Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy ...technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.
Background
The large fractional doses, steep dose gradients, and small targets found in intracranial radiosurgery require extremely low beam delivery uncertainty. In the case of Gamma Knife ...radiosurgery (GKRS), this includes minimizing patient positioning system (PPS) positioning uncertainty. Existing QA techniques are recipe based, and feature point in time pass/fail tolerances. However, modern treatment machines, including the Gamma Knife Perfexion/Icon systems, record extensive internal data in treatment logs. These data can be analyzed through statistical process control (SPC) methods which are designed to detect changes in process behavior. The purpose of this study was to characterize the long‐term (8+ year) performance of a Perfexion/Icon unit and use SPC methods to determine if performance changes could be detected at levels lower than existing QA and internal manufacturer performance tolerances.
Methods
In‐house software was developed to parse Perfexion/Icon log‐files and store relevant information on shot delivery in a relational database. A last‐in, first‐out (LIFO) queuing algorithm was created to heuristically match messages associated with a given delivered shot. Filtering criteria were developed to filter QA and uncompleted shots. The resulting matched shots were extracted. Achieved versus planned PPS position was determined for each PPS motor as well as for the vector magnitude difference in PPS position. Exponentially weighted moving average (EWMA) control charts were plotted to determine when process behavior changed over time.
Results
53833 shots were delivered over an 8+ year span in the study. The mean vector magnitude PPS difference was 32.7 µm, with 97.5% of all shots within 70.1 µm. Several changes in PPS positioning behavior were observed over time, corresponding with control system faults on several occasions requiring PPS recalibration. EWMA control charts clearly demonstrate that these faults could be identified and possibly predicted as many as 3 years before there were faults beyond control system tolerance.
Conclusion
The PPS of Gamma Knife Perfexion/Icon systems has extremely low positioning uncertainties. EWMA control chart method can be utilized to track PPS performance over time and can potentially detect changes in performance that may indicate a component requiring maintenance. This would allow planned service visits to mitigate problems and prevent unplanned downtime.
Abstract
BACKGROUND:
Gamma knife radiosurgery (GKRS) is well established in the management of inaccessible, recurrent, or residual benign skull base meningiomas. Most series report clinical outcome ...parameters and complications in the short intermediate period after radiosurgery. Reports of long-term tumor control and neurological status are still lacking.
OBJECTIVE:
To report the presentation, treatment, and long-term outcome of skull base meningiomas after GKRS.
METHODS:
From a prospectively collected institutional review board-approved database, we selected patients with a World Health Organization grade I skull base meningioma treated with a single-session GKRS and a minimum of 60 months follow-up. One hundred thirty-five patients, 54.1% males (n = 73), form the cohort. Median age was 54 years (19–80). Median tumor volume was 4.7 cm3 (0.5–23). Median margin dose was 15 Gy (7.5–36). Median follow-up was 102.5 months (60.1–235.4). Patient and tumor characteristics were assessed to determine the predictors of neurological function and tumor progression.
RESULTS:
At last follow-up, tumor volume control was achieved in 88.1% (n = 119). Post-GKRS clinical improvement or stability was reported in 61.5%. The 5-, 10-, and 15-year actuarial progression-free survival rates were 100%, 95.4%, and 68.8%, respectively. Favorable outcome (both tumor control and clinical preservation/improvement) was attained in 60.8% (n = 79). Pre-GKRS performance status (Karnofsky Performance Scale) was shown to influence tumor progression (P = .001) and post-GKRS clinical improvement/preservation (P = .003).
CONCLUSION:
GKRS offers a highly durable rate of tumor control for World Health Organization grade I skull base meningiomas, with an acceptably low incidence of neurological deficits. The Karnofsky Performance Scale at the time of radiosurgery serves as a reliable long-term predictor of overall outcome.
