TLD) phantom, MD Anderson SRS head phantom, and PseudoPatient gel phantom for independent absolute dose verification.

Results: CT-MR image registrations with known translational and rotational offsets were within tolerance (<0.5 × maximum voxel dimension). Slice thickness and distance accuracy were within 0.1 mm, and volume accuracy was within 0 to 0.11 cm . Treatment planning system volume measurement uncertainty was within 0.1 to 0.4 cm . Ion chamber point-dose measurements for a single beam in a water phantom agreed to TPS-calculated values within ±4% for collimator diameters 10 to 25 mm, and ±6% for 7.5 mm, for all measured depths (7, 50, 100, 150, and 200 mm). In homogeneous Solid Water, point-dose measurements agreed to within ±4% for cones sizes 7.5 to 25 mm. With 1-cm high/low density inserts, measurements were within ±4.2% for cone sizes 10 to 25 mm. Film-based E2E using 4/5-mm cones resulted in a gamma passing rate (%GP) of 99.8% (2%/1.5 mm). Point-dose measurements in a Lucy phantom with an ion chamber using 36 beams distributed along three noncoplanar arcs agreed to within ±4% for cone sizes 10 to 25 mm. The RPC Gamma Knife TLD phantom yielded passing results with a measured-to-expected TLD dose ratio of 1.02. The MD Anderson SRS head phantom yielded passing results, with 4% TLD agreement and %GP of 95%/93% (5%/3 mm) for coronal/sagittal film planes. The RTsafe gel phantom gave %GP of >95% (5%/2 mm) for all four targets. For our first 58 patients, film-based patient-specific quality assurance has resulted in an average %GP of 98.7% (range, 94-100%) at 2%/2 mm.

Conclusions: Core ZAP-X features were found to be functional. On the basis of our results, point-dose and planar measurements were in agreement with TPS calculations using multiple phantoms and setup geometries, validating the ZAP-X TPS beam model for clinical use.
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http://dx.doi.org/10.1002/mp.14740DOI Listing
May 2021

Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424.

Int J Radiat Oncol Biol Phys 2020 07 3;107(4):720-725. Epub 2020 Apr 3.

Miami Cancer Institute, Kendall, Florida.

Purpose: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT).

Methods And Materials: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015.

Results: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively.

Conclusions: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456814PMC
July 2020

Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma.

Int J Radiat Oncol Biol Phys 2017 11 30;99(4):797-804. Epub 2017 Jun 30.

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York. Electronic address:

Purpose: To establish the maximum tolerated dose of a 3-fraction hypofractionated stereotactic reirradiation schedule when delivered with concomitant bevacizumab to treat recurrent high-grade gliomas.

Methods And Materials: Patients with recurrent high-grade glioma with Karnofsky performance status ≥60, history of standard fractionated initial radiation, tumor volume at recurrence ≤40 cm, and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 phase 1 dose escalation trial design was utilized, with dose-limiting toxicities defined as any grade 3 to 5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10 mg/kg every 2 weeks. Hypofractionated stereotactic reirradiation was initiated after 2 bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy per fraction.

Results: A total of 3 patients were enrolled at the 9 Gy × 3 dose level cohort, 5 in the 10 Gy × 3 cohort, and 7 in the 11 Gy × 3 cohort. One dose-limiting toxicity of grade 3 fatigue and cognitive deterioration possibly related to hypofractionated stereotactic reirradiation was observed in the 11 Gy × 3 cohort, and this dose was declared the maximum tolerated dose in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival was 13 months.

Conclusions: Reirradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11 Gy × 3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison with our previous 6 Gy × 5 schedule. Promising overall survival warrants further investigation.
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http://dx.doi.org/10.1016/j.ijrobp.2017.06.2466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654655PMC
November 2017

Surgery After Primary Radiation Treatment for Sporadic Vestibular Schwannomas: Case Series.

Oper Neurosurg (Hagerstown) 2017 08;13(4):441-447

Department of Neurosurgery, University of California San Francisco, San Franci-sco, California.

Background: As radiation has become an increasingly popular primary treatment option for sporadic vestibular schwannomas, there is a minority of tumors that do not respond favorably to radiation. Data on repeat radiosurgery are emerging, and salvage surgery has been associated with increased technical difficulty and poor facial nerve outcomes.

Objective: To review the current literature and report our results with surgical resection of sporadic vestibular schwannomas that have failed primary radiation treatment.

Methods: This is a retrospective, single-surgeon case series of patients with sporadic vestibular schwannomas who failed primary radiation treatment and underwent subsequent surgical resection. We analyze demographics, clinical information, and intraoperative findings, focusing on facial nerve functional outcomes and extent of resection.

Results: Between 2006 and 2015, 10 patients with sporadic vestibular schwannomas whose only prior treatment was radiation underwent microsurgical resection. Eight of 10 patients had a postoperative House-Brackmann score of 1 at a median follow-up of 14 months, while 2 patients had House-Brackmann score of 4. Gross total resection was achieved in 7 of 10 cases. Near total resection was achieved in 2 cases, and only subtotal resection was achieved in 1 case.

