Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases.

BACKGROUND: Single session stereotactic radiosurgery (SRS) or surgical resection alone for brain metastases larger than 2 cm results in unsatisfactory local control. We conducted a phase I trial for brain metastases(>2cm) to determine the safety of preoperative SRS at escalating doses. METHODS: Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor dimension starting at: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy for >4-6 cm. Dose limiting toxicity (DLT) was defined as grade III or greater acute toxicity. RESULTS: A total of 35 patients/36 lesions were enrolled. For tumor size >2-3 cm, patients were enrolled up to the second dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the third dose level (21 Gy and 18 Gy, respectively) was reached. There were 2 DLTs in the >3-4 cm arm at 21Gy. The maximum tolerated dose (MTD) of SRS for >2-3 cm was not reached; and was 18 Gy for both >3-4 cm arm and >4-6 cm arm. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. One patient developed grade 3 radiation necrosis at 5 months. The 2-year rate of leptomeningeal disease (LMD) was 0%. CONCLUSION: Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size demonstrates acceptable acute toxicity. The phase II portion of the trial will be conducted at the maximum tolerated SRS doses.

A new conformity and dose gradient distance measure for stereotactic radiosurgery of brain metastasis.

Purpose: Competing radiosurgery plans are compared based on their conformity and gradient of dose distribution to the target volume (TV). Most widely used quality metrics such as new conformity index (NCI) and gradient index (GI) are known to have strong volume dependency on the TV of interest. A simple quality measure without the volume dependency is presented for evaluating stereotactic radiosurgery plans, expressed in distance dimension compared to the unit-less volume ratio used in NCI and GI. Methods and Materials: The conformity distance measure (CDM) is defined as the effective radius of the union volume subtracted by that of the intersection volume, where volume operations are on TV and prescription isodose volume (PIV). Gradient distance measure (GDM) is defined as the effective radius of 50% PIV (low dose volume of the plan) subtracted by that of corresponding ideal low dose volume (iLDV). Volume independency and consistent sensitivity of CDM and GDM on PIV displacement and dose spillage are analyzed using a simple two-sphere model. 2429 cases of Gamma Knife and 76 cases of Linac based radiosurgery plans for brain metastasis were retrospectively studied to demonstrate volume independency of the new measures and their implication on target coverage. Results: The sensitivity of NCI on PIV displacement and dose spillage was inversely proportional to the effective radius of the target volume, while the sensitivity of CDM on target motion and dose spillage was constant regardless the target volume. The iLDV for 50% PIV was approximately 2.4 times of PIV based on previous Linac based radiosurgery/IMRT/VMAT plans and single shot analysis from Gamma Knife (GK), ICON. Although NCI ranged from 1 to 14.7 for GK plans and from 1.2 to 20.8 for VMAT plans showing strong volume dependency, CDM showed negligible volume dependency of less than 2.1 mm for more than 90% cases and peak frequency was at 0.8 mm. CDM was correlated well with target coverage as a function of PIV displacement regardless of target volume. Target coverage, V100, was larger than 95% when PIV displacement is less than CDM. Conclusions: The new conformity and gradient measure, CDM and GDM are proposed in this paper. The new measures are volume independent which is preferred for reliable evaluation of the radiosurgery plan quality over wide range of radiosurgery targets. As represented by distance dimension similar to PTV margin, the new measures may be more adequate for image guided radiosurgery applications.

Is there a volume threshold of brain metastases for Linac-based stereotactic radiotherapy?

PURPOSE: To investigate whether there is a volume threshold in target volume of brain metastases below which a small cone size and sharp penumbra in Gamma Knife (GK) may provide improved plan quality when compared to Volumetric Modulated Arc Therapy (VMAT)-based stereotactic radiosurgery (SRS). METHODS: For patients treated on GK SRS for brain metastases in 2018-2019 in our institution, 121 patients with two and three targets were identified. Twenty-six patients with two or three brain metastases (total of 76 lesions) were selected for this study. Two VMAT plans, SmartArc (Pinnacle) and HyperArc (Eclipse), were generated retrospectively for each patient. Plan quality was evaluated based on RTOG conformity index (CI), Paddick gradient index (GI), normal tissue (NT) V12Gy and V4.5Gy. By using the receiver operating characteristic (ROC) curve for both VMAT plans (SmartArc and HyperArc) and metrics of RTOG CI and NT V12Gy, we compared GK plans to SmartArc and HyperArc plans separately to determine the threshold volume. RESULTS: For SmartArc plans, both ROC curve analyses showed a threshold volume of 0.4 cc for both CI and NT V12Gy. For HyperArc plans, the threshold volumes were 0.2 cc for the CI and 0.5 cc for NT V12Gy. GK plans produced improved dose distribution compared to VMAT for targets ≤0.4 cc, but HyperArc was found to have competing results with GK in terms of CI and NT V12Gy. For targets > 0.4 cc, both SmartArc and HyperArc showed better plan quality when compared to the GK plans. CONCLUSIONS: Target volumes ≤0.4 cc may require a small cone size and sharp penumbra in GK while for target volumes >0.4 cc, VMAT-based SRS can provide improved overall plan quality and faster treatment delivery.

