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Daniel W. Golden, Kathleen R. Lamborn, Michael W. McDermott, Sandeep Kunwar, William M. Wara, Jean L. Nakamura and Penny K. Sneed

Object

The authors conducted a study to determine whether prognostic factors and the applicability of prognostic systems vary by primary tumor site in patients treated with radiosurgery for brain metastases.

Methods

The authors evaluated data obtained in patients who underwent radiosurgery with or without whole-brain radiotherapy (WBRT) from 1991 to 2005 for newly diagnosed brain metastases. Four groups were analyzed: 1) all primary sites combined, 2) breast, 3) lung, and 4) melanoma primary sites. Kaplan–Meier, log-rank, Cox proportional hazard uni- and multivariate analysis, and recursive partitioning analysis (RPA) were used to assess prognostic factors and 4 prognostic systems: Radiation Therapy Oncology Group (RTOG) RPA, Graded Prognostic Assessment (GPA), basic score for brain metastases (BSBM), and the newly proposed Golden grading system (GGS). The GGS divides patients into 4 prognostic groups by age ≥ 65 years, Karnofsky Performance Scale (KPS) score < 70, and known presence of extracranial metastases.

Results

Data acquired in 479 newly diagnosed patients with 1664 lesions were analyzed. The median survival time from diagnosis of brain metastases was 12.1 months; the median follow-up was 25.4 months in 73 patients who were censored. Survival and prognostic factors were equivalent for 369 patients treated with radiosurgery compared with 110 patients treated with radiosurgery and WBRT, so these subsets were combined. Multivariate analysis of all primary sites combined demonstrated age < 65 years, KPS score ≥ 70, no known extracranial metastases, and ≤ 3 brain metastases were associated with longer survival, and primary tumor control was not. In subgroup multivariate analysis of patients with breast, lung, or melanoma primaries, favorable factors included only primary tumor control in 87 patients with breast primary; age < 65 years, no known extracranial metastases, and ≤ 3 brain metastases in 169 patients with lung primary; and KPS ≥ 70 years, primary tumor control, and ≤ 3 brain metastases in 137 patients with melanoma primary. The median survival for ≤ 3 versus > 3 metastases was 15.6 and 16.9 months, respectively, for breast, 16.5 and 11.3 months for lung, and 9.0 and 5.7 months for melanoma. Analysis of the 4 prognostic systems (RTOG RPA, BSBM, GPA, and GGS) showed that each prognostic system's clinical applicability varied depending on primary tumor site. The RPA confirmed that GGS and primary tumor site are significant variables for prognosis.

Conclusions

Favorable prognostic factors for patients with newly diagnosed brain metastases treated with radiosurgery vary by primary site. The 4 prognostic grading systems analyzed were applicable to different primary sites depending on which prognostic factors each individual system incorporated. Therefore, the authors recommend further development and use of primary-specific prognostic systems.

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Elias Dagnew, Jeffrey Kanski, Michael W. McDermott, Penny K. Sneed, Christopher McPherson, John C. Breneman and Ronald E. Warnick

Object

Whole-brain radiotherapy (WBRT) after resection of a single brain metastasis can cause long-term radiation toxicity. The authors evaluated the efficacy of resection and placement of 125I seeds (without concomitant WBRT) for newly diagnosed single brain metastases.

Methods

In a retrospective review from two institutions (1997–2003), 15 women and 11 men (mean age 55 years) with single brain metastasis underwent gross-total resection and placement of permanent low-activity 125I seeds. Primary systemic cancer sites varied. Patients were monitored clinically and radiographically. With neuroimaging evidence of local recurrence or new distant metastasis, further treatment was administered at the physician's discretion. By the median follow-up evaluation (12 months), the local tumor control rate was 96%. Distant metastases occurred in three patients within 3 months, suggesting synchronous metastasis, and in six patients more than 3 months after treatment, indicating metachronous metastasis. Treatment in these cases included radio-surgery in seven patients, WBRT in two, and resection together with 125I seed placement in one. Two patients who suffered radiation necrosis required operative intervention (lesion diameter > 3 cm, total activity > 40 mCi). All 26 patients who had been treated using resection and placement of 125I seeds had a stable or an improved Karnofsky Performance Scale score. At the last review, nine of 16 living patients showed no evidence of treatment failure. The median actuarial survival rate was 17.8 months (Kaplan–Meier method).

