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Bruce E. Pollock and John C. Flickinger

Object. Radiosurgery is an effective treatment strategy for properly selected patients harboring arteriovenous malformations (AVMs). Grading scales that are currently used to predict patient outcomes after AVM resection are unreliable tools for the prediction of the results of AVM radiosurgery.

Methods. A grading system was developed to predict outcomes following AVM radiosurgery, based on the multivariate analysis of data obtained in 220 patients treated between 1987 and 1991 (Group 1). The dependent variable in all analyses was excellent patient outcome (complete AVM obliteration without any new neurological deficit). The grading scale was tested on a separate set of 136 patients with AVMs treated between 1990 and 1996 at a different center (Group 2).

One hundred twenty-one (55%) of 220 Group 1 patients had excellent outcomes. Multivariate analysis identified five variables related to excellent patient outcomes: AVM volume (p = 0.001), patient age (p < 0.001), AVM location (p < 0.001), previous embolization (p = 0.02), and number of draining veins (p = 0.001). Regression analysis modeling permitted removal of two significant variables (previous embolization and number of draining veins) and resulted in the following equation to predict patient outcomes after AVM radiosurgery: AVM score = (0.1)(AVM volume in cm3) + (0.02)(patient age in years) + (0.3)(location of lesion: frontal or temporal) = 0; parietal, occipital, intraventricular, corpus callosum, cerebellar = 1; or basal ganglia, thalamic, or brainstem = 2). Seventy-nine (58%) of 136 Group 2 patients had excellent outcomes. All variables in the model remained significant for the Group 2 patients: AVM volume (p = 0.01), patient age (p = 0.01), and AVM location (p < 0.001). Testing of the entire model on the Group 2 patients demonstrated that the AVM score could be used to predict patient outcomes after radiosurgery (p < 0.0001). All patients with an AVM score of 1 or lower had an excellent outcome compared with only 39% of patients with an AVM score higher than 2. The Spetzler—Martin grade (p = 0.13), the K index (p = 0.26), and the obliteration prediction index (p = 0.21) did not correlate with excellent patient outcomes.

Conclusions. Despite significant differences in preoperative patient characteristics and dose prescription guidelines at the two centers, the proposed AVM grading system strongly correlated with patient outcomes after single-session radiosurgery for both patient groups. Although further testing of this model by independent centers using prospective methodology is still required, this system allows a more accurate prediction of outcomes from radiosurgery to guide choices between surgical and radiosurgical management for individual patients with AVMs.

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Salvador Somaza, Douglas Kondziolka, L. Dade Lunsford, John M. Kirkwood, and John C. Flickinger

✓ To determine local tumor control rates and survival of patients with melanoma metastases to the brain, the authors reviewed the results of 23 consecutive patients with a total of 32 tumors (19 patients had a solitary tumor and four had multiple tumors) who underwent adjuvant stereotactic radiosurgery. Tumor locations included the cerebral hemisphere (24 cases), brain stem (four cases), basal ganglia (two cases), and cerebellum (two cases). Fifteen patients had associated cranial symptomatology and eight had incidental metastases. All patients had tumors of 3 cm or less in diameter (mean tumor volume 2.5 cu cm), and all received fractionated whole-brain radiation therapy (30 Gy) in addition to radiosurgery (mean tumor margin dose 16 Gy). Nineteen patients were managed with both modalities at the time of diagnosis; four underwent radiosurgery 3 to 12 months after fractionated whole-brain radiotherapy. The mean patient follow-up period was 12 months (range 3 to 38 months).

After radiosurgery, eight patients improved, 13 remained stable, and two deteriorated. One patient subsequently required craniotomy because of intratumoral hemorrhage; this patient and three others are living 13 to 38 months after radiosurgery. Nineteen patients died, 18 from progression of their systemic disease and one from another hemorrhage into a new brain metastasis. The local tumor control rate was 97%. Only two patients subsequently developed new intracranial metastases. The median survival period after diagnosis was 9 months (range 3 to 38 months). The authors believe that stereotactic radiosurgery coupled with fractionated whole-brain irradiation is an effective management strategy for cerebral metastases from a melanoma. Multi-institutional trials are warranted to confirm that stereotactic radiosurgery results equal or surpass the outcome achieved with craniotomy and tumor resection.