Conclusion: Salvage surgery is a safe and effective option after failure of primary radiation and may offer benefits over repeat radiosurgery.
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http://dx.doi.org/10.1093/ons/opx023DOI Listing
August 2017

Management of Chordoma and Chondrosarcoma with Fractionated Stereotactic Radiotherapy.

Front Surg 2017 23;4:35. Epub 2017 Jun 23.

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, United States.

Objective: To evaluate the efficacy and toxicity of fractionated stereotactic radiotherapy (FSRT) for chordoma and chondrosarcoma.

Methods: Twenty consecutive patients with a histopathologic diagnosis of chordoma ( = 16) or chondrosarcoma ( = 4) treated between 2010 and 2016 were retrospectively identified. All patients underwent FSRT in five fractions to a median dose of 37.5 Gy (range: 25-40 Gy) and followed with serial magnetic resonance imaging. Overall survival (OS), local recurrence-free survival (LRFS), and event-free survival (EFS) were estimated using the Kaplan-Meier method.

Results: With a median follow-up of 28 months after FSRT and 40 months after initial surgery, crude OS and LRFS were 90%. Nine patients (45%) reported grade 1-3 acute toxicity, and two patients (10%) experienced grade 4, 5 late toxicity. One patient previously treated with proton therapy died from radiation vasculopathy 9 months after FSRT. The use of FSRT for recurrent disease or in patients with prior radiation therapy was associated with significantly decreased EFS.

Conclusion: FSRT for chordoma and chondrosarcoma is associated with high rates of OS and local control. Although many patients experience acute toxicity, there is a low incidence of late toxicity or irreversible treatment related morbidity despite the frequency of prior radiotherapy in this population. FSRT is an effective adjuvant or salvage treatment for chordoma and chondrosarcoma.
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http://dx.doi.org/10.3389/fsurg.2017.00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481320PMC
June 2017

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

J Neurosurg Spine 2017 Mar 11;26(3):299-306. Epub 2016 Nov 11.

Department of Radiation Oncology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.3171/2016.8.SPINE16121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551391PMC
March 2017

Expression and prognostic impact of immune modulatory molecule PD-L1 in meningioma.

J Neurooncol 2016 12 13;130(3):543-552. Epub 2016 Sep 13.

Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Ave, M-779, San Francisco, CA, 94143, USA.

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68-, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68- expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68- was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.
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http://dx.doi.org/10.1007/s11060-016-2256-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560602PMC
December 2016

Indications and Efficacy of Gamma Knife Stereotactic Radiosurgery for Recurrent Glioblastoma: 2 Decades of Institutional Experience.

Neurosurgery 2017 Jan;80(1):129-139

Department of Neurological Surgery and.

Background: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear.

Objective: To perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma.

Methods: We retrospectively analyzed patients who underwent Gamma Knife SRS between 1991 and 2013. We used the partitioning deletion/substitution/addition algorithm to identify potential predictor covariate cut points and Kaplan-Meier and proportional hazards modeling to identify factors associated with post-SRS and postdiagnosis survival.

Results: One hundred seventy-four glioblastoma patients (median age, 54.1 years) underwent SRS a median of 8.7 months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0 cm 3 (range, 0.3-39.0 cm 3 ) and 16.0 Gy (range, 10-22 Gy), respectively. Median overall survival was 10.6 months after SRS and 19.1 months after diagnosis. Kaplan-Meier and multivariable modeling revealed that younger age at SRS, higher prescription dose, and longer interval between original surgery and SRS are significantly associated with improved post-SRS survival. Forty-six patients (26%) underwent salvage craniotomy after SRS, with 63% showing radionecrosis or mixed tumor/necrosis vs 35% showing purely recurrent tumor. The necrosis/mixed group had lower mean isodose prescription compared with the tumor group (16.2 vs 17.8 Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4 cm 3 ; P = .009).

Conclusion: Gamma Knife may benefit a subset of focally recurrent patients, particularly those who are younger with smaller recurrences. Higher prescriptions are associated with improved post-SRS survival and do not seem to have greater risk of symptomatic treatment effect.
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http://dx.doi.org/10.1227/NEU.0000000000001344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5235998PMC
January 2017

Estimating the probability of underdosing microscopic brain metastases with hippocampal-sparing whole-brain radiation.

Radiother Oncol 2016 08 9;120(2):248-52. Epub 2016 Jul 9.

Department of Radiation Oncology, University of California, San Francisco, United States.

Purpose/objectives: Whole-brain radiation for brain metastases can result in cognitive side effects. Hippocampal-sparing techniques have been developed to decrease morbidity, but they carry the risk of underdosing lesions near the hippocampus due to the unavoidable dose gradient from the hippocampal surface to the prescription isodose surface. This study examines the impact of variable levels of hippocampal sparing on the underdosing of potential brain metastases.

Materials/methods: Helical intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were developed for hippocampal-sparing whole-brain treatment. For all plans, 30Gy was prescribed in 10 fractions to result in mean hippocampal doses of 6-12Gy. From a series of expanded shells, we determined the distance from the hippocampus at which the parenchyma would receive less than specified doses. Then, using published data, a mathematical model was constructed to predict the incident probability of potential brain metastases receiving different doses for different levels of hippocampal sparing.