Conclusions

Permanent 125I brachytherapy applied at the initial operation without WBRT provided excellent local tumor control. Local control and patient survival rates were at least as good as those reported for resection combined with WBRT. Although the authors noted a higher incidence of distant metastases compared with that reported in other studies of initial WBRT, these metastases were generally well controlled with a combination of surgery, stereotactic radiosurgery, and, less often, WBRT. Twenty-four patients (92%) never required WBRT, thus avoiding potential long-term radiation-induced neurotoxicity.

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Justin S. Smith, Ian F. Parney, Kathleen R. Lamborn, Michael W. McDermott, Penny K. Sneed and Susan M. Chang

Object

This study was designed to assess the presentation, management, and outcome of cases involving patients who had a supratentorial glioma that subsequently progressed in the posterior fossa (PF).

Methods

The authors performed a retrospective chart review of adult patients treated between 1997 and 2005 for supratentorial gliomas that progressed in the PF. The 29 patients with PF progression in this study were relatively young (median age of 34 years at original presentation). Twenty of these patients presented with symptoms. The symptoms were typically nonspecific to this population, at times leading to delays in diagnosis. Overall, these symptoms resolved in eight patients (40%) and progressed or remained unchanged in 12 (60%). Patients treated with more than 5000 cGy of radiation administered to the PF were more likely to have symptom resolution than those who received any other form of treatment, including reduced doses of radiation (p = 0.004). The patients treated with higher doses also survived significantly longer after PF progression (univariate analysis, p = 0.01, and after adjusting for tumor grade, p = 0.04).

Conclusions

Patients with PF progression of supratentorial infiltrative gliomas may benefit from treatment, and the authors recommend more than 5000 cGy of radiation to the PF if prior radiotherapy ports and doses allow.

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Hideyuki Kano, Jason Sheehan, Penny K. Sneed, Heyoung L. McBride, Byron Young, Christopher Duma, David Mathieu, Zachary Seymour, Michael W. McDermott, Douglas Kondziolka, Aditya Iyer and L. Dade Lunsford

OBJECT

Stereotactic radiosurgery (SRS) is a potentially important option for patients with skull base chondrosarcomas. The object of this study was to analyze the outcomes of SRS for chondrosarcoma patients who underwent this treatment as a part of multimodality management.

METHODS

Seven participating centers of the North American Gamma Knife Consortium (NAGKC) identified 46 patients who underwent SRS for skull base chondrosarcomas. Thirty-six patients had previously undergone tumor resections and 5 had been treated with fractionated radiation therapy (RT). The median tumor volume was 8.0 cm3 (range 0.9–28.2 cm3), and the median margin dose was 15 Gy (range 10.5–20 Gy). Kaplan-Meier analysis was used to calculate progression-free and overall survival rates.

RESULTS

At a median follow-up of 75 months after SRS, 8 patients were dead. The actuarial overall survival after SRS was 89% at 3 years, 86% at 5 years, and 76% at 10 years. Local tumor progression occurred in 10 patients. The rate of progression-free survival (PFS) after SRS was 88% at 3 years, 85% at 5 years, and 70% at 10 years. Prior RT was significantly associated with shorter PFS. Eight patients required salvage resection, and 3 patients (7%) developed adverse radiation effects. Cranial nerve deficits improved in 22 (56%) of the 39 patients who deficits before SRS. Clinical improvement after SRS was noted in patients with abducens nerve paralysis (61%), oculomotor nerve paralysis (50%), lower cranial nerve dysfunction (50%), optic neuropathy (43%), facial neuropathy (38%), trochlear nerve paralysis (33%), trigeminal neuropathy (12%), and hearing loss (10%).

CONCLUSIONS

Stereotactic radiosurgery for skull base chondrosarcomas is an important adjuvant option for the treatment of these rare tumors, as part of a team approach that includes initial surgical removal of symptomatic larger tumors.

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Zachary A. Seymour, Penny K. Sneed, Nalin Gupta, Michael T. Lawton, Annette M. Molinaro, William Young, Christopher F. Dowd, Van V. Halbach, Randall T. Higashida and Michael W. McDermott

OBJECT

Large arteriovenous malformations (AVMs) remain difficult to treat, and ideal treatment parameters for volume-staged stereotactic radiosurgery (VS-SRS) are still unknown. The object of this study was to compare VS-SRS treatment outcomes for AVMs larger than 10 ml during 2 eras; Era 1 was 1992-March 2004, and Era 2 was May 2004–2008. In Era 2 the authors prospectively decreased the AVM treatment volume, increased the radiation dose per stage, and shortened the interval between stages.