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Peter C. Gerszten, John J. Moossy, John C. Flickinger, and William C. Welch

Object. The authors of clinical studies have demonstrated a significant association between the presence of extensive post—lumbar discectomy peridural scar formation and the recurrence of low-back and radicular pain. Low-dose perioperative radiotherapy has been demonstrated to inhibit peridural fibrosis after laminectomy in animal models. The present study was designed to evaluate the clinical efficacy of preoperative irradiation in patients with failed—back surgery syndrome due to peridural fibrosis who underwent reexploration and nerve root decompression.

Methods. Ten patients with symptomatic post—discectomy peridural fibrosis were randomized. Half of the patients underwent 700-cGy external-beam irradiation to the operative site 24 hours prior to reexploration and decompressive treatment of their symptomatic nerve root(s) (treatment group) and the other half underwent reexploration and decompressive treatment without preoperative irradiation (control group). All patients underwent simulated irradiation so neither patient nor surgeon was aware of the patient's group. In all patients the antiadhesion product ADCON-L was placed over the affected nerve root at the time of surgery. Clinical outcome was assessed using the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section Lumbar Disc Herniation Study Questionnaire at baseline, 6 weeks, 3 months, and 1 year follow up.

Five men and five women (mean age 42 years) underwent randomization and surgery. Three patients underwent reexploration at L4–5, four at L5—S1, and three at both levels. No complication was associated with irradiation, and no new neurological deficits occurred. At 1-year follow-up examination, three irradiation-treated patients were pain free and two experienced improvement. In the control group, three patients experienced improved pain relief and two were unchanged. There was a trend toward better outcome at 1 year in the radiotherapy-treated group (p = 0.056).

Conclusions. Preoperative low-dose external-beam irradiation improved clinical outcomes after reexploration and decompression of nerve roots affected by postlaminectomy peridural fibrosis causing radicular pain. The addition of preoperative irradiation may improve outcome in patients who undergo reoperation for recurrent radicular pain associated with a significant amount of peridural fibrosis, particularly now that no antiadhesion product is available for clinical use.

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Patrick Breen, John C. Flickinger, Douglas Kondziolka, and Augusto J. Martinez

Object. The authors studied outcomes in patients who had undergone radiotherapy for nonfunctional pituitary adenoma to assess long-term tumor control and to identify factors affecting tumor control such as higher radiation doses, improved imaging, and histological characteristics of the tumor.

Methods. In this retrospective study, the authors evaluated 120 patients who received radiotherapy for nonfunctional pituitary adenomas between 1960 and 1991. The median follow-up period was 9 years (range 1 month–32 years). Radiation doses varied between 37.6 and 65.6 Gy (median 46.7 Gy).

Tumors progressed in 15 of the 120 patients by 1 to 25 years after radiotherapy. Actuarial tumor control rates at 10, 20, and 30 years were 87.5 ± 3.6%, 77.6 ± 6.3%, and 64.7 ± 12.9%, respectively. Tumor progression after radiotherapy occurred significantly more often (p = 0.0397) in patients with oncocytoma than in patients with nononcocytic null cell adenoma. No other factors correlated significantly with tumor control. One case of optic and oculomotor neuropathy developed 4.5 years after a maximum dose of 50 Gy in 25 fractions. Radiation-induced neoplasms (meningioma and glioblastoma multiforme) developed at a rate of 2.7% at 10 and 30 years.

Conclusions. The oncocytic variant of null cell pituitary adenoma appears less sensitive to control by radiotherapy than nononcocytic undifferentiated cell adenoma. A follow-up period extending beyond 20 years is needed adequately to assess the efficacy of radiotherapy for tumor control. Doses of 40 or 45 Gy in 20 or 25 fractions, respectively, appear optimal.

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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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Satoshi Maesawa, John C. Flickinger, Douglas Kondziolka, and L. Dade Lunsford

Object. The goal of this study was to define treatment results of repeated arteriovenous malformation (AVM) radiosurgery, namely AVM obliteration and complications.

Methods. The authors analyzed their experience with repeated AVM radiosurgery performed in 41 patients for whom follow-up review lasted at least 2 years. The median duration of follow up was 34 months (range 7–65 months) after repeated radiosurgery in this group. The residual nidus was located within the area of focus (in field) of the initial radiosurgery in 28 patients (68%). Initial doses to the margin varied from 12.5 to 20 Gy (median 18 Gy). During repeated treatment the dose to the margin varied from 12.5 to 20 Gy (median 17 Gy) and the retreated volumes ranged from 0.4 to 7 cm3 (median 2.1 cm3).