Recommendations on the practice of calibration, dosimetry, and quality assurance for gamma stereotactic radiosurgery: Report of AAPM Task Group 178.

The American Association of Physicists in Medicine (AAPM) formed Task Group 178 (TG-178) to perform the following tasks: review in-phantom and in-air calibration protocols for gamma stereotactic radiosurgery (GSR), suggest a dose rate calibration protocol that can be successfully utilized with all gamma stereotactic radiosurgery (GSR) devices, and update quality assurance (QA) protocols in TG-42 (AAPM Report 54, 1995) for static GSR devices. The TG-178 report recommends a GSR dose rate calibration formalism and provides tabulated data to implement it for ionization chambers commonly used in GSR dosimetry. The report also describes routine mechanical, dosimetric, and safety checks for GSR devices, and provides treatment process quality assurance recommendations. Sample worksheets, checklists, and practical suggestions regarding some QA procedures are given in appendices. The overall goal of the report is to make recommendations that help standardize GSR physics practices and promote the safe implementation of GSR technologies.

Fractionated Gamma Knife radiosurgery for skull base meningiomas: a single-institution experience.

OBJECTIVEGamma Knife radiosurgery (GKRS) has been successfully used for the treatment of intracranial meningiomas given its steep dose gradients and high-dose conformality. However, treatment of skull base meningiomas (SBMs) may pose significant risk to adjacent radiation-sensitive structures such as the cranial nerves. Fractionated GKRS (fGKRS) may decrease this risk, but until recently it has not been practical with traditional pin-based systems. This study reports the authors' experience in treating SBMs with fGKRS, using a relocatable, noninvasive immobilization system.METHODSThe authors performed a retrospective review of all patients who underwent fGKRS for SBMs between 2013 and 2018 delivered using the Extend relocatable frame system or the Icon system. Patient demographics, pre- and post-GKRS tumor characteristics, perilesional edema, prior treatment details, and clinical symptoms were evaluated. Volumetric analysis of pre-GKRS, post-GKRS, and subsequent follow-up visits was performed.RESULTSTwenty-five patients met inclusion criteria. Nineteen patients were treated with the Icon system, and 6 patients were treated with the Extend system. The mean pre-fGKRS tumor volume was 7.62 cm3 (range 4.57-13.07 cm3). The median margin dose was 25 Gy delivered in 4 (8%) or 5 (92%) fractions. The median follow-up time was 12.4 months (range 4.7-17.4 months). Two patients (9%) experienced new-onset cranial neuropathy at the first follow-up. The mean postoperative tumor volume reduction was 15.9% with 6 patients (27%) experiencing improvement of cranial neuropathy at the first follow-up. Median first follow-up scans were obtained at 3.4 months (range 2.8-4.3 months). Three patients (12%) developed asymptomatic, mild perilesional edema by the first follow-up, which remained stable subsequently.CONCLUSIONSfGKRS with relocatable, noninvasive immobilization systems is well tolerated in patients with SBMs and demonstrated satisfactory tumor control as well as limited radiation toxicity. Future prospective studies with long-term follow-up and comparison to single-session GKRS or fractionated stereotactic radiotherapy are necessary to validate these findings and determine the efficacy of this approach in the management of SBMs.

Gamma Knife and volumetric modulated arc therapy stereotactic radiosurgery plan quality and OAR sparing comparison for pituitary adenomas and vestibular schwannomas.

