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Ajay Niranjan, Hideyuki Kano, Aditya Iyer, Douglas Kondziolka, John C. Flickinger, and L. Dade Lunsford

OBJECT

After initial standard of care management of glioblastoma multiforme (GBM), relatively few proven options remain for patients with unresected progressive tumor. Numerous reports describe the value of radiosurgery, yet this modality appears to remain underutilized. The authors analyzed the outcomes of early adjuvant stereotactic radiosurgery (SRS) for unresected tumor or later salvage SRS for progressive GBM. Radiosurgery was performed as part of the multimodality management and was combined with other therapies. Patients continued to receive additional chemotherapy after SRS and prior to progression being documented. In this retrospective analysis, the authors evaluated factors that affected patient overall survival (OS) and progression-free survival.

METHODS

Between 1987 and 2008 the authors performed Gamma Knife SRS in 297 patients with histologically proven GBMs. All patients had received prior fractionated radiation therapy, and 66% had undergone one or more chemotherapy regimens. Ninety-six patients with deep-seated unresectable GBMs underwent biopsy only. Of those in whom excision had been possible, resection was considered to be gross total in 68 and subtotal in 133. The median patient age was 58 years (range 23–89 years) and the median tumor volume was 14 cm3 (range 0.26–84.2 cm3). The median prescription dose delivered to the imaging-defined tumor margin was 15 Gy (range 9–25 Gy). The median follow-up duration was 8.6 months (range 1.1–173 months). Cox regression models were used to analyze survival outcomes. Variables examined included age, residual versus recurrent tumor, prior chemotherapy, time to first recurrence, SRS dose, and gross tumor volume.

RESULTS

The median survival times after radiosurgery and after diagnosis were 9.03 and 18.1 months, respectively. The 1-year and 2-year OS after SRS were 37.9% and 16.7%, respectively. The 1-year and 2-year OS after diagnosis were 76.2% and 30.8%, respectively. Using multivariate analysis, factors associated with improved OS after diagnosis were younger age (< 60 years) at diagnosis (p < 0.0001), tumor volume < 14 cm3 (p < 0.001), use of prior chemotherapy (p = 0.001), and radiosurgery at the time of recurrence (p < 0.0001). Multivariate analysis showed that younger age (p < 0.0001) and smaller tumor volume (< 14 cm3) (p = 0.001) were significantly associated with increased OS after SRS. Adverse radiation effects were seen in 69 patients (23%). Fifty-eight patients (19.5%) underwent additional resection after SRS. The median survivals after diagnosis for recursive partitioning analysis Classes III, IV and V+VI were 31.6, 20.8, and 16.7 months, respectively.

CONCLUSIONS

In this analysis 30% of a heterogeneous cohort of GBM patients eligible for SRS had an OS of 2 years. Radiosurgery at the time of tumor progression was associated with a median survival of 21.8 months. The role of radiosurgery for GBMs remains controversial. The findings in this study support the need for a funded and appropriately designed clinical trial that will provide a higher level of evidence regarding the future role of SRS for glioblastoma patients in whom disease has progressed despite standard management.

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Greg Bowden, Hideyuki Kano, Ellen Caparosa, Daniel Tonetti, Ajay Niranjan, Edward A. Monaco III, John Flickinger, Yoshio Arai, and L. Dade Lunsford

OBJECT

A visual field deficit resulting from the management of an arteriovenous malformation (AVM) significantly impacts a patient's quality of life. The present study was designed to investigate the clinical and radiological outcomes of stereotactic radiosurgery (SRS) performed for AVMs involving the postgeniculate visual pathway.

METHODS

In this retrospective single-institution analysis, the authors reviewed their experience with Gamma Knife surgery for postgeniculate visual pathway AVMs performed during the period between 1987 and 2009.