Follow-up angiography performed at least 2 years postradiosurgery revealed complete AVM obliteration in 21 (70%) of 30 patients. The estimated overall 2-year obliteration rate, based on findings on magnetic resonance imaging (eight of 11 obliterated) and angiography (29 of 41 obliterated) was 71%. Obliteration rates correlated with margin doses (p = 0.0045) with a trend toward higher rates in cases with in-field nidus persistence (p = 0.0637). The dose—response curve for AVM nidus obliteration was not significantly different from that of the initial radiosurgery. In two patients (5%) intracranial AVM hemorrhage developed within 125.9 risk years after repeated radiosurgery (1.6% per patient year). Persistent symptomatic adverse radiation effects developed in two (5%) of 41 patients following repeated radiosurgery. Postradiosurgical imaging changes were identified in 11 (27%) of 41 patients, which correlated with a 12-Gy volume from repeated surgery (p = 0.019).

Conclusions. When necessary, repeated AVM radiosurgery achieves obliteration with an acceptable risk. Despite the effects of previous irradiation, repeated radiosurgery required similar or slightly higher radiation doses to achieve the same in-field obliteration rates as those needed to obliterate an AVM that had not been treated by radiation previously.

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Douglas Kondziolka, L. Dade Lunsford, Robert J. Coffey, and John C. Flickinger

✓ Stereotactic radiosurgery has an expanding role in the management of selected intracranial tumors. In an initial 30-month experience using the 201-source cobalt-60 gamma knife at the University of Pittsburgh, 50 patients with meningiomas were treated. The most frequent site of origin was the skull base. Previously, 36 patients (72%) had undergone at least one craniotomy and four patients (8%) had received fractionated external beam radiation therapy. Stereotactic radiosurgery was the primary treatment modality in 16 patients (32%) with symptomatic tumors demonstrated by neuroimaging. Computer imaging-generated isodose plans (with one to five irradiation isocenters) for single-treatment irradiation gave optimal (≥ 50% isodose line) coverage in 44 patients (88%). The proximity of cranial nerves or vascular, pituitary, and brain-stem structures to the often convoluted tumor mass was crucial to dose selection. Serial imaging studies were evaluated in all 50 patients. Twenty-four patients were examined between 12 and 36 months after treatment; 13 (54%) showed a reduction in tumor volume while nine (38%) showed no change. Of 26 patients evaluated between 6 and 12 months after treatment, four showed a decrease in tumor size while 22 showed no change. Two patients (both with large tumors that received suboptimal irradiation) had delayed tumor growth outside the radiosurgical treatment volume. The actuarial 2-year tumor growth control rate was 96%. Between 3 and 12 months after radiosurgery, three patients developed delayed neurological deficits that gradually improved, compatible with delayed radiation injury. Although extended follow-up monitoring over many years will be necessary to fully evaluate treatment, to date stereotactic radiosurgery has proved to be a relatively safe and effective therapy for selected patients with symptomatic meningiomas, including those who failed surgical resection. Radiosurgery was an effective primary treatment alternative for those patients whose advanced age, medical condition, or high-risk tumor location mitigated against surgical resection.

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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, Salvador Somaza, Douglas Kondziolka, and John C. Flickinger

✓ The authors investigated the outcome of stereotactic biopsy and radiotherapy in 35 consecutive adult patients with nonanaplastic, nonpilocytic astrocytomas who were diagnosed between 1982 and 1992. The median patient age at presentation was 32 years. All received fractionated external-beam radiation therapy (median dose 56 Gy) as the initial management strategy. Additional treatment in two patients included intracavitary irradiation with colloidal phosphorus-32.

Six patients (17%) had documented tumor progression during the follow-up interval and died. Three others died of causes unrelated to their tumor. Median survival after stereotactic biopsy and irradiation was 118 months (9.8 years). Median survival from the time of onset of neurological symptoms was 148 months (12.3 years). Only three patients required delayed cytoreductive surgery.

The outcome of brain astrocytomas, although improved because of earlier diagnosis and therapy, does not substantiate this tumor as having benign behavior; early recognition with neuroimaging, immediate histological diagnosis via stereotactic biopsy, and initial fractionated radiation therapy may provide the potential for longer survival for patients with low-grade astrocytomas. The majority of such surviving patients have a satisfactory quality of life, which is manifested by prolonged normal functional and employment status. The survival data reported in this prospective Phase I–II clinical trial suggest that stereotactic biopsy and radiation therapy are appropriate initial management strategies for astrocytomas.