Results: Whole-brain radiation plans were able to spare the hippocampi to mean doses of 7-12Gy under our planning constraints; more stringent constraints compromised brain coverage. The dose gradients were ∼4% per mm, regardless of the hippocampal constraint, and they decreased sharply by a factor of almost 4 at approximately 15mm from the hippocampi. A mathematical model was constructed and combined the plan information with published data on the distribution of brain metastases, to determine the percentage of potential brain metastases receiving specified doses, as a function of technique and level of hippocampal sparing.

Conclusions: Our results describe the characteristics of an array of hippocampal-sparing whole-brain radiation dose distributions. These can be used as a decision-making guideline for weighing the benefit of decreased dose to the hippocampi against the cost of decreased dose to potential brain metastases when deciding on a hippocampal-sparing whole-brain irradiation treatment approach.
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http://dx.doi.org/10.1016/j.radonc.2016.05.030DOI Listing
August 2016

Discovery of additional brain metastases on the day of stereotactic radiosurgery: risk factors and outcomes.

J Neurosurg 2017 Jun 1;126(6):1756-1763. Epub 2016 Jul 1.

Departments of 1 Radiation Oncology.

OBJECTIVE High-resolution double-dose gadolinium-enhanced Gamma Knife (GK) radiosurgery-planning MRI (GK MRI) on the day of GK treatment can detect additional brain metastases undiagnosed on the prior diagnostic MRI scan (dMRI), revealing increased intracranial disease burden on the day of radiosurgery, and potentially necessitating a reevaluation of appropriate management. The authors identified factors associated with detecting additional metastases on GK MRI and investigated the relationship between detection of additional metastases and postradiosurgery patient outcomes. METHODS The authors identified 326 patients who received GK radiosurgery at their institution from 2010 through 2013 and had a prior dMRI available for comparison of numbers of brain metastases. Factors predictive of additional brain metastases on GK MRI were investigated using logistic regression analysis. Overall survival was estimated by Kaplan-Meier method, and postradiosurgery distant intracranial failure was estimated by cumulative incidence measures. Multivariable Cox proportional hazards model and Fine-Gray regression modeling assessed potential risk factors of overall survival and distant intracranial failure, respectively. RESULTS The mean numbers of brain metastases (SD) on dMRI and GK MRI were 3.4 (4.2) and 5.8 (7.7), respectively, and additional brain metastases were found on GK MRI in 48.9% of patients. Frequencies of detecting additional metastases for patients with 1, 2, 3-4, and more than 4 brain metastases on dMRI were 29.5%, 47.9%, 55.9%, and 79.4%, respectively (p < 0.001). An index brain metastasis with a diameter greater than 1 cm on dMRI was inversely associated with detecting additional brain metastases, with an adjusted odds ratio of 0.57 (95% CI 0.4-0.9, p = 0.02). The median time between dMRI and GK MRI was 22 days (range 1-88 days), and time between scans was not associated with detecting additional metastases. Patients with additional brain metastases did not have larger total radiosurgery target volumes, and they rarely had an immediate change in management (abortion of radiosurgery or addition of whole-brain radiation therapy) due to detection of additional metastases. Patients with additional metastases had a higher incidence of distant intracranial failure than those without additional metastases (p = 0.004), with an adjusted subdistribution hazard ratio of 1.4 (95% CI 1.0-2.0, p = 0.04). Significantly worse overall survival was not detected for patients with additional brain metastases on GK MRI (log-rank p = 0.07), with the relative adjusted hazard ratio of 1.07, (95% CI 0.81-1.41, p = 0.65). CONCLUSIONS Detecting additional brain metastases on GK MRI is strongly associated with the number of brain metastases on dMRI and inversely associated with the size of the index brain metastasis. The discovery of additional brain metastases at time of GK radiosurgery is very unlikely to lead to aborting radiosurgery but is associated with a higher incidence of distant intracranial failure. However, there is not a significant difference in survival. ▪ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class IV.
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http://dx.doi.org/10.3171/2016.4.JNS152319DOI Listing
June 2017

New Clinical and Research Programs in Particle Beam Radiation Therapy: The University of California San Francisco Perspective.

Int J Part Ther 2016 ;2(3):471-473

Department of Radiation Oncology, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

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http://dx.doi.org/10.14338/IJPT-15-00025.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834449PMC
January 2016

Assessment of image quality and dose calculation accuracy on kV CBCT, MV CBCT, and MV CT images for urgent palliative radiotherapy treatments.

J Appl Clin Med Phys 2016 03 8;17(2):279-290. Epub 2016 Mar 8.

University of California San Francisco.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clin-ics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences > 5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥ 95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study.
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http://dx.doi.org/10.1120/jacmp.v17i2.6040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874969PMC
March 2016

Complications from radiotherapy.

Handb Clin Neurol 2016 ;134:219-34

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.