RESULTS

During the study interval, 171 patients underwent SRS for AVMs in this region. Forty-one patients (24%) had a visual deficit prior to SRS. The median target volume was 6.0 cm3 (range 0.4–22 cm3), and 19 Gy (range 14–25 Gy) was the median margin dose. Obliteration of the AVM was confirmed in 80 patients after a single SRS procedure at a median follow-up of 74 months (range 5–297 months). The actuarial rate of total obliteration was 67% at 4 years. Arteriovenous malformations with a volume < 5 cm3 had obliteration rates of 60% at 3 years and 79% at 4 years. The delivered margin dose proved significant given that 82% of patients receiving ≥ 22 Gy had complete obliteration. The AVM was completely obliterated in an additional 18 patients after they underwent repeat SRS. At a median of 25 months (range 11–107 months) after SRS, 9 patients developed new or worsened visual field deficits. One patient developed a complete homonymous hemianopia, and 8 patients developed quadrantanopias. The actuarial risk of sustaining a new visual deficit was 3% at 3 years, 5% at 5 years, and 8% at 10 years. Fifteen patients had hemorrhage during the latency period, resulting in death in 9 of the patients. The annual hemorrhage rate during the latency interval was 2%, and no hemorrhages occurred after confirmed obliteration.

CONCLUSIONS

Despite an overall treatment mortality of 5%, related to latency interval hemorrhage, SRS was associated with only a 5.6% risk of new visual deficit and a final obliteration rate close to 80% in patients with AVMs of the postgeniculate visual pathway.

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Zachary J. Tempel, Srinivas Chivukula, Edward A. Monaco III, Greg Bowden, Hideyuki Kano, Ajay Niranjan, Edward F. Chang, Penny K. Sneed, Anthony M. Kaufmann, Jason Sheehan, David Mathieu, and L. Dade Lunsford

OBJECT

Gamma Knife radiosurgery (GKRS) is the least invasive treatment option for medically refractory, intractable trigeminal neuralgia (TN) and is especially valuable for treating elderly, infirm patients or those on anticoagulation therapy. The authors reviewed pain outcomes and complications in TN patients who required 3 radiosurgical procedures for recurrent or persistent pain.

METHODS

A retrospective review of all patients who underwent 3 GKRS procedures for TN at 4 participating centers of the North American Gamma Knife Consortium from 1995 to 2012 was performed. The Barrow Neurological Institute (BNI) pain score was used to evaluate pain outcomes.

RESULTS

Seventeen patients were identified; 7 were male and 10 were female. The mean age at the time of last GKRS was 79.6 years (range 51.2–95.6 years). The TN was Type I in 16 patients and Type II in 1 patient. No patient suffered from multiple sclerosis. Eight patients (47.1%) reported initial complete pain relief (BNI Score I) following their third GKRS and 8 others (47.1%) experienced at least partial relief (BNI Scores II–IIIb). The average time to initial response was 2.9 months following the third GKRS. Although 3 patients (17.6%) developed new facial sensory dysfunction following primary GKRS and 2 patients (11.8%) experienced new or worsening sensory disturbance following the second GKRS, no patient sustained additional sensory disturbances after the third procedure. At a mean follow-up of 22.9 months following the third GKRS, 6 patients (35.3%) reported continued Score I complete pain relief, while 7 others (41.2%) reported pain improvement (BNI Scores II–IIIb). Four patients (23.5%) suffered recurrent TN following the third procedure at a mean interval of 19.1 months.

CONCLUSIONS

A third GKRS resulted in pain reduction with a low risk of additional complications in most patients with medically refractory and recurrent, intractable TN. In patients unsuitable for other microsurgical or percutaneous strategies, especially those receiving long-term oral anticoagulation or antiplatelet agents, GKRS repeated for a third time was a satisfactory, low risk option.

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Greg Bowden, Hideyuki Kano, Huai-che Yang, Ajay Niranjan, John Flickinger, and L. Dade Lunsford

Object

The outcomes of stereotactic radiosurgery for arteriovenous malformations (AVMs) within or adjacent to the ventricular system are largely unknown. This study assessed the long-term outcomes and hemorrhage risks for patients with AVMs within this region who underwent Gamma Knife surgery (GKS) at the University of Pittsburgh.

Methods

The authors retrospectively identified 188 patients with ventricular-region AVMs who underwent a single-stage GKS procedure during a 22-year interval. The median patient age was 32 years (range 3–80 years), the median target volume was 4.6 cm3 (range 0.1–22 cm3), and the median marginal dose was 20 Gy (range 13–27 Gy).