PURPOSE: To compare the plan quality and organs at risk (OAR) sparing of auto-planned volumetric modulated art therapy (VMAT) and Gamma Knife (GK) for stereotactic radiosurgery of pituitary adenomas (PA) and vestibular schwannomas (VS). METHODS: VMAT radiosurgery plans were made using auto planning tool for eight vestibular schwannoma and eight pituitary adenoma patients previously treated with GK. VMAT plans were made with three non-coplanar arcs using 315, 0 and 45 degrees angles, 6MV FFF energy at 1400 MU/min dose rate and 2.5 mm thick MLC leaves. Both GK and VMAT plans were prescribed to similar isodose lines (50% - 60%). RESULTS: Respectively for GK and VMAT, the mean Paddick conformity index (PCI) was 0.62 ± 0.08 and 0.67 ± 0.10 (p > 0.05) for PA and 0.72 ± 0.09 and 0.660 ± 0.13 (p > 0.05) for VS; the mean gradient index (GI) was 2.76 ± 0.14 and 3.14 ± 0.40 Gy (p < 0.05) for PA and 3.71 ± 1.83 and 3.60 ± 0.84 Gy (p > 0.05) for VS; mean brainstem maximum dose was 9.13 ± 3.50 Gy and 7.31 ± 2.01 Gy (p > 0.05) for PA and 11.67 ± 4.56 Gy and 12.22 ± 4.55 Gy (p > 0.05) for VS; mean optic nerve maximum dose was 9.66 ± 1.0 Gy and 7.67 ± 2.58 Gy (p < 0.05); mean cochlea mean dose was 7.31 ± 2.7 Gy and 7.23 ± 3.13 Gy (p > 0.05); and mean treatment time was 68 min and 5 min for PA and 40 min and 3 min for VS. CONCLUSIONS: Auto planning with standard template simplified the planning stage for VMAT and provided clinically acceptable plans. Comparison of GK and VMAT for plan quality and OAR sparing varied across patients but both were overall comparable.

Phase I Trial of Radiosurgery Dose Escalation Plus Bevacizumab in Patients With Recurrent/Progressive Glioblastoma.

BACKGROUND: The effectiveness of stereotactic radiosurgery (SRS) for recurrent glioblastoma (rGBM) remains uncertain. SRS has been associated with a high risk of radionecrosis in gliomas. OBJECTIVE: To determine the safety of dose escalation of single-fraction radiosurgery for rGBM in the setting of bevacizumab therapy. METHODS: We conducted a prospective trial to determine the safety and synergistic benefit of higher doses of SRS administered with bevacizumab for rGBM. A single dose of bevacizumab was given prior to SRS and continued until progression. Dose-limiting toxicity was evaluated in successive cohorts of 3 patients. RESULTS: Seven males and 2 females entered the study. The maximum linear diameter of the enhancing tumor was 2.58 cm (2.04-3.09). Prescription dose was escalated from 18 to 22 Gy. The radiosurgery target was chosen before the first dose of bevacizumab, about 1 wk prior to SRS treatment. Pre-SRS bevacizumab treatment was associated with a reduction of the mean volume of the enhancing lesion from 4.7 to 2.86 cm3 on the day of SRS (P = .103). No patient developed an acute side effect related to SRS treatment. The combination of SRS and bevacizumab resulted in a partial response in 3 patients and stable disease in 6 patients. Median progression-free and overall survival were 7.5 and 13 mo, respectively. CONCLUSION: A single dose of bevacizumab prior to SRS permitted safe prescription dose escalation up to 22 Gy for rGBM. Further evaluation of the efficacy of SRS for rGBM should be performed in the setting of bevacizumab treatment.

Stereotactic Radiosurgery for Trigeminal Neuralgia Improves Patient-Reported Quality of Life and Reduces Depression.

PURPOSE: To characterize quality-of-life (QOL) outcomes after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). METHODS AND MATERIALS: The EuroQOL 5 Dimensions (EQ-5D) and Patient Health Questionnaire 9 (PHQ-9) were prospectively collected before and after SRS for 50 patients with TN. Pain response and treatment-related facial numbness were classified by Barrow Neurological Institute (BNI) scales. Differences in pooled QOL outcomes were tested with paired t tests and sign tests. The Kaplan-Meier method was used to estimate time-dependent improvements in the EQ-5D index, EQ-5D perceived health status (PHS), PHQ-9 score, and freedom from pain failure (BNI class IV-V) or facial numbness (BNI class III-IV). RESULTS: Following SRS, the 12-month rate of freedom from pain failure was 92% (95% confidence interval [CI], 77%-97%) while the 12-month rate of freedom from facial numbness was 89% (95% CI, 66%-97%). Significant improvements in the EQ-5D index (P<.01), PHS (P=.01), and PHQ-9 (P=.03) were observed, driven by the EQ-5D subscores for self-care and for pain and/or discomfort (P=.02 and P<.01, respectively). At 12 months after SRS, the actuarial rates of improvement in the EQ-5D, PHS, and PHQ-9 were 55% (95% CI, 40%-70%), 59% (95% CI, 40%-76%), and 59% (95% CI, 39%-76%), respectively. The median time to improvement in each of the QOL measures was 9 months (95% CI, 3-36 months) for the EQ-5D index, 5 months (95% CI, 3-36 months) for PHS, and 9 months (95% CI, 3-18 months) for the PHQ-9. On multivariate analysis, only higher prescription dose (86 Gy vs ≤82 Gy) was associated with improvement in the EQ-5D index (hazard ratio, 5.73; 95% CI, 1.85-22.33; P<.01). CONCLUSIONS: Patients with TN treated with SRS reported significant improvements in multiple QOL measures, with the therapeutic benefit strongly driven by improvements in pain and/or discomfort and in self-care, along with lower rates of depression. In this analysis, there appears to be a correlation between prescription dose and treatment response as measured by the EQ-5D.

Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases.

OBJECTIVE The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (≤ 2 cm) brain metastases was evaluated. METHODS An institutional review board-approved retrospective review was performed on 896 patients with brain metastases ≤ 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months. RESULTS The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non-small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm3 and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation necrosis, independent prognostic factors included size greater than 1 cm (SHR 2.13; p < 0.001), location in the corpus callosum (SHR 5.72; p < 0.001), and uncommon pathologies (SHR 1.65; p = 0.05). Size (SHR 4.78; p < 0.001) and location (SHR 7.62; p < 0.001)-but not uncommon pathologies-were independent prognostic factors for the subgroup with symptomatic radiation necrosis. CONCLUSIONS A PD of 24 Gy results in significantly better local control of metastases measuring < 2 cm than lower doses. In addition, tumor size is an independent prognostic factor for both local progression and radiation necrosis. Some tumor pathologies and locations may also contribute to an increased risk of radiation necrosis.

Trigeminal Neuralgia Treated With Stereotactic Radiosurgery: The Effect of Dose Escalation on Pain Control and Treatment Outcomes.

PURPOSE: To analyze the effect of dose escalation on treatment outcome in patients undergoing stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). METHODS AND MATERIALS: A retrospective review was performed of 870 patients who underwent SRS for a diagnosis of TN from 2 institutions. Patients were typically treated using a single 4-mm isocenter placed at the trigeminal nerve dorsal root entry zone. Patients were divided into groups based on treatment doses: ≤82 Gy (352 patients), 83 to 86 Gy (85 patients), and ≥90 Gy (433 patients). Pain response was classified using a categorical scoring system, with fair or poor pain control representing treatment failure. Treatment-related facial numbness was classified using the Barrow Neurological Institute scale. Log-rank tests were performed to test differences in time to pain failure or development of facial numbness for patients treated with different doses. RESULTS: Median age at first pain onset was 63 years, median age at time of SRS was 71 years, and median follow-up was 36.5 months from the time of SRS. A majority of patients (827, 95%) were clinically diagnosed with typical TN. The 4-year rate of excellent to good pain relief was 87% (95% confidence interval 84%-90%). The 4-year rate of pain response was 79%, 82%, and 92% in patients treated to ≤82 Gy, 83 to 86 Gy, and ≥90 Gy, respectively. Patients treated to doses ≤82 Gy had an increased risk of pain failure after SRS, compared with patients treated to ≥90 Gy (hazard ratio 2.0, P=.0007). Rates of treatment-related facial numbness were similar among patients treated to doses ≥83 Gy. Nine patients (1%) were diagnosed with anesthesia dolorosa. CONCLUSIONS: Dose escalation for TN to doses >82 Gy is associated with an improvement in response to treatment and duration of pain relief. Patients treated at these doses, however, should be counseled about the increased risk of treatment-related facial numbness.

Calvarial and skull base metastases: expanding the clinical utility of Gamma Knife surgery.