OBJECTIVE Patients with arteriovenous malformations (AVMs) treated with Gamma Knife radiosurgery (GKRS) subsequent to embolization suffer from elevated local failure rates and differences in adverse ...radiation effects. Onyx is a common embolic material for AVMs. Onyx is formulated with tantalum, a high atomic number (Z = 73) element that has been investigated as a source of dosimetric uncertainty contributing to the less favorable clinical results. However, prior studies have not modeled the complicated anatomical and beam geometries characteristic of GKRS. This study investigated the magnitude of dose perturbation that can occur due to Onyx embolization using clinically realistic anatomical and Gamma Knife beam models. METHODS Leksell GammaPlan (LGP) was used to segment the AVM nidus and areas of Onyx from postcontrast stereotactic MRI for 7 patients treated with GKRS postembolization. The resulting contours, skull surface, and clinically selected dose distributions were exported from LGP in DICOM-RT (Digital Imaging and Communications in Medicine-radiotherapy) format. Isocenter locations and dwell times were recorded from the LGP database. Contours were converted into 3D mesh representations using commercial and in-house mesh-editing software. The resulting data were imported into a Monte Carlo (MC) dose calculation engine (Pegasos, Elekta Instruments AB) with a beam geometry for the Gamma Knife Perfexion. The MC-predicted dose distributions were calculated with Onyx assigned manufacturer-reported physical constants (MC-Onyx), and then compared with corresponding distributions in which Onyx was reassigned constants for water (MC-water). Differences in dose metrics were determined, including minimum, maximum, and mean dose to the AVM nidus; selectivity index; and target coverage. Combined differences in dose magnitude and distance to agreement were calculated as 3D Gamma analysis passing rates using tolerance criteria of 0.5%/0.5 mm, 1.0%/1.0 mm, and 3.0%/3.0 mm. RESULTS Overall, the mean percentage differences in dose metrics for MC-Onyx relative to MC-water were as follows; all data are reported as mean (SD): minimum dose to AVM = -0.7% (1.4%), mean dose to AVM = 0.1% (0.2%), maximum dose to AVM = 2.9% (5.0%), selectivity = 0.1% (0.2%), and coverage = -0.0% (0.2%). The mean percentage of voxels passing at each Gamma tolerance were as follows: 99.7% (0.1%) for 3.0%/3.0 mm, 98.2% (0.7%) for 1.0%/1.0 mm, and 52.1% (4.4%) for 0.5%/0.5 mm. CONCLUSIONS Onyx embolization appears to have a detectable effect on the delivered dose distribution. However, the small changes in dose metrics and high Gamma passing rates at 1.0%/1.0 mm tolerance suggest that these changes are unlikely to be clinically significant. Additional sources of delivery and biological uncertainty should be investigated to determine the root cause of the observed less favorable postembolization GKRS outcomes.
To evaluate the hemorrhage rates of cerebral arteriovenous malformations (AVM) and the risk factors of hemorrhage before and after Gamma Knife radiosurgery (GKS).
The annual hemorrhage rate was ...calculated as the number of hemorrhages divided by the patient-years at risk. Characteristics of patients and AVM related to hemorrhagic or nonhemorrhagic presentation were evaluated by logistic regression. Risk factors predicting AVM hemorrhage during the period from the diagnosis to GKS of AVM and during the latency period after radiosurgery were evaluated using Cox regression hazards model.
The annual hemorrhage rate before GKS was 2.0% assuming patients were at risk for hemorrhage since their birth. The hemorrhage rate calculated between the diagnosis and GKS of AVM was 6.6% and reduced to 2.5% after GKS until obliteration of the AVM. Although small and deep nidi and those with deep and single draining veins tended to present themselves with hemorrhage, only nidi with single draining veins and those ruptured before were more likely to bleed once the AVM had been diagnosed. These factors no longer predisposed the nidus to a rupture after radiosurgery and the only predicting factor for hemorrhage was a low radiosurgical prescription dose to the margin of nidus.
The AVM hemorrhage rate seems to reduce after GKS. After radiosurgery, none of the patients or nidus-related risk factors remained relevant to the occurrence of hemorrhage. The nidus treated with a high radiosurgical dose is less likely to bleed.
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. ...More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies.