Results

Arteriovenous malformation obliteration was confirmed by MRI or angiography in 89 patients during a median follow-up of 65 months (range 2–265 months). The actuarial rates of total obliteration were 32% at 3 years, 55% at 4 years, 60% at 5 years, and 64% at 10 years. Higher rates of AVM obliteration were obtained in the 26 patients with intraventricular AVMs. Twenty-five patients (13%) sustained a hemorrhage during the initial latency interval after GKS, indicating an annual hemorrhage rate of 3.4% prior to AVM obliteration. No patient experienced a hemorrhage after AVM obliteration was confirmed by imaging. Permanent neurological deficits due to adverse radiation effects developed in 7 patients (4%).

Conclusions

Although patients in this study demonstrated an elevated hemorrhage risk that remained until complete obliteration, GKS still proved to be a generally safe and effective treatment for patients with these high-risk intraventricular and periventriclar AVMs.

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Daniel Tonetti, Hideyuki Kano, Gregory Bowden, John C. Flickinger, and L. Dade Lunsford

Object

The presentation for patients with arteriovenous malformations (AVMs) is often intracranial hemorrhage; for women, this frequently occurs during the prime childbearing years. Although previous studies have addressed the risk for AVM hemorrhage during pregnancy, such studies have not assessed the risk for hemorrhage among women who become pregnant during the latency interval between stereotactic radiosurgery (SRS) and documented obliteration of the lesion. The authors sought to evaluate the risk for hemorrhage in patients who become pregnant during the latency interval after SRS.

Methods

This single-institution retrospective analysis reviewed the authors' experience with Gamma Knife SRS during 1987–2012. During this time, 253 women of childbearing age (median age 30 years, range 15–40 years) underwent SRS for intracranial AVM. The median target volume was 3.9 cm3 (range 0.1–27.1 cm3), and the median marginal dose was 20 Gy (range 14–38 Gy). For all patients, the date of AVM obliteration was recorded and the latency interval was calculated. Information about subsequent pregnancies and/or bleeding events during the latency interval was retrieved from the medical records and supplemented by telephone contact.

Results

AVM obliteration was confirmed by MRI or angiography at a median follow-up time of 39.3 months (range 10–174 months). There were 828.7 patient-years of follow-up within the latency interval between SRS and the date of confirmed AVM obliteration. Among nonpregnant women, 20 hemorrhages occurred before AVM obliteration, yielding an annual hemorrhage rate of 2.5% for nonpregnant women during the latency interval. Among women who became pregnant during the latency interval, 2 hemorrhages occurred over the course of 18 pregnancies, yielding an annual hemorrhage rate of 11.1% for women who become pregnant during the latency interval. For the 2 pregnant patients who experienced hemorrhage, the bleeding occurred during the first trimester of pregnancy.

Conclusions

The authors present the first series of data for women with intracranial AVMs who became pregnant during the latency interval after SRS. Hemorrhage during the latency interval occurred at an annual rate of 2.5% for nonpregnant women and 11.1% for pregnant women. The data suggest that pregnancy might be a risk factor for AVM hemorrhage during the interval between SRS and AVM obliteration. However, this suggestion is not statistically significant because only 18 patients in the study population became pregnant during the latency interval. To mitigate any increased risk for hemorrhage, patients should consider deferring pregnancy until treatment conclusion and AVM obliteration.

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Greg Bowden, Hideyuki Kano, Daniel Tonetti, Ajay Niranjan, John Flickinger, Yoshio Arai, and L. Dade Lunsford

Object

Sylvian fissure arteriovenous malformations (AVMs) present substantial management challenges because of the critical adjacent blood vessels and functional brain. The authors investigated the outcomes, especially hemorrhage and seizure activity, after stereotactic radiosurgery (SRS) of AVMs within or adjacent to the sylvian fissure.