OBJECT: Traditionally, the treatment of choice for patients with metastases to the calvaria or skull base has been conventional radiation therapy. Because patients with systemic malignancies are also at risk for intracranial metastases, the utility of Gamma Knife surgery (GKS) for these patients has been explored to reduce excess radiation exposure to the perilesional brain parenchyma. The purpose of this study was to report the efficacy of GKS for the treatment of calvarial metastases and skull base lesions. METHODS: The authors performed a retrospective chart review of 21 patients with at least 1 calvarial or skull base metastatic lesion treated with GKS during 2001-2013. For 7 calvarial lesions, a novel technique, in which a bolus was placed over the treatment site, was used. For determination of local control or disease progression, radiation therapy data were examined and posttreatment MR images and oncology records were reviewed. Survival times from the date of procedure were estimated by using Kaplan-Meier analyses. RESULTS: The median patient age at treatment was 57 years (range 29-84 years). A total of 19 (90%) patients received treatment for single lesions, 1 patient received treatment for 3 lesions, and 1 patient received treatment for 4 lesions. The most common primary tumor was breast cancer (24% of patients). Per lesion, the median clinical and radiographic follow-up times were 10.3 months (range 0-71.9 months) and 7.1 months (range 0-61.3 months), respectively. Of the 26 lesions analyzed, 14 (54%) were located in calvarial bones and 12 (46%) were located in the skull base. The median lesion volume was 5.3 cm(3) (range 0.3-55.6 cm(3)), and the median prescription margin dose was 15 Gy (range 13-24 Gy). The median overall survival time for all patients was 35.9 months, and the 1-year local control rate was 88.9% (95% CI 74.4%-100%). Local control rates did not differ between lesions treated with the bolus technique and those treated with traditional methods or between calvarial lesions and skull base lesions (p > 0.05). Of the 3 patients for whom local treatment failed, 1 patient received no further treatment and 2 patients responded to salvage chemotherapy. Subsequent brain parenchymal metastases developed in 2 patients, who then underwent GKS. CONCLUSIONS: GKS is an effective treatment modality for patients with metastases to the calvarial bones or skull base. For patients with superficial calvarial lesions, a novel approach with bolus application resulted in excellent rates of local control. GKS provides an effective therapeutic alternative to conventional radiation therapy and should be considered for patients at risk for calvarial metastases and brain parenchymal metastases.

Using higher isodose lines for gamma knife treatment of 1 to 3 brain metastases is safe and effective.

BACKGROUND: Higher isodose lines (IDLs) in Gamma Knife (GK) Perfexion treatment of brain metastases (BMet) could result in lower local control (LC) or higher radiation necrosis (RN) rates, but reduce treatment time. OBJECTIVE: To assess the impact of the heterogeneity index (HI) and conformality index (CFI) ion local failure (LF) for patients treated with GK for 1 to 3 BMet. METHODS: From an institutional review board-approved database, 320 patients with 496 BMet were identified, treated for 1 to 3 BMet from July 2007 to April 2011 on GK Perfexion. Cox proportional hazards regression was used to analyze significance of HI, CFI, IDL, dose, tumor diameter, recursive partitioning analysis class, tumor radioresistance, primary, smoking history, metastasis location, and whole-brain radiation therapy (WBRT) history with LF and RN. RESULTS: Median follow-up by lesion was 6.8 months (range, 0-49.6). The series median survival was 14.2 months. Per RECIST, 9.5% of lesions failed, 33.9% were stable, 38.3% partially responded, 17.1% responded completely, and 1.2% could not be assessed. The 12-month LC rate was 87.3%. On univariate analysis, a dose less than 20 Gy (hazard ratio [HR]: 2.940, P < .001); tumor size (HR: 1.674, P < .001); and cerebellum/brainstem location vs other (HR: 1.891, P = .043) were significant for LF. Non-small cell lung cancer (HR: 0.333, P = .0097) was associated with better LC. On multivariate analysis, tumor size (HR: 1.696, P < .001) and cerebellum/brainstem location vs other (HR: 1.959, P = .033) remained significant for LF. Variables not significant for LF included CI, IDL, and HI. CONCLUSION: Our study of patients with 1 to 3 BMet treated with GK demonstrated no difference in LC or RN with varying HI, indicating that physicians can treat to IDL at 70% or higher IDL to reduce treatment time without increased LF or RN.

Role of Gamma Knife surgery in patients with 5 or more brain metastases.

OBJECT: The authors evaluated overall survival and factors predicting outcome in patients with ≥ 5 brain metastases who were treated with Gamma Knife surgery (GKS). METHODS: Medical records from patients with ≥ 5 brain metastases treated with GKS between 1997 and 2010 at the Cleveland Clinic Gamma Knife Center were retrospectively reviewed. Patient demographics, tumor characteristics, treatment-related factors, and outcome data were evaluated. RESULTS: One hundred seventy patients were identified, with a median age of 58 years. The female/male ratio was 1.2:1. Gamma Knife surgery was used as an upfront treatment in 35% of patients and as salvage treatment in 65% of patients with multiple brain metastases. The median overall survival after GKS was 6.7 months (95% CI 5.5-8.1). At the time of GKS, 128 patients (75%) had concurrent extracranial metastases, and in 69 patients (41%) multiple extracranial sites were involved. Ninety-two patients (54%) had a history of whole-brain radiation therapy, and 158 patients (93%) had a Karnofsky Performance Scale (KPS) score ≥ 70. The median total intracranial disease volume was 3.2 cm(3) (range 0.2-37.2 cm(3)). A total intracranial tumor volume ≥ 10 cm(3) was observed in 32 patients (19%). Lower KPS score at the time of treatment (p < 0.0001), patient age > 60 years (p = 0.004), multiple extracranial metastases (p = 0.0001), and greater intracranial burden of disease (p = 0.03) were prognostic factors for poor outcome in the univariate and multivariate analyses. CONCLUSIONS: In this study, GKS was safe and effective for upfront and salvage treatment in patients with ≥ 5 brain metastases. Gamma Knife surgery should be considered as an additional treatment modality for these patients, especially in the subset of patients with favorable prognostic factors.

