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Hideyuki Kano, Huai-che Yang, Douglas Kondziolka, Ajay Niranjan, Yoshio Arai, John C. Flickinger, and L. Dade Lunsford

Object

To evaluate the role of stereotactic radiosurgery (SRS) in patients with recurrent or residual intracranial ependymomas after resection and fractionated radiation therapy (RT), the authors assessed overall survival, distant tumor relapse, progression-free survival (PFS), and complications.

Methods

The authors retrospectively reviewed the records of 21 children with ependymomas who underwent SRS for 32 tumors. There were 17 boys and 4 girls with a median age of 6.9 years (range 2.9–17.2 years) in the patient population. All patients underwent resection of an ependymoma followed by cranial or neuraxis (if spinal metastases was confirmed) RT. Eleven patients had adjuvant chemotherapy. Twelve patients had low-grade ependymomas (17 tumors), and 9 patients had anaplastic ependymomas (15 tumors). The median radiosurgical target volume was 2.2 cm3 (range 0.1–21.4 cm3), and the median dose to the tumor margin was 15 Gy (range 9–22 Gy).

Results

Follow-up imaging demonstrated therapeutic control in 23 (72%) of 32 tumors at a mean follow-up period of 27.6 months (range 6.1–72.8 months). Progression-free survival after the initial SRS was 78.4%, 55.5%, and 41.6% at 1, 2, and 3 years, respectively. Factors associated with a longer PFS included patients without spinal metastases (p = 0.033) and tumor volumes < 2.2 cm3 (median tumor volume 2.2 cm3, p = 0.029). An interval ≥18 months between RT and SRS was also associated with longer survival (p = 0.035). The distant tumor relapse rate despite RT and SRS was 33.6%, 41.0%, and 80.3% at 1, 2, and 3 years, respectively. Factors associated with a higher rate of distant tumor relapse included patients who had spinal metastases before RT (p = 0.037), a fourth ventricle tumor location (p = 0.002), and an RT to SRS interval < 18 months (p = 0.015). The median survival after SRS was 27.6 months (95% CI 19.33–35.87 months). Overall survival after SRS was 85.2%, 53.2%, and 23.0% at 1, 2, and 3 years, respectively. Adverse radiation effects developed in 2 patients (9.5%).

Conclusions

Stereotactic radiosurgery offers an additional option beyond repeat surgery or RT in pediatric patients with residual or recurrent ependymomas after initial management. Patients with smaller-volume tumors and a later recurrence responded best to radiosurgery.

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Huai-che Yang, Hideyuki Kano, Nasir Raza Awan, L. Dade Lunsford, Ajay Niranjan, John C. Flickinger, Josef Novotny Jr., Jagdish P. Bhatnagar, and Douglas Kondziolka

Object

Stereotactic radiosurgery (SRS) is an important management option for patients with small- and medium-sized vestibular schwannomas. To assess the potential role of SRS in larger tumors, the authors reviewed their recent experience.

Methods

Between 1994 and 2008, 65 patients with vestibular schwannomas between 3 and 4 cm in one extracanalicular maximum diameter (median tumor volume 9 ml) underwent Gamma Knife surgery. Seventeen patients (26%) had previously undergone resection.

Results

The median follow-up duration was 36 months (range 1–146 months). At the first planned imaging follow-up at 6 months, 5 tumors (8%) were slightly expanded, 53 (82%) were stable in size, and 7 (11%) were smaller. Two patients (3%) underwent resection within 6 months due to progressive symptoms. Two years later, with 63 tumors overall after the 2 post-SRS resections, 16 tumors (25%) had a volume reduction of more than 50%, 22 (35%) tumors had a volume reduction of 10–50%, 18 (29%) were stable in volume (volume change < 10%), and 7 (11%) had larger volumes (5 of the 7 patients underwent resection and 1 of the 7 underwent repeat SRS). Eighteen (82%) of 22 patients with serviceable hearing before SRS still had serviceable hearing after SRS more than 2 years later. Three patients (5%) developed symptomatic hydrocephalus and underwent placement of a ventriculoperitoneal shunt. In 4 patients (6%) trigeminal sensory dysfunction developed, and in 1 patient (2%) mild facial weakness (House-Brackmann Grade II) developed after SRS. In univariate analysis, patients who had a previous resection (p = 0.010), those with a tumor volume exceeding 10 ml (p = 0.05), and those with Koos Grade 4 tumors (p = 0.02) had less likelihood of tumor control after SRS.

