Concurrent functional and metabolic assessment of brain tumors using hybrid PET/MR imaging.

To evaluate diagnostic accuracy of perfusion weighted imaging (PWI) and positron emission tomography (PET) using an integrated PET/MR system in tumor grading as well as in differentiating recurrent tumor from treatment-induced effects (TIE) in brain tumor patients. Twenty patients (Group A: treatment naïve, 9 patients with 16 lesions; Group B: post-therapy, 11 patients with 18 lesions) underwent fluorine 18 ((18)F) fluorodeoxyglucose (FDG) brain PET/MR with PWI. Two blinded readers predicted low versus high-grade tumor (for Group A) and tumor recurrence versus TIE (for Group B) based solely on tumor rCBV (regional cerebral blood volume) and SUV (standardized uptake values). Tumor histopathology at resection was the reference standard. Using rCBV(mean) ≤ 1.74 as a cut-off, 100% sensitivity and 74% specificity were observed, whereas 75% sensitivity and 89.7% specificity were observed with SUV(mean) ≤ 4.0 as a cut-off to classify patients as test positive for low-grade tumors (Group A) and TIE (Group B). Diagnostic accuracy for detection of low-grade tumors was 90% using PWI and 40% using PET in Group A (p = 0.056); for detection of TIE in Group B, diagnostic accuracy was 94.1% using PWI and 55.6% using PET (p = 0.033). No significant correlation was demonstrated between rCBV parameters and SUV in Group A (mean values: p > 0.403), Group B (p > 0.06) and in the entire population (p > 0.07). Best overall sensitivity and specificity were obtained using rCBV(mean) ≤ 1.74 and SUV(mean) ≤ 4.0 cut-off values. PWI demonstrated better diagnostic accuracy in both groups. Poor correlation was observed between FDG and rCBV parameters.

Recursive partitioning analysis of prognostic factors for patients with four or more intracranial metastases treated with radiosurgery.

The purpose of this study was to devise a new recursive partitioning analysis (RPA) of patients with four or more intracranial metastases treated with a single radiosurgery procedure to identify a class of patients with extended survival. 205 patients underwent Gamma Knife radiosurgery for four or more intracranial metastases (median = 5, range 4-18) during one session. The median total treatment volume was 6.8 cc (range 0.6-51.0 cc). Radiosurgery was used as sole management (17% of patients), or in combination with WB-RT (46%), or after failure of WB-RT (38%). The median marginal radiosurgery dose was 16 Gy (range 12-20 Gy). RPA assessed the effects of age, Karnofsky >70, extracranial disease, visceral metastases, number of metastases, total treatment volume, history of breast and melanoma primaries on survival. The median overall survival after radiosurgery for all patients was 8 months. RPA identified a favorable subgroup of 78 patients (43% of the series) with a total treatment volume <7 cc and < 7 brain metastases (Class 1), with a median survival of 13 months. This subgroup's survival was significantly better (p <0.00005) than the remaining patients (Class 2) (n=111) with a median survival of 6 months. In conclusion, RPA of multiple brain metastasis patients identified 2 distinct cohorts of patients. Class 1 patients have a total treatment volume <7 cc and < 7 metastases (4-6) with favorable survival after Radiosurgery and Class 2 patients have a total treatment volume > or = 7 cc and/or > or = 7 metastases and have a significantly poorer survival.

Role of High-Resolution Dynamic Contrast-Enhanced MRI with Golden-Angle Radial Sparse Parallel Reconstruction to Identify the Normal Pituitary Gland in Patients with Macroadenomas.

BACKGROUND AND PURPOSE: Preoperative localization of the pituitary gland with imaging in patients with macroadenomas has been inadequately explored. The pituitary gland enhancing more avidly than a macroadenoma has been described in the literature. Taking advantage of this differential enhancement pattern, our aim was to evaluate the role of high-resolution dynamic MR imaging with golden-angle radial sparse parallel reconstruction in localizing the pituitary gland in patients undergoing trans-sphenoidal resection of a macroadenoma. MATERIALS AND METHODS: A retrospective study was performed in 17 patients who underwent trans-sphenoidal surgery for pituitary macroadenoma. Radial volumetric interpolated brain examination sequences with golden-angle radial sparse parallel technique were obtained. Using an ROI-based method to obtain signal-time curves and permeability measures, 3 separate readers identified the normal pituitary gland distinct from the macroadenoma. The readers' localizations were then compared with the intraoperative location of the gland. Statistical analyses were performed to assess the interobserver agreement and correlation with operative findings. RESULTS: The normal pituitary gland was found to have steeper enhancement-time curves as well as higher peak enhancement values compared with the macroadenoma (P < .001). Interobserver agreement was almost perfect in all 3 planes (κ = 0.89). In the 14 cases in which the gland was clearly identified intraoperatively, the correlation between the readers' localization and the true location derived from surgery was also nearly perfect (κ = 0.95). CONCLUSIONS: This study confirms our ability to consistently and accurately identify the normal pituitary gland in patients with macroadenomas with the golden-angle radial sparse parallel technique with quantitative permeability measurements and enhancement-time curves.

Sensitivity to radiation-induced apoptosis and neuron loss declines rapidly in the postnatal mouse neocortex.

Therapeutic brain irradiation can cause progressive decline in cognitive function, particularly in children, but the reason for this effect is unclear. The study explored whether age-related differences in apoptotic sensitivity might contribute to the increased vulnerability of the young brain to radiation. Postnatal day 1 (P1) to P30 mice were treated with 0-16 Gy whole-body X-irradiation. Apoptotic cells were identified and quantified up to 48 h later using the TdT-UTP nick end-labelling method (TUNEL) and immunohistochemistry for activated caspase-3. The number of neuron-specific nuclear protein (NeuN)-positive and -negative cells were also counted to measure neuronal and non-neuronal cell loss. Significantly greater TUNEL labelling occurred in the cortex of irradiated P1 animals relative to the other age groups, but there was no difference among the P7, P14 and P30 groups. Irradiation decreased the %NeuN-positive cells in the mice irradiated on P1, whereas in P14 animals, irradiation led to an increase in the %NeuN-positive cells. These data demonstrate that neocortical neurons of very young mice are more susceptible to radiation-induced apoptosis. However, this sensitivity decreases rapidly after birth. By P14, acute cell loss due to radiation occurs primarily in non-neuronal populations.

Cranial nerve preservation after stereotactic radiosurgery for small acoustic tumors.

OBJECTIVE: To assess those factors associated with and predictive of cranial nerve preservation after stereotactic radiosurgery in patients with small acoustic tumors identified by magnetic resonance imaging. DESIGN: We performed a retrospective analysis of our experience with 31 patients with preserved hearing and acoustic tumors measuring 10 mm or smaller (pons-to-petrous dimension). All patients underwent clinical and audiologic evaluations varying from 6 to 48 months (mean, 20 months) after stereotactic radiosurgery performed with use of the 201 source cobalt 60 gamma unit. RESULTS: Stabilization or reduction in tumor volume was achieved in 29 of 31 patients. One patient required delayed microsurgical resection. Useful hearing (pure tone average < or = 50 dB and speech discrimination score > or = 50%) preservation was achieved in 10 of 10 patients immediately postoperatively, eight of 10 patients at 6 months, six of 10 patients at 1 year, and five of 10 at 2 years. Preservation of some measurable hearing was possible in all patients immediately after radiosurgery, in 84% and in more than half of patients at 2 years. Preoperative facial nerve function was preserved in 19 of 20 patients at 2 years after radiosurgery. All patients returned to their preoperative employment status within 2 to 5 days after radiosurgery. CONCLUSION: Stereotactic radiosurgery performed with current technology (multiple radiation isocenters and magnetic resonance imaging guidance) is a safe and effective management strategy for patients with small acoustic tumors. The risk of facial and trigeminal neuropathy after gamma knife radiosurgery is low, and useful hearing can be preserved in up to 50% of patients with useful preoperative hearing. Stereotactic radiosurgery is a valuable alternative strategy to surgical removal for many patients with newly diagnosed small acoustic tumors.

Gamma knife radiosurgery for trigeminal neuralgia: results and expectations.

BACKGROUND: Trigeminal neuralgia is a disabling pain syndrome responsive to both medical and surgical therapies. Stereotactic radiosurgery using the gamma knife can be used to inactivate a specified volume in the brain by cross firing 201 photon beams. We evaluated pain relief and treatment morbidity after trigeminal neuralgia radiosurgery. METHODS: All evaluable patients (n = 106) had medically or surgically refractory trigeminal neuralgia. A single 4-mm isocenter of radiation was focused on the proximal trigeminal nerve just anterior to the pons. For follow-up an independent physician who was unaware of treatment parameters contacted all patients. RESULTS: After radiosurgery, 64 patients (60%) became free of pain and required no medical therapy (excellent result), 18 (17%) had a 50% to 90% reduction (good result) in pain severity or frequency (some still used medications), and 9 (9%) had slight improvement. At last follow-up (median, 18 months; range, 6-48 months), 77% of patients maintained significant relief (good plus excellent results). Only 6 (10%) of 64 patients who initially attained complete relief had some recurrent pain. Radiosurgery dose (70-90 Gy), age, surgical history, or facial sensory loss did not correlate with pain relief. Poorer results were found in patients with multiple sclerosis. Twelve patients developed new or increased facial paresthesias after radiosurgery (10%). No patient developed anesthesia dolorosa. There was no other procedural morbidity. CONCLUSIONS: Gamma knife radiosurgery is a minimally invasive technique to treat trigeminal neuralgia. It is associated with a low risk of facial paresthesias, an approximate 80% rate of significant pain relief, and a low recurrence rate in patients who initially attain complete relief. Longer-term evaluations are warranted.

Stereotactic radiosurgery of residual or recurrent craniopharyngioma, after surgery, with or without radiation therapy.

This study evaluated the role of stereotactic radiosurgery in the multimodality management of craniopharyngioma patients whose prior therapies failed. Ten consecutive patients (3 males and 7 females) had radiosurgery for craniopharyngioma during a 10-year interval. Their ages ranged from 9 to 64 years (median, 14.5 years). The median interval between diagnosis and radiosurgery was 46.5 months. In total, 12 stereotactic radiosurgical procedures were performed to control the solid component of the tumor (2 intrasellar and 10 suprasellar tumors). The median tumor volume was 1.35 cm3. One to 9 isocenters with different beam diameters were used; the median marginal dose was 16.4 Gy; and the dose to the optic apparatus was limited to less than 8 Gy. Clinical and imaging follow-up data were obtained at a median of 63 months (range, 13-150 months) from radiosurgery. Overall, 7 of 12 tumors became smaller or vanished within a median of 8.5 months. Prior visual defects objectively improved in 6 patients. One patient with prior visual defect deteriorated further and lost vision 9 months after radiosurgery. Multimodality therapy is often necessary for patients with refractory solid and cystic craniopharyngiomas. Stereotactic radiosurgery is a reasonable option in select patients with small recurrent or residual craniopharyngioma.

Functional outcomes after gamma knife thalamotomy for essential tremor and MS-related tremor.

Twelve patients with a median age of 75 years underwent gamma knife thalamotomy for essential tremor (ET) (n = 9) or MS-related tremor (n = 3). All 11 evaluable patients noted improvement in action tremor. Six of eight ET patients had complete tremor arrest, and the violent action tremor in all three patients with MS was improved. One patient developed transient arm weakness. Stereotactic radiosurgery for ET and MS-related tremor is safe and effective for patients who may be poor candidates for other procedures.

Transplantation of cultured human neuronal cells for patients with stroke.

Transplantation of cultured neuronal cells is safe in animal models and improves motor and cognitive deficits in rats with stroke. The authors studied the safety and feasibility of human neuronal cellular transplantation in patients with basal ganglia stroke and fixed motor deficits, including 12 patients (aged 44 to 75 years) with an infarct 6 months to 6 years previously (stable for at least 2 months). Serial evaluations (12 to 18 months) showed no adverse cell-related serologic or imaging-defined effects. The total European Stroke Scale score improved in six patients (3 to 10 points), with a mean improvement 2.9 points in all patients (p = 0. 046). Six of 11 PET scans at 6 months showed improved fluorodeoxyglucose uptake at the implant site. Neuronal transplantation is feasible in patients with motor infarction.

Potential human error in setting stereotactic coordinates for radiosurgery: implications for quality assurance.

PURPOSE: The error frequency in setting stereotactic coordinates for gamma knife radiosurgery was investigated to determine what quality assurance safeguards are necessary. METHODS AND MATERIALS: A prospective study of 200 consecutive isocenter settings for gamma knife radiosurgery was analyzed to identify the frequency of spontaneous errors in setting and checking stereotactic coordinates (corrected prior to treatment). An additional 25 coordinate errors were introduced at random among the next 200 consecutive isocenter settings to provide additional data on identification of errors. RESULTS: Stereotactic coordinates required resetting in 12% (24/200) of the isocenters treated due to errors of 0.25-0.50 mm (8%) and 1-20 mm (4%). This comprised 2.2% (26/1200) of the individual coordinate settings. The frequency of these errors was significantly related to the specific directional coordinate set (p = 0.0004) and experience (p = 0.016). Errors were identified by 83.5% (91/109) of the observers checking the settings (60.0% of 0.25 mm errors, 94.6% of errors > or = 0.5 mm, p = 0.0000). Verification of stereotactic coordinates by two observers reduces the probability of an undetected error > or = 0.25 mm to 1/1,392 and to 1/154,712 for errors > or = 1 mm. CONCLUSION: Errors in setting stereotactic coordinates are common (12% prior to checking) but are corrected with a high degree of confidence by a quality assurance policy requiring coordinate verification by a minimum of two observers.

Evolution in technique for vestibular schwannoma radiosurgery and effect on outcome.

PURPOSE: To define changes in treatment technique for vestibular schwannoma radiosurgery and to relate them to changes in outcome, a large single institution experience was reviewed. METHODS AND MATERIALS: Two hundred seventy-three patients with unilateral vestibular schwannomas underwent Gamma knife radiosurgery: 118 with computed tomography (CT) treatment planning during 1987-1991, and 155 with magnetic resonance imaging (MR) treatment planning in 1991-1994. Mean treatment parameters differed between the CT and MR groups: minimum tumor dose (D(min)) was 17 vs. 14 Gy, number of isocenters was 3.4 vs. 5.8, and volume was 3.5 vs 2.7 cc., respectively. RESULTS: The actuarial 7-year clinical tumor control rate (no requirement for surgical intervention) for the entire series was 96.4 +/- 2.3%, with a radiographic tumor control rate of 91.0 +/- 3.4%; these rates were similar for the CT and MR groups. Significantly lower rates of postradiosurgery facial, trigeminal, and auditory neuropathy were observed in the MR group compared to the CT group. Multivariate analyses found significant independent correlations of increasing rates of facial and trigeminal neuropathy with increasing transverse tumor diameter and D(min), as well as with CT treatment planning (compared to MR). Decreased hearing was similarly correlated with diameter and CT planning but not with D(min). CONCLUSIONS: Changes in radiosurgery technique and the use of lower doses improved the outcome after vestibular schwannoma radiosurgery by decreasing cranial neuropathy rates. MR-based treatment planning appears to have significantly contributed to this improvement. Despite decreases in radiation dose, no change in the high rate of tumor control has yet been observed.

A dose-response analysis of arteriovenous malformation obliteration after radiosurgery.

PURPOSE: Although radiosurgery is effective in obliterating the pathologic vessels of intracranial arteriovenous malformations (AVM), the relationships of both dose and volume to obliteration have not been well defined. METHODS AND MATERIALS: The results of radiosurgery in 197 AVM patients with 3-year angiographic follow-up were analyzed. Volume varied from 0.06-18 cc (median: 4.1 cc), and minimum target dose (Dmin) varied from 12.0-25.6 Gy (median: 20.0 Gy). RESULTS: Follow-up angiography revealed complete AVM obliteration in 142 out of 197 patients (72%). The targeted AVM nidus failed to obliterate in 20 patients (10%), but in-field obliteration was complete in the remaining 35 patients (18%) discovered to have residual untargeted AVM nidus. Multivariate logistic regression analysis of in-field obliteration revealed a significant independent correlation with Dmin (p = 0.04), but not with volume or maximum dose. A sigmoid dose-response curve for in-field obliteration was constructed that significantly differed from the dose-volume-response relationships that would have been expected from overall obliteration data. CONCLUSIONS: The success rate for in-field obliteration of AVM after radiosurgery depends on Dmin but does not appear to change appreciably with volume or maximum dose. Success rates for complete obliteration additionally are limited by problems defining the complete AVM nidus.

Analysis of neurological sequelae from radiosurgery of arteriovenous malformations: how location affects outcome.

PURPOSE/OBJECTIVE: To elucidate how the risks of developing temporary and permanent neurological sequelae from radiosurgery for arteriovenous malformations (AVM) are related to AVM location, the addition of stereotactic magnetic resonance (MR) imaging to angiographic targeting, and prior hemorrhage or neurological deficits. MATERIALS AND METHODS: We evaluated follow-up imaging and clinical data in 332 AVM patients who received gamma knife radiosurgery at the University of Pittsburgh between 1987 and 1994. All patients had regular clinical or imaging follow-up for a minimum of 2 years (range: 24-96 months, median = 45 months). There were 83 patients with MR-assisted planning, 187 with prior hemorrhages, and 143 with prior neurological deficits. RESULTS: Symptomatic postradiosurgery sequelae (any neurological problem including headache) developed in 30 (9%) of 332 patients. Symptoms resolved in 58% of patients within 27 months with a significantly greater proportion (p = 0.006) resolving in patients with Dmin < 20 Gy vs. > or = 20 Gy (89 vs. 36%). The 7-year actuarial rate for developing persistent symptomatic sequelae was 3.8%. We first evaluated the relative risks for different locations to construct a postradiosurgery injury expression (PIE) score for AVM location. Multivariate logistic regression analysis of symptomatic postradiosurgery sequelae identified independent significant correlations with PIE location score (p = 0.0007) and 12 Gy volume (p = 0.008), but with none of the other factors tested (p > 0.3), including the addition of MR targeting, average radiation dose in 20 cc, prior hemorrhage, or neurological deficit. We used these results to construct a risk prediction model for symptomatic postradiosurgery sequelae. The risk of radiation necrosis was significantly correlated with PIE score (p < 0.048), but not with 12-Gy volume. CONCLUSION: The risks of developing complications from AVM radiosurgery can be predicted according to location with the PIE score, in conjunction with the 12-Gy treatment volume. Further study of factors affecting persistence of these sequelae (progression to radiation necrosis) is needed.

Stereotactic radiosurgery for chordoma and chondrosarcoma: further experiences.

PURPOSE: Skull base chordomas and chondrosarcomas pose management challenges owing to their critical location, locally aggressive nature, and high recurrence rate despite multimodality treatment. We used stereotactic radiosurgery as primary or adjuvant therapy to achieve safe and effective therapeutic irradiation. METHODS AND MATERIALS: At an average of 4 years (range 1-7), we evaluated 15 patients (nine with chordomas and six with chondrosarcomas) who had gamma-knife radiosurgery as an adjunct (13 patients) or as an alternative to microsurgical resection (two patients). Patient age varied from 7 to 70 years (mean 38). There was a distinct male preponderance (2:1). Thirteen patients had undergone between one and four resections. Using conformal radiosurgical planning, a maximum tumor dose of 24-40 Gy (mean 36) and a tumor margin dose of 12-20 Gy (mean 18) was given to a mean tumor volume of 4.6 ml. RESULTS: Eight patients showed clinical improvement, three remained stable, and four died. Two of the four patients who died had tumor progression remote from the radiosurgery volume; two patients died of unrelated disorders. Among 11 surviving patients, follow-up imaging showed a reduction in tumor size in five, no further tumor growth in five, and an increase in the size of the tumor in one. The patient with further tumor growth after radiosurgery subsequently underwent repeat resection. CONCLUSION: Despite the formidable management challenge posed by these neoplasms, our long-term evaluation has shown that radiosurgery is a safe and effective treatment for patients with small volume tumors.

Phosphorus-32 intracavitary irradiation of cystic craniopharyngiomas: current technique and long-term results.

PURPOSE: The management of patients with craniopharyngiomas is often multifaceted and multidisciplinary. The purpose of this study was to examine the results of phosphorus-32 intracavitary irradiation in the treatment of patients with predominately cystic craniopharyngiomas. METHODS AND MATERIALS: Thirty patients with cystic craniopharyngiomas underwent phosphorus-32 intracavitary irradiation at our center between 1981 and 1993. The median patient age was 26 years (range, 3-70 years). Thirteen patients had intracavitary irradiation as the primary surgery for their cystic tumors, whereas 17 patients had adjuvant intracavitary irradiation after microsurgical resection, fractionated radiotherapy, or both. Patients in the adjuvant treatment group were more likely to have preoperative anterior pituitary insufficiency (p = 0.008 Fischer exact test) and diabetes insipidus (p = 0.003 Fischer exact test). The median follow-up was 37 months (mean, 46 months, range, 7-116 months). RESULTS: Phosphorus-32 intracavitary irradiation resulted in cyst regression in 28 of 32 treated cysts (88%). Ten patients (33%) have had tumor progression requiring further surgical intervention. Three patients (10%) died: two of tumor progression, and one of unrelated causes. Visual acuity and fields improved or remained stable in 63% of the patients. Fifteen patients had residual anterior pituitary function before intracavitary irradiation and 10 (67%) retained their preoperative endocrine status. New-onset diabetes insipidus occurred in 3 of 17 patients (18%) who had normal posterior pituitary function preoperatively. Fourteen of 20 adult patients (70%) continued to perform at their preoperative functional level; 3 of 5 pediatric patients who were age appropriate at the time of treatment continued to develop normally. No difference was noted between primary and adjuvant treatment patients with respect to cyst control, visual deterioration, or endocrine preservation after phosphorus-32 intracavitary irradiation. CONCLUSION: The goals of craniopharyngioma management should be tumor control with preservation of visual, endocrine, and cognitive function. Phosphorus-32 intracavitary irradiation is an important option that enhances the likelihood of achieving these goals in patients with primarily cystic craniopharyngiomas.

Quality assurance for gamma knife stereotactic radiosurgery.

PURPOSE: This quality assurance program is designed for stereotactic radiosurgical units, gamma knife, to check and maintain the unit to preclude accidents and comply with current regulations. MATERIALS AND METHODS: Over 58 stereotactic radiosurgical units using 201 focused 60Co beams have been installed in the last 7 years and are in use at hospitals throughout the world, with at least 11 additional units being prepared to come on-line in the next year. This system has been in use at the University of Pittsburgh Medical Center (UPMC) for 7 years. A comprehensive quality assurance program has been developed. It includes the physics and dosimetry parameters and safety checks required by regulatory agencies. The program, based on over 7 years of experience in measurements, and used during the treatment of over 1500 patients, is separated into three aspects, namely physics, dosimetry, and safety. The UPMC program hopefully will indicate out-of-tolerance problems. Some quality assurance items are checked on a daily basis prior to patient treatment, while other aspects are checked on a weekly, monthly, and/or annual basis. A complete list of items with their respective time tables and tolerances is provided. RESULTS: Although experience shows very small margins of error, larger values were chosen to account for variations in equipment and techniques. CONCLUSIONS: Items included in this quality assurance program should indicate and/or preclude problems encountered in the use of this unit.

Complications from arteriovenous malformation radiosurgery: multivariate analysis and risk modeling.

PURPOSE/OBJECTIVE: To assess the relationships of radiosurgery treatment parameters to the development of complications from radiosurgery for arteriovenous malformations (AVM). METHODS AND MATERIALS: We evaluated follow-up imaging and clinical data in 307 AVM patients who received gamma knife radiosurgery at the University of Pittsburgh between 1987 and 1993. All patients had regular clinical or imaging follow up for a minimum of 2 years (range: 24-96 months, median = 44 months). RESULTS: Post-radiosurgical imaging (PRI) changes developed in 30.5% of patients with regular follow-up magnetic resonance imaging, and were symptomatic in 10.7% of all patients at 7 years. PRI changes resolved within 3 years developed significantly less often (p = 0.0274) in patients with symptoms (52.8%) compared to asymptomatic patients (94.8%). The 7-year actuarial rate for developing persistent symptomatic PRI changes was 5.05%. Multivariate logistic regression modeling found that the 12 Gy volume was the only independent variable that correlated significantly with PRI changes (p < 0.0001) while symptomatic PRI changes were correlated with both 12 Gy volume (p = 0.0013) and AVM location (p = 0.0066). CONCLUSION: Complications from AVM radiosurgery can be predicted with a statistical model relating the risks of developing symptomatic post-radiosurgical imaging changes to 12 Gy treatment volume and location.

Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases.

PURPOSE: Multiple brain metastases are a common health problem, frequently diagnosed in patients with cancer. The prognosis, even after treatment with whole brain radiation therapy (WBRT), is poor with average expected survivals less than 6 months. Retrospective series of stereotactic radiosurgery have shown local control and survival benefits in case series of patients with solitary brain metastases. We hypothesized that radiosurgery plus WBRT would provide improved local brain tumor control over WBRT alone in patients with two to four brain metastases. METHODS: Patients with two to four brain metastases (all < or =25 mm diameter and known primary tumor type) were randomized to initial brain tumor management with WBRT alone (30 Gy in 12 fractions) or WBRT plus radiosurgery. Extent of extracranial cancer, tumor diameters on MRI scan, and functional status were recorded before and after initial care. RESULTS: The study was stopped at an interim evaluation at 60% accrual. Twenty-seven patients were randomized (14 to WBRT alone and 13 to WBRT plus radiosurgery). The groups were well matched to age, sex, tumor type, number of tumors, and extent of extracranial disease. The rate of local failure at 1 year was 100% after WBRT alone but only 8% in patients who had boost radiosurgery. The median time to local failure was 6 months after WBRT alone (95% confidence interval [CI], 3.5-8.5) in comparison to 36 months (95% CI, 15.6-57) after WBRT plus radiosurgery (p = 0.0005). The median time to any brain failure was improved in the radiosurgery group (p = 0.002). Tumor control did not depend on histology (p = 0.85), number of initial brain metastases (p = 0.25), or extent of extracranial disease (p = 0.26). Patients who received WBRT alone lived a median of 7.5 months, while those who received WBRT plus radiosurgery lived 11 months (p = 0.22). Survival did not depend on histology or number of tumors, but was related to extent of extracranial disease (p = 0.02). There was no neurologic or systemic morbidity related to stereotactic radiosurgery. CONCLUSIONS: Combined WBRT and radiosurgery for patients with two to four brain metastases significantly improves control of brain disease. WBRT alone does not provide lasting and effective care for most patients.

Beneficial effects of the radioprotectant 21-aminosteroid U-74389G in a radiosurgery rat malignant glioma model.

