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Douglas Kondziolka, Elad I. Levy, Ajay Niranjan, John C. Flickinger, and L. Dade Lunsford

Object. Stereotactic radiosurgery is a primary or adjuvant management approach used to treat patients with intracranial meningiomas. The goal of radiosurgery is long-term prevention of tumor growth, maintenance of the patient's neurological function, and prevention of new neurological deficits. The object of this study is to report longer-term patient outcomes.

Methods. The authors evaluated 99 consecutive patients who underwent radiosurgery for meningioma between 1987 and 1992. Evaluation was performed using serial imaging tests, clinical evaluations, and a patient survey that was administered between 5 and 10 years after radiosurgery. Four patients underwent two radiosurgery procedures for separate meningiomas. The average tumor margin dose was 16 Gy and the median tumor volume was 4.7 ml (range 0.24–24 ml). Fifty-seven patients (57%) had undergone prior resection, of which 12 procedures were considered “total.” Five patients received fractionated radiation therapy before radiosurgery. Eighty-nine patients (89%) had skull base tumors.

The clinical tumor control rate (no resection required) was 93%. Sixty-one (63%) of 97 tumors became smaller, 31 (32%) remained unchanged in size, and five (5%) were enlarged. Resection was performed in seven patients (7%), six of whom had undergone prior resection. New neurological deficits developed in five patients (5%) 3 to 31 months after radiosurgery. Twenty-seven (42%) of 65 responding patients were employed at the time of radiosurgery and 20 (74%) of these remained so. Radiosurgery was believed to have been “successful” by 67 of 70 patients who completed an outcomes questionnaire 5 to 10 years later. At least one complication was described by nine patients (14%) and in four patients the complications resolved.

Conclusions. Five to 10 years after radiosurgery, 96% of surveyed patients believed that radiosurgery provided a satisfactory outcome for their meningioma. Overall, 93% of patients required no other tumor surgery. Incidences of morbidity in this early experience were usually transitory and relatively mild. Radiosurgery provided long-term tumor control associated with high rates of neurological function preservation and patient satisfaction.

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John C. Flickinger, Douglas Kondziolka, Ajay Niranjan, and L. Dade Lunsford

Object. The goal of this study was to define tumor control and complications of radiosurgery encountered using current treatment methods for the initial management of patients with unilateral acoustic neuroma.

Methods. One hundred ninety patients with previously untreated unilateral acoustic neuromas (vestibular schwannomas) underwent gamma knife radiosurgery between 1992 and 1997. The median follow-up period in these patients was 30 months (maximum 85 months). The marginal radiation doses were 11 to 18 Gy (median 13 Gy), the maximum doses were 22 to 36 Gy (median 26 Gy), and the treatment volumes were 0.1 to 33 cm3 (median 2.7 cm3).

The actuarial 5-year clinical tumor-control rate (no requirement for surgical intervention) for the entire series was 97.1 ± 1.9%. Five-year actuarial rates for any new facial weakness, facial numbness, hearing-level preservation, and preservation of testable speech discrimination were 1.1 ± 0.8%, 2.6 ± 1.2%, 71 ± 4.7%, and 91 ± 2.6%, respectively. Facial weakness did not develop in any patient who received a marginal dose of less than 15 Gy (163 patients). Hearing levels improved in 10 (7%) of 141 patients who exhibited decreased hearing (Gardner-Robertson Classes II–V) before undergoing radiosurgery. According to multivariate analysis, increasing marginal dose correlated with increased development of facial weakness (p = 0.0342) and decreased preservation of testable speech discrimination (p = 0.0122).

Conclusions. Radiosurgery for acoustic neuroma performed using current procedures is associated with a continued high rate of tumor control and lower rates of posttreatment morbidity than those published in earlier reports.

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Norimoto Nakahara, Hideho Okada, Timothy F. Witham, Jason Attanucci, Wendy K. Fellows, William H. Chambers, Ajay Niranjan, Douglas Kondziolka, and Ian F. Pollack

Object. To determine if the combination of radiosurgery and tumor cell vaccine would enhance the therapy of metastatic lesions of the central nervous system (CNS), the authors examined the antitumoral effects of radiosurgery and cytokine-transduced tumor cell vaccine.

Methods. Fifty-five rats underwent intracranial implantation of 5 × 103 MADB106 cells. On Day 3 after tumor implantation, 34 rats were inoculated in the flank with nonirradiated MADB106 cells that had been retrovirally transduced to express granulocyte-macrophage colony-stimulating factor or interleukin-4. Twenty-seven rats (17 animals that had received the vaccine and 10 that had not) underwent radiosurgery performed using a gamma knife at maximum doses of 32 Gy on Day 5.