Prospective study of the short-term adverse effects of gamma knife radiosurgery.

Purpose of this study is to determine the types, incidence, and severity of acute complications of intracranial stereotactic radiosurgery (SRS), specifically Gamma Knife (GK). Patients who had never had previous SRS were eligible for this prospective IRB-approved study. The questionnaire used applicable questions from CTCAE v.3.0, the Brief Pain Questionnaire (Short Form), Brief Fatigue Inventory, and the Tinnitus Handicap Inventory. Questionnaires were obtained prior to Gamma Knife (GK), 1 week, 1 month, and 2 months to assess complications. Seventy-six eligible patients (median age of 62 years) had complete data and were analyzed. Diagnoses included: 26 (34%) with brain metastases, 15 (20%) with trigeminal neuralgia, 12 (16%) with schwannoma, 10 (13%) with meningioma, 7 (9%) with arteriovenous malformation, 3 (4%) with pituitary adenoma, and 3 (4%) with other. At 1 week, 24% developed minimal scalp numbness (p =0.0004 baseline compared to 1 week). Only 13% had minimal scalp numbness at 1 month and 2% at 2 months (both p=NS compared to baseline). There was no difference in scalp tingling between baseline and the various time points. Thirteen percent developed pin site pain at 1 week with a median intensity level of 2 out of 10. By one month, only 3% had pin site pain with a median intensity level of 3 out of 10. Four percent developed pin-site infection at 1 week and none at 1 and 2 months. There was no significant difference in nausea from baseline at 1 week, but there was worsening nausea at 1 month (p =0.0114). By 1 month, 10% reported new local hair loss. 23%, 16%, and 15% complained of new/worsening fatigue at 1 week, 1 month, and 2 months, respectively, but 40% reported fatigue at baseline. Balance improved following SRS over all time periods (for all comparisons, p <0.009). 1%, 6%, and 3% developed new tinnitus at 1 week, 1 month, and 2 months, respectively, which was significant when comparing baseline to non-baseline (p =0.0269). Thirty-two patients were employed prior to SRS. Three (9%) patients did not return to work. Twenty-seven (84%) patients returned to work a median of 4 days after SRS. Two people did not report their employment status after SRS. There was no significant difference in face swelling, headache, eye pain, vomiting, seizures, or passing out at any intervals compared to baseline. This prospective study demonstrates that GK is well tolerated with few patients developing major acute effects. Many patients are able to return to work shortly after GK.

Treatment of five or more brain metastases with stereotactic radiosurgery.

PURPOSE: To examine the outcomes of patients with five or more brain metastases treated in a single session with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Sixty-four patients with brain metastases treated with SRS to five or more lesions in a single session were reviewed. Primary disease type, number of lesions, Karnofsky performance score (KPS) at SRS, and status of primary and systemic disease at SRS were included. Patients were treated using dosing as defined by Radiation Therapy Oncology Group Protocol 90-05, with adjustments for critical structures. We defined prior whole-brain radiotherapy (WBRT) as WBRT completed >1 month before SRS and concurrent WBRT as WBRT completed within 1 month before or after SRS. Kaplan-Meier estimates and Cox proportional hazard regression were used to determine which patient and treatment factors predicted overall survival (OS). RESULTS: The median OS after SRS was 7.5 months. The median KPS was 80 (range, 60-100). A KPS of ≥ 80 significantly influenced OS (median OS, 4.8 months for KPS ≤ 70 vs. 8.8 months for KPS ≥ 80, p = 0.0097). The number of lesions treated did not significantly influence OS (median OS, 6.6 months for eight or fewer lesions vs. 9.9 months for more than eight, p = nonsignificant). Primary site histology did not significantly influence median OS. On multivariate Cox modeling, KPS and prior WBRT significantly predicted for OS. Whole-brain radiotherapy before SRS compared with concurrent WBRT significantly influenced survival, with a risk ratio of 0.423 (95% confidence interval 0.191-0.936, p = 0.0338). No significant differences were observed when no WBRT was compared with concurrent WBRT or when the no WBRT group was compared with prior WBRT. A KPS of ≤ 70 predicted for poorer outcomes, with a risk ratio of 2.164 (95% confidence interval 1.157-4.049, p = 0.0157). CONCLUSIONS: Stereotactic radiosurgery to five or more brain lesions is an effective treatment option for patients with metastatic cancer, especially for patients previously treated with WBRT. A KPS of ≥ 80 predicts for an improved outcome.