Radiotherapy (RT) of the brain is associated with significant stigma in the neuro-oncology community. This is primarily because of the potentially severe complications with which it may be associated. These complications, especially in subacute and latent settings, are often unpredictable, potentially progressive, and irreversible. The onset of complications may start from the first fraction of 2 Gy, continuing over several months after end of RT with persistent drowsiness and apathy. It may also extend over many years with progressive onset of neurocognitive impairments such as memory decline, and diminished focus/attention. For long-term survivors, such as young patients irradiated for a favorable low-grade glioma, quality of life can be seriously impacted by RT. It is essential, as in the pediatric field, to propose patient-specific regimens from the very outset of therapy. The use of molecular biomarkers to better predict survival, control of comorbidities along with judicious use of medications such as steroids and antiepileptics, improved targeting with the help of modern imaging and RT techniques, modulation of the dose, and fractionation aimed at limiting integral dose to the healthy brain all have the potential to minimize treatment-related complications while maintaining the therapeutic efficacy for which RT is known. Sparing "radiosensitive" areas such as hippocampi could have a modest but measurable impact with regard to cognitive preservation, an effect that can possibly be enhanced when used in conjunction with memantine and/or donepezil.
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http://dx.doi.org/10.1016/B978-0-12-802997-8.00013-XDOI Listing
December 2016

Meningiomas With Rhabdoid Features Lacking Other Histologic Features of Malignancy: A Study of 44 Cases and Review of the Literature.

J Neuropathol Exp Neurol 2016 Jan 7;75(1):44-52. Epub 2015 Dec 7.

From the Department of Anatomic Pathology (RAV, CG), Mayo Clinic, Rochester Minnesota; Department of Neurosurgery (SGC), Mayo Clinic, Jacksonville, Florida; Department of Radiation Oncology (DRR, IB), University of California, San Francisco, California; Department of Neurosurgery (MJL), Mayo Clinic, Rochester Minnesota; Department of Neurologic Surgery (MRC), Washington University, St. Louis, Missouri; Departments of Biomedical Statistics and Informatics (SMJ), Mayo Clinic, Rochester Minnesota, Departments of Biochemistry and Molecular Biology (PAA), Mayo Clinic, Rochester Minnesota; Department of Pathology (FJR, PCB), Johns Hopkins University, Baltimore, Maryland; Departments of Pathology and Immunology/Anatomic and Molecular Pathology (SD), Washington University, St. Louis, Missouri; Department of Pathology (AP), University of California, San Francisco, California.

The behavior of rhabdoid meningiomas otherwise lacking malignant features remains unknown as most of the originally reported aggressive cases showed anaplastic histologic features independently of rhabdoid phenotype. We studied 44 patients with rhabdoid meningiomas lacking anaplastic features. Median age at diagnosis was 48.6 years (range 10-79). Location was supratentorial in 28 (63.6%), skull base in 15 (34.1%), and spinal in 1 (2.3%). Tumor grade was otherwise World Health Organization grade I (n = 22, 50%) or II (n = 22, 50%). Rhabdoid cells represented <20% of the tumor in 12 cases (27.3%), 20% to 50% in 18 (40.9%), and >50% in 14 (31.8%). Median clinical follow-up, available for 38 patients, was 5.0 years (range 0.17-14.2). Recurrence occurred in 9 patients (5-year recurrence-free survival, 73.7%) with a significantly higher risk in subtotally resected tumors (p = 0.043). Rhabdoid cell percentage was not associated with recurrence. Six patients died (4 of disease, 2 of unclear causes); 5-year overall survival was 86.7%, a mortality in excess of that expected in grade I-II meningiomas but much lower than originally reported. Review of 50 similar previously reported cases confirmed our findings. We suggest that rhabdoid meningiomas be graded analogously to nonrhabdoid tumors, with caution that some may still behave aggressively and close follow-up is recommended.
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http://dx.doi.org/10.1093/jnen/nlv006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009417PMC
January 2016

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

Neuro Oncol 2016 Apr 22;18(4):565-74. Epub 2015 Oct 22.

Virginia Commonwealth University, Richmond, Virginia (C.L.R., M.S.A.); University of California, San Francisco, California (A.P., I.B.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvnia (S.P.); Cleveland Clinic Foundation, Cleveland, Ohio (M.A.V., S.T.C.); Arizona Oncology Services Foundation, Phoenix, Arizona (D.B.); McMaster University, Hamilton, Ontario, Canada (W.M.); Medical University of South Carolina, Charleston, South Carolina (J.J.); University of Utah Health Science Center, Salt Lake City, Utah (D.S.); University Hospitals, Cleveland, Ohio (A.S.); Medical College of Wisconsin, Milwaukee, Wisconsin (J.B.); University of Maryland Medical System, Baltimore, Maryland (Y.K., M.M.); Carolinas Medical Center/Levine Cancer Institute, Charlotte, North Carolina (S.H.B.); Norton Cancer Institute, Louisville, Kentucky (A.C.S.); North Shore University Hospital CCOP, Manhasset, New York (B.B.).

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.
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http://dx.doi.org/10.1093/neuonc/nov247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4799683PMC
April 2016

Interval From Imaging to Treatment Delivery in the Radiation Surgery Age: How Long Is Too Long?

Int J Radiat Oncol Biol Phys 2015 Sep 7;93(1):126-32. Epub 2015 May 7.