Methods

This retrospective single-institution analysis examined the authors' experiences with Gamma Knife surgery for AVMs of the sylvian fissure in cases treated from 1987 through 2009. During this time, 87 patients underwent SRS for AVMs in the region of the sylvian fissure. Before undergoing SRS, 40 (46%) of these patients had experienced hemorrhage and 36 (41%) had had seizures. The median target volume of the AVM was 3.85 cm3 (range 0.1–17.7 cm3), and the median marginal dose of radiation was 20 Gy (range 13–25 Gy).

Results

Over a median follow-up period of 64 months (range 3–275 months), AVM obliteration was confirmed by MRI or angiography for 43 patients. The actuarial rates of confirmation of total obliteration were 35% at 3 years, 60% at 4 and 5 years, and 76% at 10 years. Of the 36 patients who had experienced seizures before SRS, 19 (53%) achieved outcomes of Engel class I after treatment. The rate of seizure improvement was 29% at 3 years, 36% at 5 years, 50% at 10 years, and 60% at 15 years. No seizures developed after SRS in patients who had been seizure free before treatment. The actuarial rate of AVM hemorrhage after SRS was 5% at 1, 5, and 10 years. This rate equated to an annual hemorrhage rate during the latency interval of 1%; no hemorrhages occurred after confirmed obliteration. No permanent neurological deficits developed as an adverse effect of radiation; however, delayed cyst formation occurred in 3 patients.

Conclusions

Stereotactic radiosurgery was an effective treatment for AVMs within the region of the sylvian fissure, particularly for smaller-volume AVMs. After SRS, a low rate of hemorrhage and improved seizure control were also evident.

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Aditya Iyer, Gillian Harrison, Hideyuki Kano, Gregory M. Weiner, Neal Luther, Ajay Niranjan, John C. Flickinger, L. Dade Lunsford, and Douglas Kondziolka

Object

The aim of this study was to evaluate the imaging response of brain metastases after radiosurgery and to correlate the response with tumor type and patient survival.

Methods

The authors conducted a retrospective review of patients who had undergone Gamma Knife radiosurgery for brain metastases from non–small cell lung cancer (NSCLC), breast cancer, or melanoma. The imaging volumetric response by tumor type was plotted at 3-month intervals and classified as a sustained decrease in tumor volume (Type A), a transient decrease followed by a delayed increase in tumor volume (Type B), or a sustained increase in tumor volume (Type C). These imaging responses were then compared with patient survival and tumor type.

Results

Two hundred thirty-three patients with metastases from NSCLC (96 patients), breast cancer (98 patients), and melanoma (39 patients) were eligible for inclusion in this study. The patients with NSCLC were most likely to exhibit a Type A response; those with breast cancer, a Type B response; and those with melanoma, a Type C response. Among patients with NSCLC, the median overall survival was 11.2 months for those with a Type A response (76 patients), 8.6 months for those with a Type B response (6 patients), and 10.5 months for those with a Type C response (14 patients). Among patients with breast cancer, the median overall survival was 16.6 months in those with a Type A response (65 patients), 18.1 months in those with a Type B response (20 patients), and 7.5 months in those with a Type C response (13 patients). For patients with melanoma, the median overall survival was 5.2 months in those with a Type A response (26 patients) and 6.7 months in those with a Type C response (13 patients). None of the patients with melanoma had a Type B response. The imaging response was significantly associated with survival only in patients with breast cancer.

Conclusions

The various types of imaging responses of metastatic brain tumors after stereotactic radiosurgery depend in part on tumor type. However, the type of response only correlates with survival in patients with breast cancer.

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Jason P. Sheehan, Robert M. Starke, Hideyuki Kano, Anthony M. Kaufmann, David Mathieu, Fred A. Zeiler, Michael West, Samuel T. Chao, Gandhi Varma, Veronica L. S. Chiang, James B. Yu, Heyoung L. McBride, Peter Nakaji, Emad Youssef, Norissa Honea, Stephen Rush, Douglas Kondziolka, John Y. K. Lee, Robert L. Bailey, Sandeep Kunwar, Paula Petti, and L. Dade Lunsford

Object

Parasellar and sellar meningiomas are challenging tumors owing in part to their proximity to important neurovascular and endocrine structures. Complete resection can be associated with significant morbidity, and incomplete resections are common. In this study, the authors evaluated the outcomes of parasellar and sellar meningiomas managed with Gamma Knife radiosurgery (GKRS) both as an adjunct to microsurgical removal or conventional radiation therapy and as a primary treatment modality.