Conclusions

Although microsurgical resection remains the primary management choice in patients with low comorbidities, most vestibular schwannomas with a maximum diameter less than 4 cm and without significant mass effect can be managed satisfactorily with Gamma Knife radiosurgery.

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Douglas Kondziolka, Hideyuki Kano, Gillian L. Harrison, Huai-che Yang, Donald N. Liew, Ajay Niranjan, Adam M. Brufsky, John C. Flickinger, and L. Dade Lunsford

Object

To evaluate the role of stereotactic radiosurgery (SRS) in the management of brain metastases from breast cancer, the authors assessed clinical outcomes and prognostic factors for survival.

Methods

The records from 350 consecutive female patients who underwent SRS for 1535 brain metastases from breast cancer were reviewed. The median patient age was 54 years (range 19–84 years), and the median number of tumors per patient was 2 (range 1–18 lesions). One hundred seventeen patients (33%) had a single metastasis to the brain, and 233 patients (67%) had multiple brain metastases. The median tumor volume was 0.7 cm3 (range 0.01–48.9 cm3), and the median total tumor volume for each patient was 4.9 cm3 (range 0.09–74.1 cm3).

Results

Overall survival after SRS was 69%, 49%, and 26% at 6, 12, and 24 months, respectively, with a median survival of 11.2 months. Factors associated with a longer survival included controlled extracranial disease, a lower recursive partitioning analysis (RPA) class, a higher Karnofsky Performance Scale score, a smaller number of brain metastases, a smaller total tumor volume per patient, the presence of deep cerebral or brainstem metastases, and HER2/neu overexpression. Sustained local tumor control was achieved in 90% of the patients. Factors associated with longer progression-free survival included a better RPA class, fewer brain metastases, a smaller total tumor volume per patient, and a higher tumor margin dose. Symptomatic adverse radiation effects occurred in 6% of patients. Overall, the condition of 82% of patients improved or remained neurologically stable.

Conclusions

Stereotactic radiosurgery was safe and effective in patients with brain metastases from breast cancer and should be considered for initial treatment.

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Hideyuki Kano, L. Dade Lunsford, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Nasir R. Awan, Ajay Niranjan, Josef Novotny Jr., and Douglas Kondziolka

Object

The aim of this paper was to define the outcomes and risks of stereotactic radiosurgery (SRS) for Spetzler-Martin Grade I and II arteriovenous malformations (AVMs).

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs, including 217 patients with AVMs classified as Spetzler-Martin Grade I or II. The median maximum diameter and target volumes were 1.9 cm (range 0.5–3.8 cm) and 2.3 cm3 (range 0.1–14.1 cm3), respectively. The median margin dose was 22 Gy (range 15–27 Gy).

Results

Arteriovenous malformation obliteration was confirmed by MR imaging in 148 patients and by angiography in 100 patients with a median follow-up of 64 months (range 6–247 months). The actuarial rates of total obliteration determined by angiography or MR imaging after 1 SRS procedure were 58%, 87%, 90%, and 93% at 3, 4, 5, and 10 years, respectively. The median time to complete MR imaging–determined obliteration was 30 months. Factors associated with higher AVM obliteration rates were smaller AVM target volume, smaller maximum diameter, and greater marginal dose. Thirteen patients (6%) suffered hemorrhages during the latency period, and 6 patients died. Cumulative rates of AVM hemorrhage 1, 2, 3, 5, and 10 years after SRS were 3.7%, 4.2%, 4.2%, 5.0%, and 6.1%, respectively. This corresponded to rates of annual bleeding risk of 3.7%, 0.3%, and 0.2% for Years 0–1, 1–5, and 5–10, respectively, after SRS. The presence of a coexisting aneurysm proximal to the AVM correlated with a significantly higher hemorrhage risk. Temporary symptomatic adverse radiation effects developed in 5 patients (2.3%) after SRS, and 2 patients (1%) developed delayed cysts.