Department of Radiation Oncology, University of California at San Francisco, San Francisco, California.

Purpose: The purpose of this study was to evaluate workflow and patient outcomes related to frameless stereotactic radiation surgery (SRS) for brain metastases.

Methods And Materials: We reviewed all treatment demographics, clinical outcomes, and workflow timing, including time from magnetic resonance imaging (MRI), computed tomography (CT) simulation, insurance authorization, and consultation to the start of SRS for brain metastases.

Results: A total of 82 patients with 151 brain metastases treated with SRS were evaluated. The median times from consultation, insurance authorization, CT simulation, and MRI for treatment planning were 15, 7, 6, and 11 days to SRS. Local freedom from progression (LFFP) was lower in metastases with MRI ≥ 14 days before treatment (P = .0003, log rank). The 6- and 12-month LFFP rate were 95% and 75% for metastasis with interval of <14 days from MRI to treatment compared to 56% and 34% for metastases with MRI ≥ 14 days before treatment. On multivariate analysis, LFFP remained significantly lower for lesions with MRI ≥ 14 days at SRS (P = .002, Cox proportional hazards; hazard ratio: 3.4, 95% confidence interval: 1.6-7.3).

Conclusions: Delay from MRI to SRS treatment delivery for brain metastases appears to reduce local control. Future studies should monitor the timing from imaging acquisition to treatment delivery. Our experience suggests that the time from MRI to treatment should be <14 days.
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http://dx.doi.org/10.1016/j.ijrobp.2015.05.001DOI Listing
September 2015

Surgery is cost-effective treatment for young patients with vestibular schwannomas: decision tree modeling of surgery, radiation, and observation.

Neurosurg Focus 2014 Nov;37(5):E8

Department of Neurological Surgery, Northwestern University, Chicago, Illinois.

Object: Vestibular schwannomas (VSs) are managed in 3 ways: observation ("wait and scan"); Gamma Knife surgery (GKS); or microsurgery. Whereas there is considerable literature regarding which management approach is superior, there are only a few studies addressing the cost of treating VSs, and there are no cost-utility analyses in the US to date.

Methods: In this study, the authors used the University of California at San Francisco medical record and hospital accounting databases to determine total hospital charges and costs for 33 patients who underwent open surgery, 42 patients who had GKS, and 12 patients who were observed between 2010 and 2013. The authors then performed decision-tree analysis to determine which treatment paradigm produces the highest quality-adjusted life years and to calculate the incremental cost-effectiveness ratio, depending on the patient's age at VS diagnosis.

Results: The average total hospital cost over a 3-year period for surgically treated patients was $80,074 (± $49,678) versus $9737 (± $5522) for patients receiving radiosurgery and $1746 (± $2792) for patients who were observed. When modeling the most debilitating symptoms and worst outcomes of VSs (vertigo and death) at different ages at diagnosis, radiation is dominant to observation at all ages up to 70 years. Surgery is cost-effective when compared with radiation (incremental cost-effectiveness ratio < $150,000) at younger ages at diagnosis (< 45 years old).

Conclusions: In this model, surgery is a cost-effective alternative to radiation when VS is diagnosed in patients at < 45 years. For patients ≥ 45 years, radiation is the most cost-effective treatment option.
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http://dx.doi.org/10.3171/2014.8.FOCUS14435DOI Listing
November 2014

Hippocampal Dose With Radiosurgery for Multiple Intracranial Targets: The Rationale for Proactive Beam Shaping.

Technol Cancer Res Treat 2016 08 25;15(4):555-9. Epub 2015 Jun 25.

Department of Radiation Oncology, University of California, San Francisco, CA, USA.

Stereotactic radiosurgery provides conformal treatment of intracranial lesions, but when multiple lesions are treated, cumulative dose to structures such as the hippocampi may be increased. We analyzed hippocampal dose for patients treated with radiosurgery for multiple brain metastases. We then investigated a means to minimize hippocampal dose. We randomly selected 8 patients treated with single-session, frame-based radiosurgery for 6 to 12 intracranial metastases. Standard planning was employed to deliver 16 to 20 Gy to each lesion without hippocampal avoidance. Each case was replanned using the software's dynamic shaping function to minimize direct beam hippocampal irradiation, while maintaining conformality and target coverage. With standard planning, the maximum hippocampal dose varied from 0.8 to 9.0 Gy but was >3 Gy only when a lesion was <10 mm from the hippocampus. There was no clear correlation between hippocampal dose and the number or the total volume of lesions. Replanning with direct beam avoidance decreased the mean hippocampal dose by an average of 35% but increased treatment time by a mean of 20%. Sparing was most pronounced when the closest lesion was in close proximity to the hippocampus. This is the first study reporting hippocampal dose for multilesion intracranial radiosurgery. It illustrates that when multiple intracranial targets are treated with radiosurgery, substantial hippocampal dose can result. Active beam shielding and optimization can lower hippocampal dose, especially with lesions <10 mm from the hippocampus. These results raise the prospect that the risk of neurocognitive side effects may be further decreased with a hippocampal-sparing approach.
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http://dx.doi.org/10.1177/1533034615590934DOI Listing
August 2016

Response assessment criteria for brain metastases: proposal from the RANO group.