The use of radiosurgery has been well accepted for treating small to medium-size metastatic brain tumors (MBTs). However, its utility in treating large MBTs remains uncertain due to potentially ...unfavorable effects such as progressive perifocal brain edema and neurological deterioration. In this retrospective study the authors evaluated the local tumor control rate and analyzed possible factors affecting tumor and brain edema response.
The authors defined a large brain metastasis as one with a measurement of 3 cm or more in at least one of the 3 cardinal planes (coronal, axial, or sagittal). A consecutive series of 109 patients with 119 large intracranial metastatic lesions were treated with Gamma Knife surgery (GKS) between October 2000 and December 2012; the median tumor volume was 16.8 cm(3) (range 6.0-74.8 cm(3)). The pre-GKS Karnofsky Performance Status (KPS) score for these patients ranged from 70 to 100. The most common tumors of origin were non-small cell lung cancers (29.4% of cases in this series). Thirty-six patients (33.0%) had previously undergone a craniotomy (1-3 times) for tumor resection. Forty-three patients (39.4%) underwent whole-brain radiotherapy (WBRT) before GKS. Patients were treated with GKS and followed clinically and radiographically at 2- to 3-month intervals thereafter.
The median duration of imaging follow-up after GKS for patients with large MBTs in this series was 6.3 months. In the first follow-up MRI studies (performed within 3 months after GKS), 77 lesions (64.7%) had regressed, 24 (20.2%) were stable, and 18 (15.1%) were found to have grown. Peritumoral brain edema as defined on T2-weighted MRI sequences had decreased in 79 lesions (66.4%), was stable in 21 (17.6%), but had progressed in 19 (16.0%). In the group of patients who survived longer than 6 months (76 patients with 77 MBTs), 88.3% of the MBTs (68 of 77 lesions) had regressed or remained stable at the most recent imaging follow-up, and 89.6% (69 of 77 lesions) showed regression of perifocal brain edema volume or stable condition. The median duration of survival after GKS was 8.3 months for patients with large MBTs. Patients with small cell lung cancer and no previous WBRT had a significantly higher tumor control rate as well as better brain edema relief. Patients with a single metastasis, better KPS scores, and no previous radiosurgery or WBRT were more likely to decrease corticosteroid use after GKS. On the other hand, higher pre-GKS KPS score was the only factor that showed a statistically significant association with longer survival.
Treating large MBTs using either microsurgery or radiosurgery is a challenge for neurosurgeons. In selected patients with large brain metastases, radiosurgery offered a reasonable local tumor control rate and favorable functional preservation. Exacerbation of underlying edema was rare in this case series. Far more commonly, edema and steroid use were lessened after radiosurgery. Radiosurgery appears to be a reasonable option for some patients with large MBTs.
Onyx, an ethylene-vinyl alcohol copolymer mixed in a dimethyl sulfoxide solvent, is currently one of the most widely used liquid materials for embolization of intracranial arteriovenous malformations ...(AVMs). The goal of this study was to define the risks and benefits of stereotactic radiosurgery (SRS) for patients who have previously undergone partial AVM embolization with Onyx.
Among a consecutive series of 199 patients who underwent SRS between January 2007 and December 2012 at the University of Virginia, 25 patients had Onyx embolization prior to SRS (the embolization group). To analyze the obliteration rates and complications, 50 patients who underwent SRS without prior embolization (the no-embolization group) were matched by propensity score method. The matched variables included age, sex, nidus volume before SRS, margin dose, Spetzler-Martin grade, Virginia Radiosurgery AVM Scale score, and median imaging follow-up period.
After Onyx embolization, 18 AVMs were reduced in size. Total obliteration was achieved in 6 cases (24%) at a median of 27.5 months after SRS. In the no-embolization group, total obliteration was achieved in 20 patients (40%) at a median of 22.4 months after SRS. Kaplan-Meier analysis demonstrated obliteration rates of 17.7% and 34.1% in the embolization group at 2 and 4 years, respectively. In the no-embolization group, the corresponding obliteration rates were 27.0% and 55.9%. The between-groups difference in obliteration rates after SRS did not achieve statistical significance. The difference in complications, including adverse radiation effects, hemorrhage episodes, seizure control, and patient mortality also did not reach statistical significance.