Conclusions

Stereotactic radiosurgery is a gradually effective and relatively safe option for patients with smaller volume Spetzler-Martin Grade I or II AVMs who decline initial resection. Hemorrhage after obliteration did not occur in this series. Patients remain at risk for a bleeding event during the latency interval until obliteration occurs. Patients with aneurysms and an AVM warrant more aggressive surgical or endovascular treatment to reduce the risk of a hemorrhage in the latency period after SRS.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Nasir R. Awan, Ajay Niranjan, Josef Novotny Jr., and L. Dade Lunsford

Object

The authors conducted a study to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for pediatric arteriovenous malformations (AVMs).

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs; 135 patients were younger than 18 years of age. The median maximum diameter and target volumes were 2.0 cm (range 0.6–5.2 cm) and 2.5 cm3 (range 0.1–17.5 cm3), respectively. The median margin dose was 20 Gy (range 15–25 Gy).

Results

The actuarial rates of total obliteration documented by angiography or MR imaging at 71.3 months (range 6–264 months) were 45%, 64%, 67%, and 72% at 3, 4, 5, and 10 years, respectively. The median time to complete angiographically documented obliteration was 48.9 months. Of 81 patients with 4 or more years of follow-up, 57 patients (70%) had total obliteration documented by angiography. Factors associated with a higher rate of documented AVM obliteration were smaller AVM target volume, smaller maximum diameter, and larger margin dose. In 8 patients (6%) a hemorrhage occurred during the latency interval, and 1 patient died. The rates of AVM hemorrhage after SRS were 0%, 1.6%, 2.4%, 5.5%, and 10.0% at 1, 2, 3, 5, and 10 years, respectively. The overall annual hemorrhage rate was 1.8%. Larger volume AVMs were associated with a significantly higher risk of hemorrhage after SRS. Permanent neurological deficits due to adverse radiation effects developed in 2 patients (1.5%) after SRS, and in 1 patient (0.7%) delayed cyst formation occurred.

Conclusions

Stereotactic radiosurgery is a gradually effective and relatively safe management option for pediatric patients in whom surgery is considered to pose excessive risks. Although hemorrhage after AVM obliteration did not occur in the present series, patients remain at risk during the latency interval until obliteration is complete. The best candidates for SRS are pediatric patients with smaller volume AVMs located in critical brain regions.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Nasir R. Awan, Ajay Niranjan, Josef Novotny Jr., and L. Dade Lunsford

Object

The object of this study was to evaluate the outcomes and risks of repeat stereotactic radiosurgery (SRS) for incompletely obliterated cerebral arteriovenous malformations (AVMs).

Methods

Between 1987 and 2006, Gamma Knife surgery was performed in 996 patients with AVMs. During this period, repeat SRS was performed in 105 patients who had incompletely obliterated AVMs at a median of 40.9 months after initial SRS (range 27.5–139 months). The median AVM target volume was 6.4 cm3 (range 0.2–26.3 cm3) at initial SRS but was reduced to 2.3 cm3 (range 0.1–18.2 cm3) at the time of the second procedure. The median margin dose at both initial SRS and repeat SRS was 18 Gy.