Lancet Oncol 2015 Jun 27;16(6):e270-8. Epub 2015 May 27.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.
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http://dx.doi.org/10.1016/S1470-2045(15)70057-4DOI Listing
June 2015

Factors predicting recurrence after resection of clival chordoma using variable surgical approaches and radiation modalities.

Neurosurgery 2015 Feb;76(2):179-85; discussion 185-6

‡Center for Minimally Invasive Skull Base Surgery (MISB), University of California at San Francisco, San Francisco, California; §Department of Neurosurgery, Center for Minimally Invasive Skull Base Surgery (MISB), University of California at San Francisco, San Francisco, California; ¶Department of Radiation Oncology, University of California at San Francisco, San Francisco, California; ‖Department of Neurosurgery, Northwestern University, Chicago, Illinois; #Skull Base and Cerebrovascular Laboratory, University of California at San Francisco, San Francisco, California; **Department of Otolaryngology, University of California at San Francisco, San Francisco, California.

Background: Clival chordomas frequently recur because of their location and invasiveness.

Objective: To investigate clinical, operative, and anatomic factors associated with clival chordoma recurrence.

Methods: Retrospective review of clival chordomas treated at our center from 1993 to 2013.

Results: Fifty patients (56% male) with median age of 59 years (range, 8-76) were newly diagnosed with clival chordoma of mean diameter 3.3 cm (range, 1.5-6.7). Symptoms included headaches (38%), diplopia (36%), and dysphagia (14%). Procedures included transsphenoidal (n=34), transoral (n=4), craniotomy (n=5), and staged approaches (n=7). Gross total resection (GTR) rate was 52%, with 83% mean volumetric reduction, values that improved over time. While the lower third of the clivus was the least likely superoinferior zone to contain tumor (upper third=72%/middle third=82%/lower third=42%), it most frequently contained residual tumor (upper third=33%/middle third=38%/lower third=63%; P<.05). Symptom improvement rates were 61% (diplopia) and 53% (headache). Postoperative radiation included proton beam (n=19), cyberknife (n=7), intensity-modulated radiation therapy (n=6), external beam (n=10), and none (n=4). At last follow-up of 47 patients, 23 (49%) remain disease-free or have stable residual tumor. Lower third of clivus progressed most after GTR (upper/mid/lower third=32%/41%/75%). In a multivariate Cox proportional hazards model, male gender (hazard ratio [HR]=1.2/P=.03), subtotal resection (HR=5.0/P=.02), and the preoperative presence of tumor in the middle third (HR=1.2/P=.02) and lower third (HR=1.8/P=.02) of the clivus increased further growth or regrowth, while radiation modality did not.

Conclusion: Our findings underscore long-standing support for GTR as reducing chordoma recurrence. The lower third of the clivus frequently harbored residual or recurrent tumor, despite staged approaches providing mediolateral (transcranial+endonasal) or superoinferior (endonasal+transoral) breadth. There was no benefit of proton-based over photon-based radiation, contradicting conventional presumptions.
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http://dx.doi.org/10.1227/NEU.0000000000000611DOI Listing
February 2015

Radiation therapy of glioblastoma.

Cancer Treat Res 2015 ;163:49-73

Departments of Radiation Oncology and Neurological Surgery, University of California, 505 Parnassus Avenue, Room L08B, San Francisco, CA, 94143-0226, USA,

Glioblastoma multiforme (GBM) is the most common malignant brain tumor that affects approximately 17,000 patients annually. Clear survival advantages have been demonstrated with postoperative radiation therapy (RT) to doses of 5,000-6,000 cGy but dose-escalation attempts beyond 6,000 cGy have resulted in increased toxicity but no additional survival benefit. To improve local control and limit toxicity to normal brain tissue with these infiltrating tumors, novel imaging techniques are actively being explored to better define tumor extent and associated RT treatment fields. Hyperfractionated RT has been associated with a survival detriment. Current standard-of-care treatment involves concurrent use of temozolomide and RT to 6,000 cGy over 30 days followed by adjuvant temozolomide treatment for 6 months. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but tend to be associated with notable toxicity. More recently, re-irradiation strategies employ concurrent use of bevacizumab to limit treatment-related injury while still permitting delivery of meaningful doses. These clinical trials are ongoing and merits of these strategies are not yet clear but appear promising.
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http://dx.doi.org/10.1007/978-3-319-12048-5_4DOI Listing
February 2015

The management of central neurocytoma: radiotherapy.

Neurosurg Clin N Am 2015 Jan;26(1):45-56

Department of Radiation Oncology, University of California, San Francisco, 505 Parnassus Avenue, Room L-08, San Francisco, CA 94143-0226, USA.