No animals in the untreated group or in the vaccine-alone groups survived longer than 21 days. Animals treated by radiosurgery alone displayed prolonged survival in comparison with untreated animals (p < 0.0001), but only one of 10 animals survived longer than 55 days. In contrast, 14 of 17 animals that received the combination therapy of radiosurgery and vaccination survived longer than 55 days (p = 0.0003 compared with animals that underwent radiosurgery alone). On Day 55, the long-term survivors were challenged by parental MADB106 cells, which were implanted in the contralateral hemisphere. All animals from the combination therapy groups survived longer than 50 days after this challenge, but the single survivor from the radiosurgery-alone group died of tumor growth in 27 days.

Conclusions. The combination of radiosurgery and cytokine gene—transduced tumor cell vaccine markedly prolonged animal survival and protected animals from a subsequent challenge by parental tumor cells placed in the CNS. The data provided by this study indicate that this combination therapy represents a strategy that may have clinical applicability for single and/or multiple metastatic brain tumors.

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Constantinos G. Hadjipanayis, Douglas Kondziolka, Paul Gardner, Ajay Niranjan, Shekhar Dagam, John C. Flickinger, and L. Dade Lunsford

Object. The goal of this study was to examine the role of stereotactic radiosurgery in the treatment of patients with recurrent or unresectable pilocytic astrocytomas.

Methods. During a 13-year interval, 37 patients (median age 14 years) required multimodal treatment of recurrent or unresectable pilocytic astrocytomas. Tumors involved the brainstem in 18 patients, cerebellum in three, thalamus in five, temporal lobe in four, and parietal lobe in two, as well as the hypothalamus, optic tract, corpus callosum, insular cortex, and third ventricle in one patient each. Diagnosis was confirmed with the aid of stereotactic biopsy in 12 patients, open biopsy in five, partial resection in eight, and near-total resection in 12. Multimodal treatment included fractionated radiation therapy in 10 patients, stereotactic intracavitary irradiation of tumor in four, chemotherapy in two, cyst drainage in six, ventriculoperitoneal shunt placement in three, and additional cytoreductive surgery in four. Tumor volumes varied from 0.42 to 25 cm3. The median radiosurgical dose to the tumor margin was 15 Gy (range 9.6–22.5 Gy).

After radiosurgery, serial imaging demonstrated complete tumor resolution in 10 patients, reduced tumor volume in eight, stable tumor volume in seven, and delayed tumor progression in 12. No procedure-related death was encountered. Thirty-three (89%) of 37 patients are alive at a median follow-up period of 28 months after radiosurgery and 59 months after diagnosis. Eight patients participated in follow-up review for more than 60 months. Three patients died of local tumor progression.

Conclusions. Stereotactic radiosurgery is a valuable adjunctive strategy in the management of recurrent or unresectable pilocytic astrocytomas. Despite the favorable histological characteristics and prognosis usually associated with this neoplasm, an adverse location, recurrence, or progression of this disease requires alternative therapeutic approaches such as radiosurgery.

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John Y. K. Lee, Ajay Niranjan, James McInerney, Douglas Kondziolka, John C. Flickinger, and L. Dade Lunsford

Object. To evaluate long-term outcomes of patients who have undergone stereotactic radiosurgery for cavernous sinus meningiomas, the authors retrospectively reviewed their 14-year experience with these cases.

Methods. One hundred seventy-six patients harbored meningiomas centered within the cavernous sinus. Seventeen patients were lost to follow-up review, leaving 159 analyzable patients, in whom 164 procedures were performed. Seventy-six patients (48%) underwent adjuvant radiosurgery after one or more attempts at surgical resection. Eighty-three patients (52%) underwent primary radiosurgery. Two patients (1%) had previously received fractionated external-beam radiation therapy. Four patients (2%) harbored histologically verified atypical or malignant meningiomas. Conformal multiple isocenter gamma knife surgery was performed. The median dose applied to the tumor margin was 13 Gy.

Neurological status improved in 46 patients (29%), remained stable in 99 (62%), and eventually worsened in 14 (9%). Adverse effects of radiation occurred after 11 procedures (6.7%). Tumor volumes decreased in 54 patients (34%), remained stable in 96 (60%), and increased in nine (6%). The actuarial tumor control rate for patients with typical meningiomas was 93.1 ± 3.3% at both 5 and 10 years. For the 83 patients who underwent radiosurgery as their sole treatment, the actuarial tumor control rate at 5 years was 96.9 ± 3%.