Results

The actuarial rate of total obliteration by angiography or MR imaging after repeat SRS was 35%, 68%, 77%, and 80% at 3, 4, 5, and 10 years, respectively. The median time to complete angiographic or MR imaging obliteration after repeat SRS was 39 months. Factors associated with a higher rate of AVM obliteration were smaller residual AVM target volume (p = 0.038) and a volume reduction of 50% or more after the initial procedure (p = 0.014). Seven patients (7%) had a hemorrhage in the interval between initial SRS and repeat SRS. Seventeen patients (16%) had hemorrhage after repeat SRS and 6 patients died. The cumulative actuarial rates of new AVM hemorrhage after repeat SRS were 1.9%, 8.1%, 10.1%, 10.1%, and 22.4% at 1, 2, 3, 5, and 10 years, respectively, which translate to annual hemorrhage rates of 4.05% and 1.79% of patients developing new post–repeat-SRS hemorrhages per year for Years 0–2 and 2–10 following repeat SRS. Factors associated with a higher risk of hemorrhage after repeat SRS were a greater number of prior hemorrhages (p = 0.008), larger AVM target volume at initial SRS (p = 0.010), larger target volume at repeat SRS (p = 0.002), initial AVM volume reduction less than 50% (p = 0.019), and a higher Pollock-Flickinger score (p = 0.010). Symptomatic adverse radiation effects developed in 5 patients (4.8%) after initial SRS and in 10 patients (9.5%) after repeat SRS. Prior embolization (p = 0.022) and a higher Spetzler-Martin grade (p = 0.004) were significantly associated with higher rates of adverse radiation effects after repeat SRS. Delayed cyst formation occurred in 5 patients (4.8%) at a median of 108 months after repeat SRS (range 47–184 months).

Conclusions

Repeat SRS for incompletely obliterated AVMs increases the eventual obliteration rate. Hemorrhage after obliteration did not occur in this series. The best results for patients with incompletely obliterated AVMs were seen in patients with a smaller residual nidus volume and no prior hemorrhages.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Ajay Niranjan, Josef Novotny Jr., and L. Dade Lunsford

Object

The authors conducted a study to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for arteriovenous malformations (AVMs) of the basal ganglia and thalamus.

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs; 56 patients had AVMs of the basal ganglia and 77 had AVMs of the thalamus. In this series, 113 (85%) of 133 patients had a prior hemorrhage. The median target volume was 2.7 cm3 (range 0.1–20.7 cm3) and the median margin dose was 20 Gy (range 15–25 Gy).

Results

Obliteration of the AVM eventually was documented on MR imaging in 78 patients and on angiography in 63 patients in a median follow-up period of 61 months (range 2–265 months). The actuarial rates documenting total obliteration after radiosurgery were 57%, 70%, 72%, and 72% at 3, 4, 5, and 10 years, respectively. Factors associated with a higher rate of AVM obliteration included AVMs located in the basal ganglia, a smaller target volume, a smaller maximum diameter, and a higher margin dose. Fifteen (11%) of 133 patients suffered a hemorrhage during the latency period and 7 patients died. The rate of post-SRS AVM hemorrhage was 4.5%, 6.2%, 9.0%, 11.2%, and 15.4% at 1, 2, 3, 5, and 10 years, respectively. The overall annual hemorrhage rate was 4.7%. When 5 patients with 7 hemorrhages occurring earlier than 6 months after SRS were removed from this analysis, the annual hemorrhage rate decreased to 2.7%. Larger volume AVMs had a higher risk of hemorrhage after SRS. Permanent neurological deficits due to adverse radiation effects (AREs) developed in 6 patients (4.5%), and in 1 patient a delayed cyst developed 56 months after SRS. No patient died of AREs. Factors associated with a higher risk of symptomatic AREs were larger target volume, larger maximum diameter, lower margin dose, and a higher Pollock-Flickinger score.