METHODS

All cases of VS-SRS treatment for AVM performed at a single institution were retrospectively reviewed.

RESULTS

Of 69 patients intended for VS-SRS, 63 completed all stages. The median patient age at the first stage of VS-SRS was 34 years (range 9–68 years). The median modified radiosurgery-based AVM score (mRBAS), total AVM volume, and volume per stage in Era 1 versus Era 2 were 3.6 versus 2.7, 27.3 ml versus 18.9 ml, and 15.0 ml versus 6.8 ml, respectively. The median radiation dose per stage was 15.5 Gy in Era 1 and 17.0 Gy in Era 2, and the median clinical follow-up period in living patients was 8.6 years in Era 1 and 4.8 years in Era 2. All outcomes were measured from the first stage of VS-SRS. Near or complete obliteration was more common in Era 2 (log-rank test, p = 0.0003), with 3- and 5-year probabilities of 5% and 21%, respectively, in Era 1 compared with 24% and 68% in Era 2. Radiosurgical dose, AVM volume per stage, total AVM volume, era, compact nidus, Spetzler-Martin grade, and mRBAS were significantly associated with near or complete obliteration on univariate analysis. Dose was a strong predictor of response (Cox proportional hazards, p < 0.001, HR 6.99), with 3- and 5-year probabilities of near or complete obliteration of 5% and 16%, respectively, at a dose < 17 Gy versus 23% and 74% at a dose ≥ 17 Gy. Dose per stage, compact nidus, and total AVM volume remained significant predictors of near or complete obliteration on multivariate analysis. Seventeen patients (25%) had salvage surgery, SRS, and/or embolization. Allowing for salvage therapy, the probability of cure was more common in Era 2 (log-rank test, p = 0.0007) with 5-year probabilities of 0% in Era 1 versus 41% in Era 2. The strong trend toward improved cure in Era 2 persisted on multivariate analysis even when considering mRBAS (Cox proportional hazards, p = 0.055, HR 4.01, 95% CI 0.97–16.59). The complication rate was 29% in Era 1 compared with 13% in Era 2 (Cox proportional hazards, not significant).

CONCLUSIONS

VS-SRS is an option to obliterate or downsize large AVMs. Decreasing the AVM treatment volume per stage to ≤ 8 ml with this technique allowed a higher dose per fraction and decreased time to response, as well as improved rates of near obliteration and cure without increasing complications. Reducing the volume of these very large lesions can facilitate a surgical approach for cure.

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Shannon Fogh, Lijun Ma, Nalin Gupta, Arjun Sahgal, Jean L. Nakamura, Igor Barani, Penny K. Sneed, Michael McDermott and David A. Larson

Object

The goal of this study was to develop a technique for performing submillimeter high-precision volume-staged Gamma Knife surgery and investigate its potential benefits in comparison with hypofractionated stereotactic radiotherapy (SRT) for treating large arteriovenous malformations (AVMs).

Methods

The authors analyzed 7 pediatric AVM cases treated with volume-staged stereotactic radiosurgery (SRS) using the Gamma Knife Perfexion at the University of California, San Francisco. The target and normal tissue contours from each case were exported for hypofractionated treatment planning based on the Gamma Knife Extend system or the CyberKnife SRT. Both the Gamma Knife Extend and CyberKnife treatment plans were matched to yield the same level of target coverage (95%–98%) and conformity indices (1.24–1.46). Finally, hypofractionated treatment plans were compared with volume-staged treatment plans for sparing normal brain by using biologically equivalent 12-Gy normal brain volumes.

Results

Hypofractionated Gamma Knife Extend and CyberKnife treatment plans exhibited practically identical sparing of normal brain for the studied cases. However, when matching such values with volume-staged treatments for the biological effective dose, only conservative dose fractionation schemes, such as 27.3 Gy in 5 fractions and 25 Gy in 4 fractions, were found to be comparable to the volume-staged treatments. On average, this represents a mean 18.7% ± 7.3% reduction in the single-fraction biologically equivalent dose for hypofractionated treatments versus the reference volume-staged treatments (p < 0.001).

Conclusions

Volume staging remains advantageous over hypofractionation in delivering a higher dose to the target and for better sparing of normal brain tissue in the treatment of large AVMs. More clinical data are needed, however, to justify the clinical superiority of this increased dose when compared with a hypofractionated treatment regimen.