Onyx embolization can effectively reduce the size of many AVMs. This case-control study did not show any statistically significant difference in the rates of embolization or complications after SRS in patients who had previously undergone Onyx embolization and those who had not.
Genetic diversity of germline variants in breast cancer (BC) predisposition genes is unexplored in miscegenated populations, such those living in Latin America. We evaluated 1663 Brazilian BC ...patients, who underwent hereditary multigene panel testing (20-38 cancer susceptibility genes), to determine the spectrum and prevalence of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUS). Associations between P/LP variants and BC risk were estimated in a case-control analysis of BC patients and 18,919 Brazilian reference controls (RC). In total, 335 (20.1%) participants carried germline P/LP variants: 167 (10.0%) in BRCA1/2, 122 (7.3%) in BC actionable non-BRCA genes and 47 (2.8%) in candidate genes or other cancer predisposition genes. Overall, 354 distinctive P/LP variants were identified in 23 genes. The most commonly mutated genes were: BRCA1 (27.4%), BRCA2 (20.3%), TP53 (10.5%), monoallelic MUTYH (9.9%), ATM (8.8%), CHEK2 (6.2%) and PALB2 (5.1%). The Brazilian variant TP53 R337H (c.1010G>A, p.Arg337His), detected in 1.6% of BC patients and 0.1% of RC, was strongly associated with risk of BC, OR = 17.4 (95% CI: 9.4-32.1; p < 0.0001); monoallelic MUTYH variants c.1187G>A and c.536A>G, detected in 1.2% (0.9% RC) and 0.8% (0.4% RC) of the patients, respectively, were not associated with the odds of BC, the former with OR = 1.4 (95% CI: 0.8-2.4; p = 0.29) and the latter with OR = 1.9 (95% CI: 0.9-3.9; p = 0.09). The overall VUS rate was 46.1% for the entire patient population. Concluding, the use of multigene panel testing almost doubled the identification of germline P/LP variants in clinically actionable predisposition genes in BC patients. In Brazil, special attention should be given to TP53 P/LP variants.
Stereotactic radiosurgery (SRS) has been shown to offer a high probability of tumor control for Grade I meningiomas. However, SRS can sometimes incite edema or exacerbate preexisting edema around the ...targeted meningioma. The current study evaluates the incidence, timing, and degree of edema around parasagittal or parafalcine meningiomas following SRS.
A retrospective review was undertaken of a prospectively maintained database of patients treated with Gamma Knife radiosurgery at the University of Virginia Health System. All patients with WHO Grade I parafalcine or parasagittal meningiomas with at least 6 months of clinical follow-up were identified, resulting in 61 patients included in the study. The median radiographic follow-up was 28 months (range 6-158 months). Rates of new or worsening edema were quantitatively assessed using volumetric analysis; edema indices were computed as a function of time following radiosurgery. Statistical methods were used to identify favorable and unfavorable prognostic factors for new or worsening edema.
Progression-free survival at 2 and 5 years was 98% and 90%, respectively, according to Kaplan-Meier analysis. After SRS, new peritumoral edema occurred or preexisting edema worsened in 40% of treated meningiomas. The median time to onset of peak edema was 36 months post-SRS. Persistent and progressive edema was associated with 11 tumors, and resection was undertaken for these lesions. However, 20 patients showed initial edema progression followed by regression at a median of 18 months after radiosurgery (range 6-24 months). Initial tumor volume greater than 10 cm3, absence of prior resection, and higher margin dose were significantly (p<0.05) associated with increased risk of new or progressive edema after SRS.
Stereotactic radiosurgery offers a high rate of tumor control in patients with parasagittal or parafalcine meningiomas. However, it can lead to worsening peritumoral edema in a minority of patients. Following radiosurgery, transient edema occurs earlier than persistent and progressive edema. Longitudinal follow-up of meningioma patients after SRS is required to detect and appropriately treat transient as well as progressive edema.
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