Conclusions

Stereotactic radiosurgery is a gradually effective and relatively safe management option for deep-seated AVMs in the basal ganglia and thalamus. Although hemorrhage after obliteration did not occur in the present series, patients remain at risk during the latency interval between SRS and obliteration. The best candidates for SRS are patients with smaller volume AVMs located in the basal ganglia.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Huai-che Yang, Thomas J. Flannery, Ajay Niranjan, Josef Novotny Jr., and L. Dade Lunsford

Object

In this paper, the authors' goal was to define the long-term outcomes and risks of stereotactic radiosurgery (SRS) for arteriovenous malformations (AVMs) of the medulla, pons, and midbrain.

Methods

Between 1987 and 2006, the authors performed Gamma Knife surgery in 996 patients with brain AVMs; 67 patients had AVMs in the brainstem. In this series, 51 patients (76%) had a prior hemorrhage. The median target volume was 1.4 cm3 (range 0.1–13.4 cm3). The median margin dose was 20 Gy (range 14–25.6 Gy).

Results

Obliteration of the AVMs was eventually documented in 35 patients at a median follow-up of 73 months (range 6–269 months). The actuarial rates of documentation of total obliteration were 41%, 70%, 70%, and 76% at 3, 4, 5, and 10 years, respectively. Higher rates of AVM obliteration were associated only with a higher margin dose. Four patients (6%) suffered a hemorrhage during the latency period, and 2 patients died. The rate of AVM hemorrhage after SRS was 3.0%, 3.0%, and 5.8% at 1, 5, and 10 years, respectively. The overall annual hemorrhage rate was 1.9%. Permanent neurological deficits due to adverse radiation effects (AREs) developed in 7 patients (10%) after SRS, and a delayed cyst developed in 2 patients (3%). One patient died at an outside institution with symptoms of AREs and unrecognized hydrocephalus. Higher 12-Gy volumes and higher Spetzler-Martin grades were associated with a higher risk of symptomatic AREs. Ten of 22 patients who had ocular dysfunction before SRS had improvement, 9 were unchanged, and 3 were worse due to AREs. Eight of 14 patients who had hemiparesis before SRS improved, 5 were unchanged, and 1 was worse.

Conclusions

Although hemorrhage after obliteration did not occur in this series, patients remained at risk during the latency interval until obliteration occurred. Thirty-eight percent of the patients who had neurological deficits due to prior hemorrhage improved. Higher dose delivery in association with conformal and highly selective SRS is required for safe and effective radiosurgery.

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Hideyuki Kano, Douglas Kondziolka, John C. Flickinger, Kyung-Jae Park, Phillip V. Parry, Huai-che Yang, Sait Sirin, Ajay Niranjan, Josef Novotny Jr., and L. Dade Lunsford

Object

The object of this study was to define the long-term outcomes and risks of arteriovenous malformation (AVM) management using 2 or more stages of stereotactic radiosurgery (SRS) for symptomatic large-volume lesions unsuitable for surgery.

Methods

In 1992, the authors prospectively began to stage the treatment of anatomical components to deliver higher single doses to AVMs with a volume of more than 10 cm3. Forty-seven patients with such AVMs underwent volume-staged SRS. In this series, 18 patients (38%) had a prior hemorrhage and 21 patients (45%) underwent prior embolization. The median interval between the first-stage SRS and the second-stage SRS was 4.9 months (range 2.8–13.8 months). The median target volume was 11.5 cm3 (range 4.0–26 cm3) in the first-stage SRS and 9.5 cm3 in the second-stage SRS. The median margin dose was 16 Gy (range 13–18 Gy) for both stages.

Results

In 17 patients, AVM obliteration was confirmed after 2–4 SRS procedures at a median follow-up of 87 months (range 0.4–209 months). Five patients had near-total obliteration (volume reduction > 75% but residual AVM). The actuarial rates of total obliteration after 2-stage SRS were 7%, 20%, 28%, and 36% at 3, 4, 5, and 10 years, respectively. The 5-year total obliteration rate after the initial staged volumetric SRS with a margin dose of 17 Gy or more was 62% (p = 0.001). Sixteen patients underwent additional SRS at a median interval of 61 months (range 33–113 months) after the initial 2-stage SRS. The overall rates of total obliteration after staged and repeat SRS were 18%, 45%, and 56% at 5, 7, and 10 years, respectively. Ten patients sustained hemorrhage after staged SRS, and 5 of these patients died. Three of 16 patients who underwent repeat SRS sustained hemorrhage after the procedure and died. Based on Kaplan-Meier analysis (excluding the second hemorrhage in the patient who had 2 hemorrhages), the cumulative rates of AVM hemorrhage after SRS were 4.3%, 8.6%, 13.5%, and 36.0% at 1, 2, 5, and 10 years, respectively. This corresponded to annual hemorrhage risks of 4.3%, 2.3%, and 5.6% for Years 0–1, 1–5, and 5–10 after SRS. Multiple hemorrhages before SRS correlated with a significantly higher risk of hemorrhage after SRS. Symptomatic adverse radiation effects were detected in 13% of patients, but no patient died as a result of an adverse radiation effect. Delayed cyst formation did not occur in any patient after SRS.

Conclusions

Prospective volume-staged SRS for large AVMs unsuitable for surgery has potential benefit but often requires more than 2 procedures to complete the obliteration process. To have a reasonable chance of benefit, the minimum margin dose should be 17 Gy or greater, depending on the AVM location. In the future, prospective volume-staged SRS followed by embolization (to reduce flow, obliterate fistulas, and occlude associated aneurysms) may improve obliteration results and further reduce the risk of hemorrhage after SRS.

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Jason P. Sheehan, Shota Tanaka, Michael J. Link, Bruce E. Pollock, Douglas Kondziolka, David Mathieu, Christopher Duma, A. Byron Young, Anthony M. Kaufmann, Heyoung McBride, Peter A. Weisskopf, Zhiyuan Xu, Hideyuki Kano, Huai-che Yang, and L. Dade Lunsford

Object

Glomus tumors are rare skull base neoplasms that frequently involve critical cerebrovascular structures and lower cranial nerves. Complete resection is often difficult and may increase cranial nerve deficits. Stereotactic radiosurgery has gained an increasing role in the management of glomus tumors. The authors of this study examine the outcomes after radiosurgery in a large, multicenter patient population.

Methods

Under the auspices of the North American Gamma Knife Consortium, 8 Gamma Knife surgery centers that treat glomus tumors combined their outcome data retrospectively. One hundred thirty-four patient procedures were included in the study (134 procedures in 132 patients, with each procedure being analyzed separately). Prior resection was performed in 51 patients, and prior fractionated external beam radiotherapy was performed in 6 patients. The patients' median age at the time of radiosurgery was 59 years. Forty percent had pulsatile tinnitus at the time of radiosurgery. The median dose to the tumor margin was 15 Gy. The median duration of follow-up was 50.5 months (range 5–220 months).

Results

Overall tumor control was achieved in 93% of patients at last follow-up; actuarial tumor control was 88% at 5 years postradiosurgery. Absence of trigeminal nerve dysfunction at the time of radiosurgery (p = 0.001) and higher number of isocenters (p = 0.005) were statistically associated with tumor progression–free tumor survival. Patients demonstrating new or progressive cranial nerve deficits were also likely to demonstrate tumor progression (p = 0.002). Pulsatile tinnitus improved in 49% of patients who reported it at presentation. New or progressive cranial nerve deficits were noted in 15% of patients; improvement in preexisting cranial nerve deficits was observed in 11% of patients. No patient died as a result of tumor progression.

Conclusions

Gamma Knife surgery was a well-tolerated management strategy that provided a high rate of long-term glomus tumor control. Symptomatic tinnitus improved in almost one-half of the patients. Overall neurological status and cranial nerve function were preserved or improved in the vast majority of patients after radiosurgery.