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Lijun Ma, Arjun Sahgal, Ke Nie, Andrew Hwang, Aliaksandr Karotki, Brian Wang, Dennis C. Shrieve, Penny K. Sneed, Michael McDermott and David A. Larson

Object

Determining accurate target volume is critical for both prescribing and evaluating stereotactic radiosurgery (SRS) treatments. The aim of this study was to determine the reliability of contour-based volume calculations made by current major SRS platforms.

Methods

Spheres ranging in diameter from 6.4 to 38.2 mm were scanned and then delineated on imaging studies. Contour data sets were subsequently exported to 6 SRS treatment-planning platforms for volume calculations and comparisons. This procedure was repeated for the case of a patient with 12 metastatic lesions distributed throughout the brain. Both the phantom and patient datasets were exported to a stand-alone workstation for an independent volume-calculation analysis using a series of 10 algorithms that included approaches such as slice stacking, surface meshing, point-cloud filling, and so forth.

Results

Contour data–rendered volumes exhibited large variations across the current SRS platforms investigated for both the phantom (−3.6% to 22%) and patient case (1.0%–10.2%). The majority of the clinical SRS systems and algorithms overestimated the volumes of the spheres, compared with their known physical volumes. An independent algorithm analysis found a similar trend in variability, and large variations were typically associated with small objects whose volumes were < 0.4 cm3 and with those objects located near the end-slice of the scan limits.

Conclusions

Significant variations in volume calculation were observed based on data obtained from the SRS systems that were investigated. This observation highlights the need for strict quality assurance and benchmarking efforts when commissioning SRS systems for clinical use and, moreover, when conducting multiinstitutional cross-SRS platform clinical studies.

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Martina Descovich, Penny K. Sneed, Nicholas M. Barbaro, Michael W. McDermott, Cynthia F. Chuang, Igor J. Barani, Jean L. Nakamura and Lijun Ma

Object

The Leksell Gamma Knife and the Accuray CyberKnife systems have been used in the radiosurgical treatment of trigeminal neuralgia. The 2 techniques use different delivery methods and different treatment parameters. In the past, CyberKnife treatments have been associated with an increased incidence of treatment-related complications, such as facial numbness. The goal of this study was to develop a method for planning a CyberKnife treatment for trigeminal neuralgia that would reproduce the dosimetric characteristics of a Gamma Knife plan. A comparison between Gamma Knife and CyberKnife treatment plans obtained with this method is presented.

Methods

Five patients treated using the Gamma Knife Perfexion Unit were selected for this study. All patients underwent CT cisternography to accurately identify the position of the trigeminal nerve. The Gamma Knife plans used either one 4-mm-diameter collimator or two coincident 4-mm collimators (one open and one with sector blocking) placed at identical isocenter coordinates. A maximum local dose of 80 Gy was prescribed. Critical structures and representative isodose lines were outlined in GammaPlan and exported to the CyberKnife treatment planning platform. CyberKnife treatments were developed using the 5-mm-diameter cone and the trigeminal node set, which provides an effective collimation diameter of 4 mm at the isocenter. The 60-Gy isodose volume imported from GammaPlan was used as the target in the CyberKnife plans. The CyberKnife treatments were optimized to achieve target dose and critical structure sparing similar to the Gamma Knife plans. Isocentric and nonisocentric delivery techniques were investigated. Treatment plans were compared in terms of dosimetric characteristics, delivery, and planning efficiency.

Results

CyberKnife treatments using the 5-mm cone and the trigeminal node set can closely reproduce the dose distribution of Gamma Knife plans. CyberKnife isocentric and nonisocentric plans provide comparable results. The average length of the trigeminal nerve receiving a dose of 60 Gy was 4.5, 4.5, and 4.4 mm for Gamma Knife, nonisocentric CyberKnife, and isocentric CyberKnife, respectively. However, minimizing the dose to the critical structures was more difficult with the CyberKnife and required the use of tuning structures. In addition, the dose falloff away from the target was steeper in Gamma Knife plans, probably due to the larger number of beams (192 beams for Perfexion vs ~ 100 beams for CyberKnife). While the treatment time with the CyberKnife is generally shorter, the planning time is significantly longer.

Conclusions

CyberKnife radiosurgical parameters can be optimized to mimic the dose distribution of Gamma Knife plans. However, Gamma Knife plans result in superior sparing of critical structures (brainstem, temporal lobe, and cranial nerves VII and VIII) and in steeper dose falloff away from the target. The clinical significance of these effects is unknown.