The importance of the conformality, heterogeneity, and gradient indices in evaluating Gamma Knife radiosurgery treatment plans for intracranial meningiomas.

PURPOSE: To investigate the relationship between the conformality index (CIn), heterogeneity index (HIn), and gradient index (GIn) and the development of toxicity in patients treated with Gamma Knife radiosurgery (GKRS) for intracranial meningiomas. METHODS AND MATERIALS: Treatment records of patients treated from 1997 to 2009 with at least 6 months of follow-up were reviewed. The following parameters were collected: CIn, HIn, GIn (ratio of the volume receiving half the prescription isodose to the volume receiving the full prescription isodose), brainstem (BS) maximum dose (MD), BS volume receiving ≥ 12 Gy (V12), optic apparatus (OA) MD, OA V8 Gy, OA V10, number of isocenters, number of isocenters outside target volume, and the occurrence of six toxicities. Univariate and multivariate logistic regression modeling were used for analysis. RESULTS: This study included 145 patients (148 meningiomas) with a median follow-up time of 27 months (range, 6-113.9 months). The majority of meningiomas were located in the skull base (53%). The median prescription dose was 13 Gy (range, 10-24 Gy) to the 51.50% (range, 50-92%) isodose. A lower HIn was correlated with a higher GIn (p = 0.007). CIn was not associated with any toxicity. Higher HIn was associated with the development of dizziness (odds ratio [OR] 1.9; p = 0.02), whereas a lower GIn was associated with motor deficits (OR 0.38; p = 0.04) and auditory changes (OR 0.59; p = 0.04). The OA MD, V8, and V12 were not associated with visual changes, but visual changes were associated with a higher number of isocenters outside the target volume (OR 1.93; p = 0.07). BS V12 was correlated with the development of auditory changes (OR 1.05; p = 0.05), whereas patients with higher BS MD tended to have increased toxicity. CONCLUSIONS: Close attention must be paid to all three indices (CIn, HIn, GIn) when optimal treatment plans are determined. We recommend that the target CIn should be ≤ 2.0, the HIn ≤ 2.0, and the GIn ≥ 3.0 for intracranial meningiomas.

Long-term outcomes of Gamma Knife radiosurgery in patients with vestibular schwannomas.

OBJECT: The authors sought to determine the long-term tumor control and side effects of Gamma Knife radiosurgery (GKRS) in patients with vestibular schwannomas (VS). METHODS: One hundred seventeen patients with VS underwent GKRS between January 1997 and February 2003. At the time of analysis, at least 5 years had passed since GKRS in all patients. The mean patient age was 60.9 years. The mean maximal tumor diameter was 1.77 ± 0.71 cm. The mean tumor volume was 1.95 ± 2.42 ml. Eighty-two percent of lesions received 1300 cGy and 14% received 1200 cGy. The median dose homogeneity ratio was 1.97 and the median dose conformality ratio was 1.78. Follow-up included MR imaging or CT scanning approximately every 6-12 months. Rates of progression to surgery were calculated using the Kaplan-Meier method. RESULTS: Of the 117 patients in whom data were analyzed, 103 had follow-up MR or CT images and 14 patients were lost to follow-up. Fifty-three percent of patients had stable tumors and 37.9% had a radiographically documented response. Imaging-documented tumor progression was present in 8 patients (7.8%), but in 3 of these the lesion eventually stabilized. Only 5 patients required a neurosurgical intervention. The estimated 1-, 3-, and 5-year rates of progression to surgery were 1, 4.6, and 8.9%, respectively. One patient (1%) developed trigeminal neuropathy, 4 patients (5%) developed permanent facial neuropathy, 3 patients (4%) reported vertigo, and 7 patients (18%) had new gait imbalance following GKRS. CONCLUSIONS: Gamma Knife radiosurgery results in excellent local control rates with minimal toxicity for patients with VS. The authors recommend standardized follow-up to gain a better understanding of the long-term effects of GKRS.

Stereotactic radiosurgery for single brainstem metastases: the cleveland clinic experience.