Intraventricular neurocytomas (IVNs) are rare tumors of neuronal differentiation, accounting for 0.1% to 0.5% of all primary brain tumors. Complete surgical resection is highly recommended, but at least one-third to one-half are subtotally resected. Stereotactic radiosurgery (SRS) and conventional radiotherapy have been used for management of residual and recurrent tumors, but the optimal treatment following subtotal surgical resection is less clear. Although there are trends toward higher local tumor control and survival rates with lower complications among IVNs treated with SRS, higher quality data are required to confirm these findings.
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http://dx.doi.org/10.1016/j.nec.2014.09.014DOI Listing
January 2015

A treatment paradigm for high-grade brain arteriovenous malformations: volume-staged radiosurgical downgrading followed by microsurgical resection.

J Neurosurg 2015 Feb 28;122(2):419-32. Epub 2014 Nov 28.

Departments of 1 Neurological Surgery and.

Object: The surgical treatment of many large arteriovenous malformations (AVMs) is associated with substantial risks, and many are considered inoperable. Furthermore, AVMs larger than 3 cm in diameter are not usually treated with conventional single-session radiosurgery encompassing the entire AVM volume. Volume-staged stereotactic radiosurgery (VS-SRS) is an option for large AVMs, but it has mixed results. The authors report on a series of patients with high-grade AVMs who underwent multiple VS-SRS sessions with resultant downgrading of the AVMs, followed by resection.

Methods: A cohort of patients was retrieved from a single-institution AVM patient registry consisting of prospectively collected data. VS-SRS was performed as a planned intentional treatment. Surgery was considered as salvage therapy in select patients.

Results: Sixteen AVMs underwent VS-SRS followed by surgery. Four AVMs presented with rupture. The mean patient age was 25.3 years (range 13-54 years). The average initial Spetzler-Martin grade before any treatment was 4, while the average supplemented Spetzler-Martin grade (Spetzler-Martin plus Lawton-Young) was 7.1. The average AVM size in maximum dimension was 5.9 cm (range 3.3-10 cm). All AVMs were supratentorial in location and all except one were in eloquent areas of the brain, with 7 involving primary motor cortex. The mean number of VS-SRS sessions was 2.7 (range 2-5 sessions). The mean interval between first VS-SRS session and resection was 5.7 years. There were 4 hemorrhages that occurred after VS-SRS. The average Spetzler-Martin grade was reduced to 2.5 (downgrade, -1.5) and the average supplemented Spetzler-Martin grade was reduced to 5.6 (downgrade, -1.5). The maximum AVM size was reduced to an average of 3.0 cm (downsize=-2.9 cm). The mean modified Rankin Scale (mRS) scores were 1.2, 2.3, and 2.2 before VS-SRS, before surgery, and at last follow-up, respectively (mean follow-up, 6.9 years). Fifteen AVMs were cured after surgery. Ten patients had good outcomes at last follow-up (7 with mRS Score 0 or 1, and 3 with mRS Score 2). There were 2 deaths (both mRS Score 1 before treatment) and 4 patients with mRS Score 3 outcome (from mRS Scores 0, 1, and 2 [n=2]).

Conclusions: Volume-staged SRS can downgrade AVMs, transforming high-grade AVMs (initially considered inoperable) into operable AVMs with acceptable surgical risks. This treatment paradigm offers an alternative to conservative observation for young patients with unruptured AVMs and long life expectancy, where the risk of hemorrhage is substantial. Difficult AVMs were cured in 15 patients. Surgical morbidity associated with downgraded AVMs is reduced to that of postradiosurgical/preoperative supplemented Spetzler-Martin grades, not their initial AVM grades.
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http://dx.doi.org/10.3171/2014.10.JNS1424DOI Listing
February 2015

Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review.

J Neurosurg 2015 Jan;122(1):4-23

GammaWest Cancer Services, Radiation Oncology, Salt Lake City, Utah;

Evolving interest in meningioma, the most common primary brain tumor, has refined contemporary management of these tumors. Problematic, however, is the paucity of prospective clinical trials that provide an evidence-based algorithm for managing meningioma. This review summarizes the published literature regarding the treatment of newly diagnosed and recurrent meningioma, with an emphasis on outcomes stratified by WHO tumor grade. Specifically, this review focuses on patient outcomes following treatment (either adjuvant or at recurrence) with surgery or radiation therapy inclusive of radiosurgery and fractionated radiation therapy. Phase II trials for patients with meningioma have recently completed accrual within the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer consortia, and Phase III studies are being developed. However, at present, there are no completed prospective, randomized trials assessing the role of either surgery or radiation therapy. Successful completion of future studies will require a multidisciplinary effort, dissemination of the current knowledge base, improved implementation of WHO grading criteria, standardization of response criteria and other outcome end points, and concerted efforts to address weaknesses in present treatment paradigms, particularly for patients with progressive or recurrent low-grade meningioma or with high-grade meningioma. In parallel efforts, Response Assessment in Neuro-Oncology (RANO) subcommittees are developing a paper on systemic therapies for meningioma and a separate article proposing standardized end point and response criteria for meningioma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062955PMC
http://dx.doi.org/10.3171/2014.7.JNS131644DOI Listing
January 2015

Predictors of individual tumor local control after stereotactic radiosurgery for non-small cell lung cancer brain metastases.

Int J Radiat Oncol Biol Phys 2014 Oct 30;90(2):407-13. Epub 2014 Jul 30.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

Purpose: To evaluate local control rates and predictors of individual tumor local control for brain metastases from non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS).