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Matthew D. Smyth, Penny K. Sneed, Samuel F. Ciricillo, Michael S. Edwards, William M. Wara, David A. Larson, Michael T. Lawton, Philip H. Gutin and Michael W. Mcdermott

Object. Stereotactic radiosurgery for arteriovenous malformations (AVMs) is an accepted treatment option, but few reports have been published on the results of this treatment in children. In this study the authors describe a series of pediatric patients with a minimum follow-up duration of 36 months.

Methods. From 1991 to 1997, 40 children (26 boys and 14 girls) with AVMs were treated with radiosurgery at the University of California at San Francisco (UCSF). Follow-up information was available for 31 children (20 boys and 11 girls) in whom the median age at initial treatment was 11.2 years (range 3.4–17.5 years). The median follow-up duration was 60 months (range 6–99 months). Sixteen percent of the AVMs were Spetzler—Martin Grade II; 68%, Grade III; 10%, Grade IV; and 6%, Grade V. The mean volume of the AVMs was 5.37 cm3 and the median volume was 1.6 cm3. The mean marginal dose of radiation was 16.7 Gy and the median dose was 18 Gy (range 12–19 Gy).

Angiography performed in 26 children confirmed obliteration of the AVM nidus in nine patients (35%), partial response in 16 patients (62%), and no response in one patient (4%). In five patients who refused angiography, magnetic resonance (MR) imaging revealed obliteration in two patients and partial response in three patients, bringing the overall obliteration rate associated with initial radiosurgery to 35%. Logistic regression analysis confirmed a significant correlation between marginal dose prescription and response (p = 0.025); in AVMs that received at least 18 Gy there was a 10-fold increase in the obliteration rate (63%) over AVMs that received a lower dose. Lesions smaller than 3 cm3 were associated with a sixfold increased obliteration rate (53%) over lesions larger than 3 cm3 (8%), but AVM volume was not a statistically significant predictor of response (p = 0.09). Twelve patients have since undergone repeated radiosurgery and are currently being followed up with serial MR imaging studies (in five cases, the AVM is now obliterated). During the follow-up period (1918 patient-months) there were eight hemorrhages in five patients, with a cumulative posttreatment hemorrhage rate of 3.2%/patient/year in the 1st year and a rate of 4.3%/patient/year over the first 3 years. There were two permanent neurological complications (6%) and no deaths in this study.

Conclusions. The lower overall obliteration rate reported in this series is most likely due to the larger mean AVM volumes treated at UCSF as well as conservative dose—volume prescriptions delivered to children. Significantly higher obliteration rates were observed when a marginal radiation dose of at least 18 Gy was delivered. The permanent complication rate is low and should encourage those treating children to use doses similar to those used in adults.

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Steven G. Ojemann, Penny K. Sneed, David A. Larson, Philip H. Gutin, Mitchel S. Berger, Lynn Verhey, Vernon Smith, Paula Petti, William Wara, Elaine Park and Michael W. McDermott

Object. The initial treatment of malignant meningiomas in the past has included surgical removal followed by fractionated external-beam radiotherapy. Radiosurgery has been added to the options for treatment of primary or recurrent tumors over the last 10 years. The authors report their results of using gamma knife radiosurgery (GKS) to treat 22 patients over an 8-year period.

Methods. Twenty-two patients who underwent GKS for malignant meningioma between December 1991 and May 1999 were evaluated. Three patients were treated with GKS as a boost to radiotherapy and 19 for recurrence following radiotherapy. Outcome factors including patient survival, freedom from progression, and complications were analyzed. In addition, in the recurrent group, variables such as patient age, sex, tumor location, target volume, margin dose, and maximum dose were also analyzed. Univariate and multivariate analyses were performed.

Overall 5-year survival and progression-free survival estimates were 40% and 26%, respectively. Age (p ≤ 0.003) and tumor volume (p ≤ 0.05) were significant predictors of time to progression and survival in both univariate and multivariate analyses. Five patients (23%) developed radiation necrosis. Significant relationships between complications and treatment variables or patient characteristics could not be established.

Conclusions. Tumor control following GKS is greater in patients with smaller-sized tumors (< 8 cm3) and in younger patients. Gamma knife radiosurgery can be performed to treat malignant meningioma with acceptable toxicity. The efficacy of GKS relative to other therapies for recurrent malignant meningioma as well as the value of GKS as a boost to radiotherapy will require further evaluation.