Conclusions. Stereotactic radiosurgery provided safe and effective management of cavernous sinus meningiomas. We believe it is the preferred management strategy for tumors of suitable volume (average tumor diameter ≤ 3 cm or volume ≤ 15 cm3).

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Keisuke Maruyama, Douglas Kondziolka, Ajay Niranjan, John C. Flickinger, and L. Dade Lunsford

Object. Management options for arteriovenous malformations (AVMs) of the brainstem are limited. The long-term results of stereotactic radiosurgery for these disease entities are poorly understood. In this report the authors reviewed both neurological and radiological outcomes following stereotactic radiosurgery for brainstem AVMs over 15 years of experience.

Methods. Fifty patients with brainstem AVMs underwent gamma knife surgery between 1987 and 2002. There were 29 male and 21 female patients with an age range of 7 to 79 years (median 35 years). Anatomical locations of these AVMs included the midbrain (39 lesions), pons (20 lesions), and medulla oblongata (three lesions). The radiation dose applied to the margin of the AVM varied from 12 to 26 Gy (median 20 Gy). Forty-five patients were followed up from 5 to 176 months (mean 72 months). The angiographically confirmed actuarial obliteration rate was 66% at the final follow-up examination. Two patients experienced a hemorrhage before obliteration. The annual hemorrhage rate was 1.7% for the first 3 years after radiosurgery and 0% thereafter. Patients who had received irradiation at two or fewer isocenters had higher obliteration rates (80% compared with 44% for > two isocenters, p = 0.006), and this was related to a more spherical nidus shape. The rate of persistent neurological complications in patients treated using magnetic resonance imaging—based dose planning after 1993 was 7%, compared with 20% in patients treated before 1993. An older patient age, a lesion located in the tectum, and a higher radiosurgery-based score were significantly associated with greater neurological complications.

Conclusions. Stereotactic radiosurgery provided complete obliteration of AVMs in two thirds of the patients with a low risk of latency-interval hemorrhage. Better three-dimensional imaging studies and conformal dose planning reduced the risk of adverse radiation effects. Younger patients harboring more spherical AVMs that did not involve the tectal plate had the best outcomes.

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L. Dade Lunsford, Ajay Niranjan, John C. Flickinger, Ann Maitz, and Douglas Kondziolka

Object. Management options for vestibular schwannomas (VSs) have greatly expanded since the introduction of stereotactic radiosurgery. Optimal outcomes reflect long-term tumor control, preservation of cranial nerve function, and retention of quality of life. The authors review their 15-year experience.

Methods. Between 1987 and 2002, some 829 patients with VSs underwent gamma knife surgery (GKS). Dose selection, imaging, and dose planning techniques evolved between 1987 and 1992 but thereafter remained stable for 10 years. The average tumor volume was 2.5 cm3. The median margin dose to the tumor was 13 Gy (range 10–20 Gy).

No patient sustained significant perioperative morbidity. The average duration of hospital stay was less than 1 day. Unchanged hearing preservation was possible in 50 to 77% of patients (up to 90% in those with intracanalicular tumors). Facial neuropathy risks were reduced to less than 1%. Trigeminal symptoms were detected in less than 3% of patients whose tumors reached the level of the trigeminal nerve. Tumor control rates at 10 years were 97% (no additional treatment needed).

Conclusions. Superior imaging, multiple isocenter volumetric conformal dose planning, and optimal precision and dose delivery contributed to the long-term success of GKS, including in those patients in whom initial microsurgery had failed. Gamma knife surgery provides a low risk, minimally invasive treatment option for patients with newly diagnosed or residual VS. Cranial nerve preservation and quality of life maintenance are possible in long-term follow up.

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Jason P. Sheehan, Ajay Niranjan, Jonas M. Sheehan, John A. Jane Jr., Edward R. Laws, Douglas Kondziolka, John Flickinger, Alex M. Landolt, Jay S. Loeffler, and L. Dade Lunsford

Object. Pituitary adenomas are very common neoplasms, constituting between 10 and 20% of all primary brain tumors. Historically, the treatment armamentarium for pituitary adenomas has included medical management, microsurgery, and fractionated radiotherapy. More recently, radiosurgery has emerged as a viable treatment option. The goal of this research was to define more fully the efficacy, safety, and role of radiosurgery in the treatment of pituitary adenomas.

