Assessment of organs-at-risk contouring practices in radiosurgery institutions around the world - The first initiative of the OAR Standardization Working Group.

BACKGROUND AND PURPOSE: This study was an initiative of the Organs-at-Risk Standardization Working Group for evaluating the current degree of variability in the clinical practice of contouring organs-at-risk (OAR) for radiosurgery planning. MATERIALS AND METHODS: Imaging datasets for typical lesions (cavernous sinus meningioma, vestibular schwannoma, pituitary adenoma) treated with Leksell Gamma Knife Perfexion were circulated to 12 centers. Observers were asked to contour the target and OARs as per their standard clinical practice. The analyzed parameters were the intersection (AV100), union volumes (AV100/N) and the 50% agreement volume (AV50). The ratio of AV100 and AV100/N (the Agreement Volume Index, AVI) was used as a measure of agreement level together with a generalized conformity index (CIgen) and a pairwise averaged conformity index (CIpairs). The maximum doses were also determined. RESULTS: Results showed a wide variability in terminology, choice of structures contoured and in the size and shape of the contoured structures. The highest variability was observed for the left and right optic tract for cavernous sinus meningioma where the AV100 was zero. The highest consistency was observed for the right optic nerve in the cavernous sinus case followed by the cochlea for the vestibular schwannoma case for which the AVI was still only 0.13 and 0.054, respectively. Corresponding results for the CIgen and CIpairs also showed the highest variability for the right optic tract and the highest consistency in contours for the right optic nerve, both in the cavernous sinus meningioma case. CONCLUSION: The results quantify the large variability in OAR contouring in clinical practice across Gamma Knife radiosurgery centers with respect to the choice of OARs to be contoured, nomenclature and size and shape of OARs. This motivates future effort to standardize practices to enable more effective collaboration.

Although Non-diagnostic Between Necrosis and Recurrence, FDG PET/CT Assists Management of Brain Tumours After Radiosurgery.

AIM: To re-evaluate the role of (18)F-fluoro-deoxy-D-glucose (FDG) positron emission tomography/ computer assisted tomography (PET/CT) co-registered with magnetic resonance imaging (MRI) in differentiating adverse radiation effect (ARE) from tumour recurrence after Gamma Knife radiosurgery of brain tumours. PATIENTS AND METHODS: Twenty-seven PET/CT studies co-registered with MRI were performed on 16 patients after radiosurgery, with 12/16 patients having multiple radiosurgery treatments. Long term follow-up was used for evaluation, with 3/16 patients being histopathologically confirmed. RESULTS: PET/CT was positive in all studies in 6/16 patients, negative in all studies in 6/16 and changed from negative to positive in one. In 2/16 patients, PET/CT was both positive and negative in separate tumour foci. In 9/16 cases with a positive PET/CT, tumour was confirmed. In 6/16 patients with a negative PET/CT, 3/6 had recurrence and 3/6 ARE. In 1/16, equivocal results became negative after retreatment. PET/CT/MRI identified tumour within ARE. Sensitivity of PET/CT/MRI proved to be 64.7%, and specificity 100%. CONCLUSION: PET/CT/MRI assists management, by revealing metabolism rather than histology.

Management of brain metastasis in a patient with advanced epithelial ovarian carcinoma by gamma-knife radiosurgery.

INTRODUCTION: Brain metastases from epithelial ovarian cancer (EOC) are rare events. We present a rare case of single ovarian cancer metastasis to the brain treated with gamma-knife radiosurgery (GKRS). CASE OUTLINE: A 65-year-old woman with advanced EOC presented with severe neurologic symptoms. A single brain metastasis of 3.2 cm with surrounding edema in the left parietal lobe was detected by brain magnetic resonance imaging (MRI) scan during the work-up. The decision to perform GKRS was due to a surgical inaccessibility of intracranial lesion. Twelve weeks after the procedure, the MRI scan showed reduction in the diameter of brain metastasis and surrounding edema and the patient returned to good mental and motor performance.The patient survived for 22 months following treatment and died from a progressive intra-abdominal disease. Prognosis of ovarian cancer patients with brain metastases is generally poor regardless of treatment. CONCLUSION: Our case shows that GKRS as primary treatment modality for the control of ovarian cancer metastases to the brain was effective and can be considered as a treatment of choice if international selection criteria are followed.

Malignant transformation in vestibular schwannoma: report of a single case, literature search, and debate.

OBJECT: The significance of radiation in the induction of malignancy in vestibular schwannomas (VSs) after radiosurgery is unclear despite an increasing number of case reports. The authors describe a new case of verified malignant transformation in a vestibular schwannoma (MTVS) and provide a new evaluation of such cases previously reported in the literature. METHODS: A 46-year-old woman underwent subtotal resection of a right-sided VS in 2004. The histological characteristics of the lesion were typical and benign. In early 2007 Gamma Knife surgery (GKS) was performed to treat a residual enlarging remnant. The radiosurgery parameters included the following: target volume 3.5 cm(3), prescription dose 12 Gy, prescription isodose 45%, maximum dose 26.7 Gy, and coverage 97%. At 2 years' follow-up the lesion was enlarged to 5.2 cm(3), but by 5 years it had decreased to 2.3 cm(3). Six months later the lesion was 8.4 cm(3). Repeated surgery was performed, and a histological analysis revealed a malignant peripheral nerve sheath tumor. The case was further managed with repeated GKS performed in the spring of 2013. At that time, the radiosurgery parameters included the following: target volume 3.5 cm(3), prescription dose 16 Gy, prescription isodose 45%, maximum dose 35.6 Gy, and coverage 91%. This Gamma Knife Department has treated a total of 205 patients with VS (local incidence of MTVS 0.49%). A search of the literature published up to and including 2013 was performed using PubMed as well as more informal search methods. RESULTS: This patient is the 29th reported case of MTVS after radiation therapy. Of these cases, 40.7% were patients with neurofibromatosis (NF). In those cases in which histology showed tumors with previously benign characteristics, totally conforming to the criteria for MTVS, the mean delay to malignant expression was 68 months (median delay 72 months). The authors also retrieved papers reporting 30 cases of malignant VS in patients who had not undergone radiation treatment. Five of those cases were malignant transformation of a benign entity, and in 4 of them histology had verified that the initial disease was benign. In those 4 cases, there was a mean delay to malignant expression of 7.2 months (median delay 8 months). CONCLUSIONS: Despite more frequent reports of MTVS after radiation treatment recently, there has been no accurate quantification of the risk, except in patients with NF, in whom the incidence of malignancy is high in relation to the numbers treated. The present analysis indicates that the risk of malignancy over 20 years in cases in which no radiation treatment has occurred is 1.32-2.08 per 100,000, and this risk decreases to 1.09-1.74 per 100,000 if cases of NF are excluded. After radiation treatment, the overall risk over 20 years is 25.1 per 100,000, and this risk decreases to 15.6 per 100,000 if cases of NF are excluded. Radiation treatment increases the risk by approximately 10 times in non-NF cases.

A simple and efficient methodology to improve geometric accuracy in gamma knife radiation surgery: implementation in multiple brain metastases.

PURPOSE: To propose, verify, and implement a simple and efficient methodology for the improvement of total geometric accuracy in multiple brain metastases gamma knife (GK) radiation surgery. METHODS AND MATERIALS: The proposed methodology exploits the directional dependence of magnetic resonance imaging (MRI)-related spatial distortions stemming from background field inhomogeneities, also known as sequence-dependent distortions, with respect to the read-gradient polarity during MRI acquisition. First, an extra MRI pulse sequence is acquired with the same imaging parameters as those used for routine patient imaging, aside from a reversal in the read-gradient polarity. Then, "average" image data are compounded from data acquired from the 2 MRI sequences and are used for treatment planning purposes. The method was applied and verified in a polymer gel phantom irradiated with multiple shots in an extended region of the GK stereotactic space. Its clinical impact in dose delivery accuracy was assessed in 15 patients with a total of 96 relatively small (<2 cm) metastases treated with GK radiation surgery. RESULTS: Phantom study results showed that use of average MR images eliminates the effect of sequence-dependent distortions, leading to a total spatial uncertainty of less than 0.3 mm, attributed mainly to gradient nonlinearities. In brain metastases patients, non-eliminated sequence-dependent distortions lead to target localization uncertainties of up to 1.3 mm (mean: 0.51 ± 0.37 mm) with respect to the corresponding target locations in the "average" MRI series. Due to these uncertainties, a considerable underdosage (5%-32% of the prescription dose) was found in 33% of the studied targets. CONCLUSIONS: The proposed methodology is simple and straightforward in its implementation. Regarding multiple brain metastases applications, the suggested approach may substantially improve total GK dose delivery accuracy in smaller, outlying targets.

Standardization of terminology in stereotactic radiosurgery: Report from the Standardization Committee of the International Leksell Gamma Knife Society: special topic.

OBJECT: This report has been prepared to ensure more uniform reporting of Gamma Knife radiosurgery treatment parameters by identifying areas of controversy, confusion, or imprecision in terminology and recommending standards. METHODS: Several working group discussions supplemented by clarification via email allowed the elaboration of a series of provisional recommendations. These were also discussed in open session at the 16th International Leksell Gamma Knife Society Meeting in Sydney, Australia, in March 2012 and approved subject to certain revisions and the performance of an Internet vote for approval from the whole Society. This ballot was undertaken in September 2012. RESULTS: The recommendations in relation to volumes are that Gross Target Volume (GTV) should replace Target Volume (TV); Prescription Isodose Volume (PIV) should generally be used; the term Treated Target Volume (TTV) should replace TVPIV, GTV in PIV, and so forth; and the Volume of Accepted Tolerance Dose (VATD) should be used in place of irradiated volume. For dose prescription and measurement, the prescription dose should be supplemented by the Absorbed Dose, or DV% (for example, D95%), the maximum and minimum dose should be related to a specific tissue volume (for example, D2% or preferably D1 mm3), and the median dose (D50%) should be recorded routinely. The Integral Dose becomes the Total Absorbed Energy (TAE). In the assessment of planning quality, the use of the Target Coverage Ratio (TTV/ GTV), Paddick Conformity Index (PCI = TTV2/[GTV · PIV]), New Conformity Index (NCI = [GTV · PIV]/TTV2), Selectivity Index (TTV/PIV), Homogeneity Index (HI = [D2% ­D98%]/D50%), and Gradient Index (GI = PIV0.5/PIV) are reemphasized. In relation to the dose to Organs at Risk (OARs), the emphasis is on dose volume recording of the VATD or the dose/volume limit (for example, V10) in most cases, with the additional use of a Maximum Dose to a small volume (such as 1 mm3) and/or a Point Dose and Mean Point Dose in certain circumstances, particularly when referring to serial organs. The recommendations were accepted by the International Leksell Gamma Knife Society by a vote of 92% to 8%. CONCLUSIONS: An agreed-upon and uniform terminology and subsequent standardization of certain methods and procedures will advance the clinical science of stereotactic radiosurgery.

Phase II study of neoadjuvant imatinib in glioblastoma: evaluation of clinical and molecular effects of the treatment.

PURPOSE: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies. EXPERIMENTAL DESIGN: Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase signaling pathways. Pharmacokinetic studies were also done. RESULTS: Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre- and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation. CONCLUSIONS: Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients.

Mechanical and dose delivery accuracy evaluation in radiosurgery using polymer gels.

The polymer gel-Magnetic Resonance Imaging (MRI) dosimetry technique was employed to evaluate the mechanical and dose delivery accuracy in Leksell gamma knife stereotactic radiosurgery for the treatment of multiple targets. Two different polymer gel dosimeter formulations that have been reported in the literature were prepared in-house. A plan for the treatment of four brain metastases (targets) was generated. The plan involved the delivery of four, 8 mm collimator shots using different prescription isodose lines and different prescription doses for each target, keeping the maximum dose constant for all the targets. A sample of each gel formulation was irradiated using a custom made phantom with an experimental procedure capable of testing the increased nominal mechanical accuracy of stereotactic radiosurgery. The irradiated dosimeters were evaluated using a clinical 1.5 T Philips ACS NT MR imager. Result manipulation in 3-D allowed for the determination of the mechanical accuracy in the delivery of each shot through the comparison of measured versus planned shot center coordinates. Dose delivery accuracy was also evaluated by comparison of maximum dose values measured at the center of each shot as well as dose distribution measurements, with corresponding treatment planning calculations. Polymer gel dosimetry was found capable of verifying the complete chain of radiosurgery treatment in gamma knife applications involving the irradiation of multiple targets.