PURPOSE: To evaluate the radioprotectant effects of the 21-aminosteroid U-74389G on the rat C6 glioma model after stereotactic radiosurgery. Because radiosurgery causes both tumor cytotoxicity, as well as regional brain edema, we hypothesized that this drug might exhibit advantageous or deleterious effects on healthy and neoplastic tissue. METHODS: Rats were implanted with 10(6) C6 glioma cells into the right frontal brain and randomized to a Control Group (n = 18), radiosurgery on Day 14 (50% isodose = 35 Gy) (n = 15), or radiosurgery preceded by a single 15 mg/kg intravenous dose of 21-aminosteroid (n = 27). All animals were killed by 90 days and evaluated for survival, tumor size, the presence or absence of regional parenchymal edema, or radiation-induced vasculopathy. RESULTS: After tumor implantation, median survival in the Control Group was 23 days. Significant improvements in median survival were noted after RS alone (median, 31 days; p = 0.02), and RS plus 21-aminosteroid (median, 59 days; p < 0.0001). In the Control Group, mean tumor diameter was 5.4 mm. After RS alone, the mean diameter was 3.2 mm (p = 0.002), and after RS plus 21-aminosteroid, 2.9 mm (p = 0.0002). In the Control Group, the tumor grew as a hypercellular, compact mass. Only 3 of 18 animals had peritumoral edema. In contrast, 7 of 15 animals in the RS group had evidence of edema (p = 0.006), but rats that received 21-aminosteroid showed no increase compared to controls (p = 0.38). Similarly, 6 of 15 animals that had radiosurgery alone showed evidence of vasculopathy (p = 0.005) compared to no animals in the control group and only 2 of 27 aminosteroid-treated animals. CONCLUSIONS: The 21-aminosteroid U-74389G exhibits a radioprotectant effect on normal brain tissue, but does not appear to protect the tumor in an in vivo rat radiosurgery model. We believe that the observed beneficial effects on healthy brain led to significant prolongation of animal survival; perhaps, by limiting the adverse effects of high-dose radiosurgery. This radioprotectant should now be evaluated in randomized clinical trials in patients with malignant brain tumors.

Stereotactic radiosurgery for cerebral metastatic melanoma: factors affecting local disease control and survival.

PURPOSE: The development of a brain metastasis represents an ominous event for patients with malignant melanoma. We evaluated results after stereotactic radiosurgery (SR) for patients with metastastic melanoma to identify patient outcomes and factors for survival. METHODS: The authors reviewed the management results of 60 consecutive patients with melanoma metastases, with a total of 118 melanoma brain metastases, undergoing SR during a 9-year interval. Of these, 51 also had whole-brain radiation therapy (WBRT). A total of 118 tumors of mean volume of 2.95 ml (range, 0.1-25.5 ml) were treated by SR with a mean margin dose of 16.4 Gy (range, 10 to 20 Gy). Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival in 60 patients. RESULTS: Median survival was 7 months after SR in all 60 patients and 10 months from brain tumor diagnosis (mean follow-up period, 9.3 months). Lack of active systemic disease and a solitary metastasis were associated with improved survival in multivariate analysis (median, 15 months). The imaging-defined local control rate of evaluable tumors (n = 72) was 90% (disappearance = 11%, shrinkage = 44%, and stable = 35%). Local recurrence developed in 7 patients and remote brain disease developed in 14 patients. WBRT combined with radiosurgery did not improve survival nor local tumor control. New brain metastases developed less often when WBRT was added to SR (23% vs. 44%), but this difference was not significant. Only 4 patients (7%) died from progression of a radiosurgery-managed tumor. No patient developed a delayed radiation-related complication, but 3 patients developed delayed intratumoral hemorrhage at the radiosurgery site, 2 of whom had new symptoms. CONCLUSIONS: Stereotactic radiosurgery for melanoma brain metastasis is effective and is associated with few complications. The use of radiosurgery alone is an appropriate management strategy for many patients with solitary tumors.