Methods. Medical literature databases were searched for articles pertaining to pituitary adenomas and stereotactic radiosurgery. Each study was examined to determine the number of patients, radiosurgical parameters (for example, maximal dose and tumor margin dose), duration of follow-up review, tumor growth control rate, complications, and rate of hormone normalization in the case of functioning adenomas.

A total of 35 peer-reviewed studies involving 1621 patients were examined. Radiosurgery resulted in the control of tumor size in approximately 90% of treated patients. The reported rates of hormone normalization for functioning adenomas varied substantially. This was due in part to widespread differences in endocrinological criteria used for the postradiosurgical assessment. The risks of hypopituitarism, radiation-induced neoplasia, and cerebral vasculopathy associated with radiosurgery appeared lower than those for fractionated radiation therapy. Nevertheless, further observation will be required to understand the true probabilities. The incidence of other serious complications following radiosurgery was quite low.

Conclusions. Although microsurgery remains the primary treatment modality in most cases, stereotactic radiosurgery offers both safe and effective treatment for recurrent or residual pituitary adenomas. In rare instances, radiosurgery may be the best initial treatment for patients with pituitary adenomas. Further refinements in the radiosurgical technique will likely lead to improved outcomes.

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Ajay Niranjan, Wendy Fellows, William Stauffer, Edward A. Burton, Chang-Sook Hong, L. Dade Lunsford, Douglas Kondziolka, Joseph C. Glorioso, and Glenn T. Gobbel

Object

Authors of previous studies have reported that adult transplanted neural progenitor cells (NPCs) are suitable for brain cell replacement or gene delivery. In this study, the authors evaluated survival and integration of adult rat–derived NPCs after transplantation and explored the potential impact on transplant survival of various mechanical and biological factors of clinical importance.

Methods

Adult female Fischer 344 rats were used both as a source and recipient of transplanted NPCs. Both 9L and RG2 rat glioma cells were used to generate in vivo brain tumor models. On the 5th day after tumor implantation, NPCs expressing green fluorescent protein (GFP) were administered either intravenously (3.5 × 107 cells) or by stereotactic injection (1 × 104–1 × 106 cells) into normal or tumor-bearing brain. The authors evaluated the effect of delivery method (sharp compared with blunt needles, normal compared with zero-volume needles, phosphate-buffered saline compared with medium as vehicle), delivery sites (intravenous compared with intratumoral compared with intraparenchymal), and pretreatment with an immunosuppressive agent (cyclosporin) or brain irradiation (20–40 Gy) on survival and integration of transplanted NPCs.

Results

Very few cells survived when less than 105 cells were transplanted. When 105 cells or more were transplanted, only previously administered brain irradiation significantly affected survival and integration of NPCs. Although GFP-containing NPCs could be readily detected 1 day after injection, few cells survived 4 days to 1 week unless preceded by whole-brain radiation (20 or 40 Gy in a single fraction), which increased the number of GFP-containing NPCs within the tissue more than fivefold.

Conclusions

he authors' findings indicate that most NPCs, including those from a syngeneic autologous source, do not survive at the site of implantation, but that brain irradiation can facilitate subsequent survival in both normal and tumor-bearing brain. An understanding of the mechanisms of this effect could lead to improved survival and clinical utility of transplanted NPCs.

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Juan J. Martin, Ajay Niranjan, Douglas Kondziolka, John C. Flickinger, Karl A. Lozanne, and L. Dade Lunsford

Object

Chordomas and chondrosarcomas of the skull base are aggressive and locally destructive tumors with a high tendency for local progression despite treatment. The authors evaluated the effect of stereotactic radiosurgery (SRS) on local tumor control and survival.

Methods

Twenty-eight patients with histologically confirmed chordomas (18) or chondrosarcomas (10) underwent Gamma Knife SRS either as primary or adjuvant treatment. Their ages ranged from 17 to 72 years (median 44 years). The most common presenting symptom was diplopia (26 patients, 93%). In two patients, SRS was the sole treatment. Twenty-six patients underwent between one and five additional surgical procedures. Two underwent an initial trans-sphenoidal biopsy. The average tumor volume was 9.8 cm3. The median dose to the tumor margin was 16 Gy.

Results

No patient was lost to follow-up. Transient symptomatic adverse radiation effects developed in only one patient. The actuarial local tumor control for chondrosarcomas at 5 years was 80 ± 10.1%. For chordomas both the actuarial tumor control and survival was 62.9 ± 10.4%.

Conclusions

Stereotactic radiosurgery is an important option for skull base chordomas and chondrosarcomas either as primary or adjunctive treatment. Multimodal management appears crucial to improve tumor control in most patients.