Faculty Bibliography

We discuss the current literature on the role of stereotactic radiosurgery in the multidisciplinary management of brain metastases and focus on the level of evidence that addresses key management questions. We reviewed the literature on the different roles of radiosurgery, radiotherapy, and resection, and in particular the 2009 Guidelines project of the Joint Section on Tumors of the AANS/CNS. Retrospective case series, matched cohort studies, and randomized trials show specific survival and local tumor control benefits after radiosurgery. Radiosurgery is an effective and safe minimally invasive option for patients with brain metastases. Randomized trials include tumors of different histologies which can detract from their relevance to specific tumor types.

BACKGROUND: Trigeminal neuralgia (TN) may recur after treatment by gamma knife stereotactic radiosurgery (GKSR). OBJECTIVE: To evaluate management outcomes in patients who underwent repeat GKSR for TN. METHODS: The authors reviewed their experience with repeat GKSR in 119 patients with recurrent TN. The median patient age was 74 years (range, 34-96 years). The median interval between procedures was 26 months. The median target dose for repeat GKSR was 70 Gy (range, 50-90 Gy) and the median cumulative dose was 145 Gy (range, 120-170 Gy). The median follow-up was 48 months (range, 6-187 months) after repeat GKSR. RESULTS: After repeat GKSR, 87% of patients achieved initial pain relief (Barrow Neurological Institute pain score I-IIIb). Pain relief was maintained in 87.8% at 1 year, 69.8% at 3 years, and 44.2% at 5 years. Facial sensory dysfunction occurred in 21% of patients within 18 months after GKSR. Longer pain relief was observed in patients who had recurrent pain in a reduced pain distribution of the face compared with the pain distribution at the time of their initial GKSR, and in those who developed additional trigeminal sensory loss after a repeat procedure. A cumulative edge of brainstem dose >/= 44 Gy was more likely to be associated with the development of sensory loss. CONCLUSION: Repeat GKSR provides a similar rate of pain relief as the first procedure. The best responses were observed in patients who had good pain control after the first procedure and those who developed new sensory dysfunction in the affected trigeminal distribution.

OBJECT: Vertebrobasilar ectasia (VBE) is an unusual cause of trigeminal neuralgia (TN). The surgical options for patients with medically refractory pain include percutaneous or microsurgical rhizotomy and microvascular decompression (MVD). All such procedures can be technically challenging. This report evaluates the response to a minimally invasive procedure, Gamma Knife surgery (GKS), in patients with TN associated with severe vascular compression caused by VBE. METHODS: Twenty patients underwent GKS for medically refractory TN associated with VBE. The median patient age was 74 years (range 48-95 years). Prior surgical procedures had failed in 11 patients (55%). In 9 patients (45%), GKS was the first procedure they had undergone. The median target dose for GKS was 80 Gy (range 75-85 Gy). The median follow-up was 29 months (range 8-123 months) after GKS. The treatment outcomes were compared with 80 case-matched controls who underwent GKS for TN not associated with VBE. RESULTS: Intraoperative MR imaging or CT scanning revealed VBE that deformed the brainstem in 50% of patients. The trigeminal nerve was displaced in cephalad or lateral planes in 60%. In 4 patients (20%), the authors could identify only the distal cisternal component of the trigeminal nerve as it entered into the Meckel cave. After GKS, 15 patients (75%) achieved initial pain relief that was adequate or better, with or without medication (Barrow Neurological Institute [BNI] pain scale, Grades I-IIIb). The median time until pain relief was 5 weeks (range 1 day-6 months). Twelve patients (60%) with initial pain relief reported recurrent pain between 3 and 43 months after GKS (median 12 months). Pain relief was maintained in 53% at 1 year, 38% at 2 years, and 10% at 5 years. Some degree of facial sensory dysfunction occurred in 10% of patients. Eventually, 14 (70%) of the 20 patients underwent an additional surgical procedure including repeat GKS, percutaneous procedure, or MVD at a median of 14 months (range 5-50 months) after the initial GKS. At the last follow-up, 15 patients (75%) had satisfactory pain control (BNI Grades I-IIIb), but 5 patients (25%) continued to have unsatisfactory pain control (BNI Grade IV or V). Compared with patients without VBE, patients with VBE were much less likely to have initial (p = 0.025) or lasting (p = 0.006) pain relief. CONCLUSIONS: Pain control rates of GKS in patients with TN associated with VBE were inferior to those of patients without VBE. Multimodality surgical or medical management strategies were required in most patients with VBE.

We evaluated the efficacy and safety of gamma knife stereotactic radiosurgery (GKSR) followed by bevacizumab combined with chemotherapy in 11 patients with recurrent glioblastoma multiforme who experienced tumor progression despite aggressive initial multi-modality treatment. Our experience included eight male and three female patients. The median patient age at GKSR was 62 years (range 46-72 years). At the time of GKSR, seven patients had a first recurrence and four had two or more recurrences. The median interval from the initial diagnosis until GKSR was 17 months (range 5-34.5 months). The median tumor volume was 13.6 cm(3) (range 1.2-45.1 cm(3)) and the median margin dose of GKSR was 16 Gy (range 13-18 Gy). Following GKSR, bevacizumab was administrated with irinotecan in nine patients and with temozolomide in one patient. One patient was treated with bevacizumab monotherapy. The treatment outcomes were compared to 44 case-matched controls who underwent GKSR without additional bevacizumab. At a median of 13.7 months (range 4.6-28.3 months) after radiosurgery, tumor progression was evident in seven patients. The median progression-free survival (PFS) was 15 months (95% confidential interval (CI), 6.5-23.3 months). Six-month and 1-year PFS rates were 73 and 55%, respectively. The median overall survival (OS) from GKSR was 18 months (95% CI, 10.1-25.7 months) and 1-year OS rate was 73%. One patient (9%) experienced grade III toxicity and one patient (9%) had major adverse radiation effects. Compared with patients who did not receive bevacizumab, the patients who received bevacizumab had significantly prolonged PFS (15 months vs. 7 months, P = 0.035) and OS (18 months vs. 12 months, P = 0.005), and were less likely to develop an adverse radiation effect (9 vs. 46%, P = 0.037). The combination of salvage GKSR followed by bevacizumab added potential benefit and little additional risk in a small group of patients with progressive glioblastoma. Further experience is needed to define the efficacy and long-term toxicity with this strategy.

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 cm(3) (range 0.2-26.3 cm(3)) at initial SRS but was reduced to 2.3 cm(3) (range 0.1-18.2 cm(3)) 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.

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 cm(3) (range 0.1-14.1 cm(3)), 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.

Histopathological investigations revealed acute-, subacute-, and chronic-type tissue responses, accompanied by inflammatory cell reaction in radiosurgery treated cerebral metastases originating from different primary cancers. Immunohistochemistry demonstrated that the preponderance of CD68-positive macrophages and CD3-positive T lymphocytes in the inflammatory infiltration developed in better controlled metastases ( > 5 months). In contrast, it was sparse or absent in poorly controlled neoplasms ( < 5 months) after radiosurgery. This inflammatory reaction may be stimulated by the ionizing energy, probably influenced by the general condition of the patients' immune system as well, and seems to play a role in local tumor control after focused radiation.