Methods And Materials: Between June 1998 and May 2011, 401 brain metastases in 228 patients were treated with Gamma Knife single-fraction SRS. Local failure was defined as an increase in lesion size after SRS. Local control was estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis. Receiver operating characteristic analysis was used to identify an optimal cutpoint for conformality index relative to local control. A P value <.05 was considered statistically significant.

Results: Median age was 60 years (range, 27-84 years). There were 66 cerebellar metastases (16%) and 335 supratentorial metastases (84%). The median prescription dose was 20 Gy (range, 14-24 Gy). Median overall survival from time of SRS was 12.1 months. The estimated local control at 12 months was 74%. On multivariate analysis, cerebellar location (hazard ratio [HR] 1.94, P=.009), larger tumor volume (HR 1.09, P<.001), and lower conformality (HR 0.700, P=.044) were significant independent predictors of local failure. Conformality index cutpoints of 1.4-1.9 were predictive of local control, whereas a cutpoint of 1.75 was the most predictive (P=.001). The adjusted Kaplan-Meier 1-year local control for conformality index ≥ 1.75 was 84% versus 69% for conformality index <1.75, controlling for tumor volume and location. The 1-year adjusted local control for cerebellar lesions was 60%, compared with 77% for supratentorial lesions, controlling for tumor volume and conformality index.

Conclusions: Cerebellar tumor location, lower conformality index, and larger tumor volume were significant independent predictors of local failure after SRS for brain metastases from NSCLC. These results warrant further investigation in a prospective setting.
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http://dx.doi.org/10.1016/j.ijrobp.2014.05.047DOI Listing
October 2014

Role of stereotactic body radiotherapy in spinal metastasis and subsequent fracture risk: identifying and treating the at-risk patient.

CNS Oncol 2013 Sep;2(5):437-45

University of California, San Francisco, Department of Radiation Oncology, Room L-08, Box 0226, 505 Parnassus Avenue, San Francisco, CA 94143-0628, USA.

The treatment of spinal metastasis has considerably improved with the advent of stereotactic body radiotherapy. Technological advances have enabled the precise delivery of high-dose radiation that may supplant surgery and standard fractionation postoperative radiation as a treatment for spinal metastasis without cord compression. Unfortunately, the higher biologically equivalent doses conferred by stereotactic body radiotherapy can also result in radiation toxicity, notably myelitis and vertebral body fracture. These are toxicities that the radiation oncologist must be able to anticipate, mitigate and manage. Although myelitis can be prevented largely by instituting dose constraints, it is less clear what the fracture risk of a structurally compromised vertebra is, and what should be done in terms of stabilization and dosimetry to mitigate this risk. This review answers these questions by defining the appropriate patient for stereotactic body radiotherapy, and what dose, fractionation and spinal stabilization should be used for potentially unstable spines.
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http://dx.doi.org/10.2217/cns.13.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136102PMC
September 2013

Variable dose interplay effects across radiosurgical apparatus in treating multiple brain metastases.

Int J Comput Assist Radiol Surg 2014 Nov 20;9(6):1079-86. Epub 2014 Apr 20.

Department of Radiation Oncology, Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Canada.

Purpose: Normal brain tissue doses have been shown to be strongly apparatus dependent for multi-target stereotactic radiosurgery. In this study, we investigated whether inter-target dose interplay effects across contemporary radiosurgical treatment platforms are responsible for such an observation.

Methods: For the study, subsets ([Formula: see text] and 12) of a total of 12 targets were planned at six institutions. Treatment platforms included the (1) Gamma Knife Perfexion (PFX), (2) CyberKnife, (3) Novalis linear accelerator equipped with a 3.0-mm multi-leaf collimator (MLC), and the (4) Varian Truebeam flattening-filter-free (FFF) linear accelerator also equipped with a 2.5 mm MLC. Identical dose-volume constraints for the targets and critical structures were applied for each apparatus. All treatment plans were developed at individual centers, and the results were centrally analyzed.

Results: We found that dose-volume constraints were satisfied by each apparatus with some differences noted in certain structures such as the lens. The peripheral normal brain tissue doses were lowest for the PFX and highest for TrueBeam FFF and CyberKnife treatment plans. Comparing the volumes of normal brain receiving 12 Gy, TrueBeam FFF, Novalis, and CyberKnife were 180-290% higher than PFX. The mean volume of normal brain-per target receiving 4-Gy increased by approximately 3.0 cc per target for TrueBeam, 2.7 cc per target for CyberKnife, 2.0 cc per target for Novalis, and 0.82 cc per target for PFX. The beam-on time was shortest with the TrueBeam FFF (e.g., 6-9 min at a machine output rate of 1,200 MU/min) and longest for the PFX (e.g., 50-150 mins at a machine output rate of 350 cGy/min).

Conclusion: The volumes of normal brain receiving 4 and 12 Gy were higher, and increased more swiftly per target, for Linac-based SRS platforms than for PFX. Treatment times were shortest with TrueBeam FFF.
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http://dx.doi.org/10.1007/s11548-014-1001-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215114PMC
November 2014
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