Methods

A multicenter study of patients with benign sellar and parasellar meningiomas was conducted through the North American Gamma Knife Consortium. For the period spanning 1988 to 2011 at 10 centers, the authors identified all patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were also required to have a minimum of 6 months of imaging and clinical follow-up after GKRS. Factors predictive of new neurological deficits following GKRS were assessed via univariate and multivariate analyses. Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression.

Results

The authors identified 763 patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were assessed clinically and with neuroimaging at routine intervals following GKRS. There were 567 females (74.3%) and 196 males (25.7%) with a median age of 56 years (range 8–90 years). Three hundred fifty-five patients (50.7%) had undergone at least one resection before GKRS, and 3.8% had undergone prior radiation therapy. The median follow-up after GKRS was 66.7 months (range 6–216 months). At the last follow-up, tumor volumes remained stable or decreased in 90.2% of patients. Actuarial progression-free survival rates at 3, 5, 8, and 10 years were 98%, 95%, 88%, and 82%, respectively. More than one prior surgery, prior radiation therapy, or a tumor margin dose < 13 Gy significantly increased the likelihood of tumor progression after GKRS.

At the last clinical follow-up, 86.2% of patients demonstrated no change or improvement in their neurological condition, whereas 13.8% of patients experienced symptom progression. New or worsening cranial nerve deficits were seen in 9.6% of patients, with cranial nerve (CN) V being the most adversely affected nerve. Functional improvements in CNs, especially in CNs V and VI, were observed in 34% of patients with preexisting deficits. New or worsened endocrinopathies were demonstrated in 1.6% of patients; hypothyroidism was the most frequent deficiency. Unfavorable outcome with tumor growth and accompanying neurological decline was statistically more likely in patients with larger tumor volumes (p = 0.022) and more than 1 prior surgery (p = 0.021).

Conclusions

Gamma Knife radiosurgery provides a high rate of tumor control for patients with parasellar or sellar meningiomas, and tumor control is accompanied by neurological preservation or improvement in most patients.

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Mohamed Samy Elhammady and Roberto C. Heros

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Hideyuki Kano, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Daniel Tonetti, Ajay Niranjan, and L. Dade Lunsford

Object

The purpose of this study was to define the outcomes and risks of stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) Grade III arteriovenous malformations (AVMs).

Methods

Between 1987 and 2009, SRS was performed in 474 patients with SM Grade III AVMs. The AVMs were categorized by scoring the size (S), drainage (D), and location (L): IIIa was a small AVM (S1D1L1, N = 282); IIIb was a medium/deep AVM (S2D1L0, N = 44); and IIIc was a medium/eloquent AVM (S2D0L1, N = 148). The median target volume was 3.8 ml (range 0.1–26.3 ml) and the margin dose was 20 Gy (range 13–25 Gy). Eighty-one patients (17%) underwent prior embolization, and 58 (12%) underwent prior resection.

Results

At a mean follow-up of 89 months, the total obliteration rates documented by angiography or MRI for all SM Grade III AVMs increased from 48% at 3 years to 69% at 4 years, 72% at 5 years, and 77% at 10 years. The SM Grade IIIa AVMs were more likely to obliterate than other subgroups. The cumulative rate of hemorrhage was 2.3% at 1 year, 4.4% at 2 years, 5.5% at 3 years, 6.4% at 5 years, and 9% at 10 years. The SM Grade IIIb AVMs had a significantly higher cumulative rate of hemorrhage. Symptomatic adverse radiation effects were detected in 6%.

Conclusions

Treatment with SRS was an effective and relatively safe management option for SM Grade III AVMs. Although patients with residual AVMs remained at risk for hemorrhage during the latency interval, the cumulative 10-year 9% hemorrhage risk in this series may represent a significant reduction compared with the expected natural history.