PURPOSE: To assess the imaging and clinical outcomes of patients with single brainstem metastases treated with stereotactic radiosurgery (SRS). MATERIALS AND METHODS: We retrospectively reviewed the data from patients with single brainstem metastases treated with SRS. Locoregional control and survival were calculated using the Kaplan-Meier method. Prognostic factors were assessed using a Cox proportional hazards model. RESULTS: Between 1997 and 2007, 43 patients with single brainstem metastases were treated with SRS. The median age at treatment was 59 years, the median Karnofsky performance status was 80, and the median follow-up was 5.3 months. The median dose was 15 Gy (range, 9.6-24), and the median conformality and heterogeneity index was 1.7 and 1.9, respectively. The median survival was 5.8 months from the procedure date. Of the 33 patient with post-treatment imaging available, a complete radiographic response was achieved in 2 (4.7%), a partial response in 8 (18.6%), and stable disease in 23 (53.5%). The 1-year actuarial rate of local control, distant brain control, and overall survival was 85%, 38.3%, and 31.5%, respectively. Of the 43 patients, 8 (19%) died within 2 months of undergoing SRS, and 15 (36%) died within 3 months. On multivariate analysis, greater performance status (hazard ratio [HR], 0.95, p = .004), score index for radiosurgery (HR, 0.7; p = .004), graded prognostic assessment score (HR, 0.48; p = .003), and smaller tumor volume (HR, 1.23, p = .002) were associated with improved survival. No Grade 3 or 4 toxicities were observed. CONCLUSION: The results of our study have shown that SRS is a safe and effective local therapy for patients with brainstem metastases.

Salvage stereotactic radiosurgery effectively treats recurrences from whole-brain radiation therapy.

BACKGROUND: The purpose of the current study was to examine overall survival (OS) and time to local failure (LF) in patients who received salvage stereotactic radiosurgery (SRS) for recurrent brain metastases (BM) after initial management that included whole-brain radiation therapy (WBRT). METHODS: The records of 1789 BM patients from August 1989 to November 2004 were reviewed. Of these, 111 underwent WBRT as part of their initial management and SRS as salvage. Patients were stratified by Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis class, primary disease, dimension of the largest metastases and number of BM at initial diagnosis, and time to first brain recurrence after WBRT. Overall survival, survival after SRS, and time to local and distant failure were analyzed. RESULTS: The median OS from the initial diagnosis of BM was 17.7 months. Median survival after salvage SRS for the entire cohort was 9.9 months. Median survival after salvage SRS was 12.3 months in patients who had their first recurrence >6 months after WBRT versus 6.8 months for those who developed disease recurrence < or = 6 months after (P = .0061). Primary tumor site did not appear to affect survival after SRS. Twenty-eight patients (25%) developed local recurrence after their first SRS with a median time of 5.2 months. A dose <22 grays and lesion size >2 cm were found to be predictive of local failure. CONCLUSIONS: In this study, patients who recurred after WBRT and were treated with salvage SRS were found to have good local control and survival after SRS. WBRT provided good initial control, as 45% of these patients failed >6 months after WBRT. Those with a longer time to failure after WBRT had significantly longer survival after SRS.

Repeat trigeminal nerve radiosurgery for refractory cluster headache fails to provide long-term pain relief.

OBJECTIVE/BACKGROUND: Medically refractory cluster headache (MRCH) is a debilitating condition that has proven resistant to many modalities. Previous reports have indicated that radiosurgery for MRCH provides little long-term pain relief, with moderate/significant morbidity. However, there have been no reports of repeated radiosurgery in this patient population. We present our findings from the first reports of repeat radiosurgery for MRCH. METHODS: Two patients with MRCH underwent repeat gamma knife radiosurgery at our institution. Each fulfilled clinical criteria for treatment, including complete resistance to pharmacotherapy, pain primarily localized to the ophthalmic division of the trigeminal nerve, and psychological stability. Both patients previously received gamma knife radiosurgery (75 Gy) for MRCH with no morbidity, but no long-term improvement of pain relief (Patient 1 = 5 months, Patient 2 = 10 months) after treatment. For repeat radiosurgery, each patient received 75 Gy to the 100% isodose line delivered to the root entry zone of the trigeminal nerve, and was evaluated postretreatment. Pain relief was defined as: excellent (free of MRCH with minimal/no medications), good (50% reduction of MRCH severity/frequency with medications), fair (25% reduction), or poor (less than 25% reduction). RESULTS: Following repeat radiosurgery, long-term pain relief was poor in both patients. Neither patient sustained any immediate morbidity following radiosurgery. Patient 2 experienced right facial numbness 4 months postretreatment, while Patient 1 experienced no morbidity. CONCLUSION: Repeat radiosurgery of the trigeminal nerve fails to provide long-term pain relief for MRCH. Given the reported failures of initial and repeat radiosurgery for MRCH, trigeminal nerve radiosurgery should not be offered for MRCH.