Abstract ID: 222 Clinical implementation of a Monte Carlo based QA platform for validation of Tomotherapy and Cyberknife treatment plans.

INTRODUCTION: This work describes the clinical implementation of a Monte Carlo based platform for treatment plan validation for Tomotherapy and Cyberknife, including a semi-automatic plan evaluation module based on dose constraints for organs-at-risk (OAR). METHODS: The Monte Carlo-based platform Moderato [1] is based on BEAMnrc/DOSXYZnrc and allows for automated re-calculation of doses planned with Tomotherapy and Cyberknife techniques. The Prescription/Validation module generates a set of dose constraints based on the anatomical region and fractionation scheme considered. Upon achievement of the planning, dose results are displayed with visual warnings in case of constraint violation. The system was tested on 83 patient cases in order to evaluate the influence of difference in calculation algorithms on OAR constraints. RESULTS: The first results with the Tomotherapy plans allowed for detecting and correcting a problem with the CT Hounsfield units when using a large reconstruction diameter (a CT artifact that lead to air voxels with an overestimated density). The Cyberknife results also showed some dose differences associated with different energy thresholds between Moderato and the Monte Carlo algorithm used in the Treatment Planning Station. Regarding OAR constraints, re-calculation generated few violations in thoracic, pelvic and abdominal cases. However, in spinal and head cases, significant differences can appear (-11% to +6%) on optic pathways and spinal cord, leading to doses above the limits. CONCLUSIONS: The Moderato platform constitutes a promising tool for the validation of plan quality, offering both dose re-calculation and OAR constraints evaluation. First results show the importance of this verification for some specific regions. Further work is ongoing to optimize the quantity and relevance of the information displayed, before fully introducing the system in clinical routine.

Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.

The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.

Cilengitide targets pediatric glioma and neuroblastoma cells through cell detachment and anoikis induction.

The prognosis of children with high-grade glioma or high-risk neuroblastoma remains poor. Cilengitide is a selective antagonist of αvß3 and αvß5 integrins, which are involved in tumor growth and development of metastasis. We have evaluated the effects of cilengitide on pediatric glioma and neuroblastoma cell lines for the first time. Expression levels of αvß3 and αvß5 were determined by flow cytometry in three neuroblastoma and five pediatric glioma cell lines compared with adult U87-MG before and after irradiation. Cell detachment, cytotoxicity, and cell growth under nonadhesive conditions were measured using the MTS assay. Cell death and apoptosis were assessed by annexin-V/propidium iodide staining. The varying αvß3 and αvß5 expression levels were unrelated to tumor grade. Irrespective of the αvß5 expression level, the pediatric cells expressing αvß3 were dose dependently sensitive to cilengitide. UW479 cells expressed only αvß5 integrin and were not sensitive to cilengitide, suggesting that cilengitide's action largely depends on αvß3 inhibition. Cell detachment resulted in a higher cytotoxicity in pediatric glioma compared with U87-MG cells, which seem able to grow despite the significant cilengitide-induced cell detachment. Growth kinetics on polyHEMA showed that only pediatric glioma cells were sensitive to anoikis and so died after cilengitide-induced detachment. Furthermore, irradiation of glioma cells increased αvß3 expression slightly but not cilengitide sensitivity. Cilengitide's action on glioma and neuroblastoma cells appears to be dependent on αvß3 expression and sensitivity to anoikis. Cilengitide is able to target pediatric glioma and neuroblastoma cells in vitro directly and efficiently. Tumor context could validate these promising observations.

Extracranial stereotactic radiotherapy: preliminary results with the CyberKnife.

In the field of radiation oncology, equipment for fractionated radiotherapy and single-dose radiosurgery has become increasingly accurate, together with the introduction of robotized treatments. A robot is a device that can be programmed to carry out accurate, repeated and adjusted tasks in a given environment. Treatment of extracranial lesions involves taking into account organ mobility (tumor and healthy tissue) whilst retaining the ability to stereotactically locate the target. New imaging techniques (single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), positron emission tomography (PET)) provide further relevant information to slice images (computed tomography (CT) scans, MRI) for target definition. Hypo-fractionated treatments can only be used for curative treatment if the target is accurately defined and tracked during treatment. The CyberKnife is a non-invasive system of radiosurgery and fractionated stereotactic radiotherapy. For intracranial lesions treated by single-dose radiosurgery, it has been used to treat meningioma, acoustic neuromas, pituitary adenoma, metastases, arteriovenous malformations and refractory pain (trigeminal neuralgia). More than 10,000 patients have been treated worldwide. Currently, the most significant developments are in the field of extracranial stereotactic radiotherapy (lung, liver, reirradiation, prostate, etc.). Clinical results obtained in the CyberKnife Nord-Ouest program after 1 year of experience are presented.

A preliminary investigation into the effects of X-ray radiation on superficial cranial vascularization.

Radiation therapy (RT) is an established treatment modality for malignant neoplasms. RT induces tissue damage that may lead to osteoradionecrosis in more severe cases. Suitable animal models to study RT-induced changes in membranous craniofacial bone are currently not available. The aim of this study was therefore to quantify RT-induced changes in cranial microcirculation using a newly developed calvaria chamber model and to relate these changes to RT-induced histological damage. New Zealand white rabbits received a total radiation dose of 18.75 Gy through the calvaria chamber, and the number of vessels, the vessel length density (VLD), and angiogenic sprouting were quantified on a weekly basis during a 12-week period. At the end of 12 weeks, the RT-treated (n = 5) or control (n = 5) calvarias were biopsied for histopathological analysis. RT resulted in a steep reduction in the number of vessels and the VLD during the first 3 weeks, particularly in larger-diameter vessels, followed by a flat stabilization/remodeling phase in the subsequent 9 weeks that never restored to baseline values. Histomorphometric analysis revealed a high degree of osteocytic depletion, prominent hypocellularity in the lacunae and intraosseous vasculature, enlarged and nonconcentric Haversian systems, and a severely disorganized bone matrix in the RT-treated calvarias. Despite the prevalence of some angiogenic potential, the RT-induced effects in the early phase persisted in the intermediate to late phase, which may have contributed to the poor recovery of the RT-treated bone.

Clinical outcomes after Gamma Knife surgery for idiopathic trigeminal neuralgia: review of 76 consecutive cases.

OBJECT: Stereotactic radiosurgery is an increasingly used, and the least invasive, surgical option for patients with trigeminal neuralgia (TN). In this study, the authors performed a retrospective evaluation of the safety and efficacy of this method for idiopathic TN. METHODS: The authors reviewed data from 76 patients with idiopathic TN who underwent Gamma Knife surgery (GKS). The mean age of the patients was 64 years (range 27-83 years). All patients had typical features of TN. Thirty patients (39.5%) had previously undergone surgery. The intervention consisted of GKS on the retrogasserian cisternal portion of the fifth cranial nerve. The mean maximum GKS dose used was 85.1 Gy (range 75-90 Gy). RESULTS: Patients were followed-up from 6 to 42 months (mean 20.3 months) after GKS. Complete pain relief was achieved in 83.1% of the patients within 1 year, 70.9% within 2 years, and 62.5% within 3 years. Patients who underwent previous surgery demonstrated a lower rate of pain relief (p < 0.05). Twenty patients (26.3%) reported pain recurrence between 6 and 42 months after treatment. New or worsened persistent trigeminal dysfunction developed after GKS in 16 patients (21%); 8 of these patients described some facial numbness/not bothersome, and 8 reported some facial numbness/somewhat bothersome. None of the patients developed troublesome dysesthesia or anesthesia dolorosa. CONCLUSIONS: Gamma Knife surgery for idiopathic TN proved to be safe and effective and was associated with a particularly low rate of complications.