On the stability of Leksell Vantage stereotactic head frame fixation in Gamma Knife radiosurgery: a study based on cone-beam computed tomography imaging and the High Definition Motion Management system.

OBJECTIVE: The authors' objective was to investigate the stability of the newly introduced Vantage stereotactic frame fixation in single-fraction Gamma Knife radiosurgery. METHODS: A total of 255 patients were included in this work and treated with the Vantage frame and Leksell Gamma Knife (LGK) Icon equipped with cone-beam computed tomography (CBCT) imaging. After the frame was mounted on the patient's head, a CT scan was acquired. After the patient was positioned on the couch of LGK, CBCT was acquired to verify the target position before treatment delivery. A second CBCT examination was acquired after treatment delivery to assess intrafractional motion. During treatment delivery, the High Definition Motion Management (HDMM) system was enabled to track a marker on the nose tip of the patient as a surrogate of intracranial motion. The stability of the Vantage frame was deconstructed into two parts: 1) motion between CT and the first CBCT prior to treatment delivery (CT-CBCT1), and 2) motion between CBCT procedures during treatment delivery (CBCT1-CBCT2). Transformation between CT and CBCT1 was given by Leksell GammaPlan, whereas transformation between CBCT1 and CBCT2 required mathematical processing of the transformation and coregistration matrices in the source files. RESULTS: The average CT-CBCT1 displacement vector was 0.31 mm, with a range as great as 1.09 mm, and 89% and 97% of cases were within 0.5 mm and 0.7 mm, respectively. The CBCT1-CBCT2 displacement vectors averaged at 0.09 mm, with 97% of cases being within 0.2 mm. Spatial shift in the posterior direction was evident, with 94% of cases demonstrating this trend and averaging 0.05 mm. This was attributed to increased pressure on the posterior fixation pins. The HDMM displacement vectors presented larger values with an average of 0.4 mm and a range as great as 1.6 mm, and 98% of cases were within 1.0 mm. The correlation between CBCT1-CBCT2 and HDMM displacements was weak, which was attributed to the high stability of the Vantage frame and consequently small target displacements coupled with the sensitivity of HDMM to face mimics. CONCLUSIONS: This work demonstrated that the Vantage frame possess the same degree of submillimeter stability as the well-established Leksell Coordinate Frame G (G-frame). Displacements between CT and CBCT1 were 3 times higher than between CBCT1 and CBCT2. A suggested HDMM threshold of 1.2 mm ensures a target accuracy within 0.2 mm in Vantage frame treatments.

Range optimization for mono- and bi-energetic proton modulated arc therapy with pencil beam scanning.

The development of rotational proton therapy plans based on a pencil-beam-scanning (PBS) system has been limited, among several other factors, by the energy-switching time between layers, a system-dependent parameter that ranges between a fraction of a second and several seconds. We are investigating mono- and bi-energetic rotational proton modulated arc therapy (PMAT) solutions that would not be affected by long energy switching times. In this context, a systematic selection of the optimal proton energy for each arc is vital. We present a treatment planning comparison of four different range selection methods, analyzing the dosimetric outcomes of the resulting treatment plans created with the ranges obtained. Given the patient geometry and arc definition (gantry and couch trajectories, snout elevation) our in-house treatment planning system (TPS) FoCa was used to find the maximum, medial and minimum water-equivalent thicknesses (WETs) of the target viewed from all possible field orientations. Optimal ranges were subsequently determined using four methods: (1) by dividing the max/min WET interval into equal steps, (2) by taking the average target midpoints from each field, (3) by taking the average WET of all voxels from all field orientations, and (4) by minimizing the fraction of the target which cannot be reached from any of the available angles. After the range (for mono-energetic plans) or ranges (for bi-energetic plans) were selected, the commercial clinical TPS in use in our institution (Varian Eclipse™) was used to produce the PMAT plans using multifield optimization. Linear energy transfer (LET) distributions of all plans were also calculated using FoCa and compared among the different methods. Mono- and bi-energetic PMAT plans, composed of a single 180° arc, were created for two patient geometries: a C-shaped target located in the mediastinal area of a thoracic tissue-equivalent phantom and a small brain tumor located directly above the brainstem. All plans were optimized using the same procedure to (1) achieve target coverage, (2) reduce dose to OAR and (3) limit dose hot spots in the target. Final outcomes were compared in terms of the resulting dose and LET distributions. Data shows little significant differences among the four studied methods, with superior results obtained with mono-energetic plans. A streamlined systematic method has been implemented in an in-house TPS to find the optimal range to maximize target coverage with rotational mono- or bi-energetic PBS rotational plans by minimizing the fraction of the target that cannot be reached by any direction.

Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species.

Glioblastoma multiforme (GBM) is among the most lethal of human malignancies. Most GBM tumors are refractory to cytotoxic therapies. Glioma stem cells (GSCs) significantly contribute to GBM progression and post-treatment tumor relapse, therefore serving as a key therapeutic target; however, GSCs are resistant to conventional radiation therapy. Proton therapy is one of the newer cancer treatment modalities and its effects on GSCs function remain unclear. Here, by utilizing patient-derived GSCs, we show that proton radiation generates greater cytotoxicity in GSCs than x-ray photon radiation. Compared with photon radiation, proton beam irradiation induces more single and double strand DNA breaks, less H2AX phosphorylation, increased Chk2 phosphorylation, and reduced cell cycle recovery from G2 arrest, leading to caspase-3 activation, PARP cleavage, and cell apoptosis. Furthermore, proton radiation generates a large quantity of reactive oxygen species (ROS), which is required for DNA damage, cell cycle redistribution, apoptosis, and cytotoxicity. Together, these findings indicate that proton radiation has a higher efficacy in treating GSCs than photon radiation. Our data reveal a ROS-dependent mechanism by which proton radiation induces DNA damage and cell apoptosis in GSCs. Thus, proton therapy may be more efficient than conventional x-ray photon therapy for eliminating GSCs in GBM patients.

Proposed linear energy transfer areal detector for protons using radiochromic film.

Radiation therapy depends on predictably and reliably delivering dose to tumors and sparing normal tissues. Protons with kinetic energy of a few hundred MeV can selectively deposit dose to deep seated tumors without an exit dose, unlike x-rays. The better dose distribution is attributed to a phenomenon known as the Bragg peak. The Bragg peak is due to relatively high energy deposition within a given distance or high Linear Energy Transfer (LET). In addition, biological response to radiation depends on the dose, dose rate, and localized energy deposition patterns or LET. At present, the LET can only be measured at a given fixed point and the LET spatial distribution can only be inferred from calculations. The goal of this study is to develop and test a method to measure LET over extended areas. Traditionally, radiochromic films are used to measure dose distribution but not for LET distribution. We report the first use of these films for measuring the spatial distribution of the LET deposited by protons. The radiochromic film sensitivity diminishes for large LET. A mathematical model correlating the film sensitivity and LET is presented to justify relating LET and radiochromic film relative sensitivity. Protons were directed parallel to radiochromic film sandwiched between solid water slabs. This study proposes the scaled-normalized difference (SND) between the Treatment Planning system (TPS) and measured dose as the metric describing the LET. The SND is correlated with a Monte Carlo (MC) calculation of the LET spatial distribution for a large range of SNDs. A polynomial fit between the SND and MC LET is generated for protons having a single range of 20 cm with narrow Bragg peak. Coefficients from these fitted polynomial fits were applied to measured proton dose distributions with a variety of ranges. An identical procedure was applied to the protons deposited from Spread Out Bragg Peak and modulated by 5 cm. Gamma analysis is a method for comparing the calculated LET with the LET measured using radiochromic film at the pixel level over extended areas. Failure rates using gamma analysis are calculated for areas in the dose distribution using parameters of 25% of MC LET and 3 mm. The processed dose distributions find 5%-10% failure rates for the narrow 12.5 and 15 cm proton ranges and 10%-15% for proton ranges of 15, 17.5, and 20 cm and modulated by 5 cm. It is found through gamma analysis that the measured proton energy deposition in radiochromic film and TPS can be used to determine LET. This modified film dosimetry provides an experimental areal LET measurement that can verify MC calculations, support LET point measurements, possibly enhance biologically based proton treatment planning, and determine the polymerization process within the radiochromic film.

Linear energy transfer painting with proton therapy: a means of reducing radiation doses with equivalent clinical effectiveness.

PURPOSE: The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LETd) while keeping the radiobiologically weighted dose (DRBE) to the target the same. METHODS AND MATERIALS: The target is painted with LETd by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning [STP]). As the LETd within the target increases with increasing number of fields, D decreases to maintain the DRBE the same as the conventional treatment planning method by using beams treating the full target (full target planning [FTP]). RESULTS: The LETd increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LETd led to a decrease of D with 5.3 ± 0.6 Gy for 2STP, 4.4 ± 0.7 Gy for 4STP, and 5.3 ± 1.1 Gy for 7STP, keeping the Drbe at 90% of the volume (Drbe, 90) constant to FTP. CONCLUSIONS: LETd painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment.