La technique de radiothérapie VMAT (Volumetric Modulated Arc Therapy), diffusée en 2009, combine les avantages des techniques d'arc thérapie dynamique aux avantages des techniques de radiothérapie conformationnelle avec modulation d'intensité (RCMI) par faisceaux stationnaires. L'objectif de la thèse est de rendre optimales les conditions de mise en œuvre du VMAT autour d'un accélérateur linéaire d'électrons Synergy/Elekta afin de sécuriser la technique et de pouvoir bénéficier de l'apport clinique potentiellement attendu. Sur la base d'une analyse de l'influence des différents paramètres de la chaîne de traitement, nous proposons des éléments d'optimisation du traitement à la fois sur la planification dosimétrique et sur le contrôle de son exécution sur la machine. Nous montrons que si la qualité de l'optimisation de la technique dépend des caractéristiques intrinsèques de l'accélérateur, elle est également fortement influencée par le paramétrage du système de planification des traitements (TPS). Nous mettons en évidence des différences comparées des collimateurs Beam Modulateur (largeur de lames de 4 mm) et MLCi2 (largeur de lames de 10 mm) tant sur le plan de la distribution de dose obtenue que sur l'efficience. Nous montrons que, si pour deux principaux TPS commercialisés (Pinnacle/Philips et Monaco/Elekta) les distributions de dose aux volumes cibles sont peu modifiées, les différences de méthodes implémentées influencent la distribution de dose aux tissus sains. Nous proposons des programmes de contrôles de qualité au niveau de l'accélérateur, des plans dosimétriques de traitement et de l'exécution des traitements. Afin de garantir un niveau de confiance élevé sur la dose délivrée, nous proposons une méthode d'évaluation de la fluence délivrée en cours de traitement basée sur l'analyse des paramètres machines. Nous établissons que le processus de traitement VMAT optimisé fournit des performances de qualité supérieure que les techniques de RCMI par faisceaux stationnaires pour quatre localisations tumorales majeures étudiées. / VMAT (Volumetric Modulated Arc Therapy) technique has been introduced in 2009, it combines advantage of arctherapy techniques with advantage of IMRT (Intensity Modulated Radio Therapy) techniques delivered with stationary beams. The purpose of the thesis is to optimise implementation conditions of VMAT for a Synergy/Elekta linear accelerator in order to secure the technique and to be able to benefit from potentially expected clinical improvement. From analysis of influence of various work flow parameters, we propose treatment optimisation factors both on dosimetric planning and on delivering control on the accelerator. We show that if optimisation quality depends on intrinsic accelerator characteristics, it also depends very much on configuration of treatment planning system (TPS). We highlight compared differences between Beam Modulateur (leaf width of 4 mm) and MLCi2 (leaf width of 10 mm) on dose distribution and on efficiency. We show that if differences of dose distributions are small for two major TPS (Pinnacle/Philips and Monao/Elekta), the differences of implemented methods affect dose distribution of healthy tissues. We suggest quality control set for accelerators, for treatment plans and for treatment delivery. In order to provide a high safety level on delivered dose, we suggest an evaluation method of the real fluence provided during treatment delivery by analysing accelerator parameters. We establish that optimised process of VMAT treatment provides better performance than RCMI techniques delivered with stationary beams for the four major cancer cases that has been studied.

Volumetric modulated arc therapy (VMAT) is an efficient and conformal radiation therapy technique. It accomplishes this by dynamically varying multi-leaf collimator (MLC) positions, dose rates and gantry velocity. This work investigated the effect of varying the maximum MLC speed and maximum dose rate on the quality, efficiency and accuracy of treatment plans. The Pinnacle3 SmartArc treatment planning software was used to generate plans on prostate and head and neck (H&N) sites. A range of maximum MLC leaf speeds (0.55 cm/s to 2.20 cm/s) and maximum dose rates (200 MU/min to 600 MU/min) restrictions were applied to each plan to investigate their effect on the treatment quality, efficiency and accuracy. Each plan had their monitor units (MU) per fraction, delivery time, mean dose rate and leaf speed analysed. The dose volume histogram (DVH) data was used in the assessment of the conformity, homogeneity and plan quality. The treatments were delivered on Varian iX accelerator equipped with 120-leaf millennium MLC. Quality assurance measurements were performed using the ArcCHECK™ 3D diode array and results were assessed based on gamma analysis of dose fluence maps, beam delivery statistics and Dynalog data. The number of VMAT fields was found to be a key factor in how significant the maximum MLC leaf speed affected the plan parameters investigated. Single arc treatments were shown to have lower MU, dose rate and plan quality, while also exhibiting a slight increase in estimated delivery time. For dual arc treatments, MU, delivery time, dose rate and plan quality were largely independent of the maximum MLC speed allowed. The QA showed that higher MLC leaf speeds were prone to an increase in the discrepancy between planned and delivered control point (CP) fluence and higher MLC positioning errors. None of these were at a clinically significant level, and the overall fluence distribution and point dose comparisons were independent of maximum MLC leaf speed. The only clinically significant effect that modulation of the maximum dose rate had was on the delivery time. Lower maximum dose rates resulted in longer treatment delivery, which is an important consideration in minimising the intra-fractional motion during treatment. The results of the MLC leaf speed evaluation showed that the lower the maximum leaf speed the more accurate the delivered treatment, -however the quality of the plan is reduced. This indicates that there could be an optimum maximum MLC leaf speed which produces high quality plans that can be accurately delivered. Based on this work a maximum MLC leaf speed of 1.38 cm/s was shown to have no reduction in plan quality however it showed improvement in delivery accuracy. There was no justification found for reducing the maximum dose rate below the recommended 600 MU/min.

The purpose of this work is to evaluate quasi-3D arrays for use with intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) and to determine their clinical relevance. This is achieved using a Delta4 from Scandidos and ArcCheck from Sun Nuclear and the associated software. While certain aspects of these devices and software have been previously evaluated, the main goal of this work is to evaluate the new aspects, such as reconstructing dose on a patient CT set, and extending the capabilities. This includes the capability to reconstruct the dose based on a helical delivery as well as studying the dose to a moving target using measurement-guided motion simulations. It was found that Sun Nuclear's ArcCheck/3DVH system exhibited excellent agreement for dose reconstruction for IMRT/VMAT using a traditional C-arm linear accelerator and stringent 2%/2mm comparison constraints. It also is a powerful tool for measurement-guided dose estimates for moving targets, allowing for many simulations to be performed based on one measurement and the target motion data. For dose reconstruction for a helical delivery, the agreement was not as good for the stringent comparison but was reasonable for the clinically acceptable 3%/3mm comparison. Scandidos' Delta4 shows good agreement with stringent 2%/2mm constraints for its dose reconstruction on the phantom. However, the dose reconstruction on the patient CT set was poor and needs more work. Overall, it was found that quasi-3D arrays are powerful tools for dose reconstruction and treatment plan comparisons. The ability to reconstruct the dose allows for a dose resolution comparable to the treatment plan, which negates the previous issues with inadequate sampling and resolution issues found when just comparing the diodes. The ability to quickly and accurately compare many plans and target motions with minimum setup makes the quasi-3D array an attractive tool for both commissioning and patient specific quality assurance.

Purpose/Objectives: Intensity Modulated Radiation Therapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) provide advantages in delivery of radiation allowing conformality of delivered dose to the planning target and reducing dose to organs at risk (OAR), however, at the potential cost of low dose spread. Due to the central location of the esophagus and GE junction, dose to lungs, heart, spinal cord, liver, and kidneys must be considered. Low dose spread is of particular concern with respect to healthy lung tissue. This study comprehensively compares volumetric dose statistics of the standard three-dimensional conformal radiation therapy (3D-CRT) compared with VMAT and IMRT for distal esophageal cancer treatment. Materials/Methods: Forty patients who underwent pre-operative radiation therapy for esophageal cancer between 2012-2014 were retrieved from our database. Pinnacle planning software was used to create 3D-CRT, VMAT and IMRT radiation plans for all patients. Forty-five (45) Gy was prescribed for each patient with D95% > 42.75Gy for the planning target volume (PTV). All plans were optimized to maintain PTV coverage while reducing dose to OAR with specific emphasis on lung and heart dose. Volumetric dose statistics were obtained, and Wilcoxon signed rank test was used to compare 3D-CRT vs IMRT and VMAT for Conformity Index, Integral Dose, Monitor Units, lung (V5Gy, V20Gy, mean, max), heart (V30Gy, mean, max), spinal cord max, bilateral kidneys (V20Gy, mean) and liver mean dose. Comparison was also made for IMRT vs VMAT. Results: For both IMRT and VMAT compared with 3D-CRT, statistically significant pairwise differences were noted for Conformity Index (-28.51%, -30.70%, P<.001), Integral Dose (-14.0%, -14.8%, P<.001), Monitor Units (107.2%, 80.4%, P<.001), lung (V20Gy: -49.7%,-57.4%, mean: -20.3%,-24.9%, P <.001), heart (V30Gy : -10.1%,-14.3%, mean -10.4%,-13.4%, P <.001), spinal cord (max 13.3%,9.5%, P <.001) and liver (mean -29.9%,-24.3%, P <.001). No significant differences were noted for VMAT and IMRT compared with 3D-CRT for lung (V5Gy, max dose), heart (max dose) and bilateral kidneys (mean). VMAT did offer statistically significant improvement in Conformity Index, Monitor Units, lung V20Gy and mean dose as well as heart V30Gy and mean dose compared to IMRT. Conclusion: VMAT and IMRT offer excellent sparing of key organs (lung, heart) with respect to volumetric constraints. Max point doses as well as lung V5Gy, which can be an indication of low dose spread for esophageal treatment, were not conclusively different. While 3D-CRT offers acceptable treatment, VMAT should be the standard modality of radiation treatment where facilities exist. / Thesis / Master of Science (MSc)

External beam radiotherapy is delivered from outside the body aimed at cancer cells to damage their DNA making them unable to divide and reproduce. The beams travel through the body and may damage nearby healthy tissues unless carefully planned. Therefore, the goal of treatment plan optimization is to find the best system configuration to deliver sufficient dose to target structures while avoiding damage to healthy tissues. This thesis investigates optimization approaches for two external beam radiation therapy techniques: Intensity-Modulated Radiation Therapy (IMRT) and Volumetric-Modulated Arc Therapy (VMAT). We develop an automated treatment planning technology for IMRT which generates several high-quality treatment plans satisfying the provided requirements in a single invocation and without human guidance. Our approach is based on an existing linear programming-based fluence map optimization model that approximates dose-volume requirements using conditional value-at-risk (C-VaR) constraints. We show how the parameters of the C-VaR constraints can be used to control various metrics of treatment plan quality. A novel bi-criteria scoring based beam selection algorithm is developed which finds the best beam configuration at least ten times faster for real-life brain, prostate, and head and neck cases as compared to an exact mixed integer programming model. Patient anatomy changes due to breathing during the treatment of lung cancer need to be considered in treatment planning. To date, a single phase of the breathing cycle is typically selected for treatment and radiation is shut-off in other phases. We investigate optimization technology that finds optimal fluence maps for each phase of the breathing cycle by considering the overall dose delivered to a patient using image registration algorithms to track target structures and organs at risk. Because the optimization exploits the opportunities provided in each phase, better treatment plans are obtained. The improvements are shown on a real-life lung case. VMAT is a recent radiation treatment technology which has the potential to provide treatments in less time compared to other delivery techniques. This enhances patient comfort and allows for the treatment of more patients. We build a large-scale mixed-integer programming model for VMAT treatment plan optimization. The solution of this model is computationally prohibitive. Therefore, we develop an iterative MIP-based heuristic algorithm which solves the model multiple times on a reduced set of decision variables. We introduce valid inequalities that decrease solution times, and, more importantly, that identify higher quality integer solutions within specified time limits. Computational studies on a spinal tumor and a prostate tumor case produce clinically acceptable results.

Background: External Beam Radiotherapy is essential in the management of locally advanced cervical cancer (LACC). Generally, VMAT is thought to achieve higher conformity to the Planned Target Volume (PTV) and better sparing of organs at risk (OAR) when compared to 3D-CRT. This study focused on these principles as it applied to treatment and potential toxicity in the management of LACC. Aim: To compare dosimetric parameters between VMAT and 3D-CRT in the management of LACC. Setting: The study analysed patients treated at Groote Schuur Hospital between May and December 2017. Method: A non-randomized comparative retrospective study. EBRT plans for 3D-CRT and VMAT were generated and data on treatment parameters for PTV D50%, Dmax, Dmean, Conformity Index (CI), Homogeneity Index, Treated Volume (TV), Irradiated Volume (IV) and OAR constraints; femoral heads, bladder, bowel bag, rectum and bone marrow were collected. Results: Of the 45 patients assessed, VMAT showed significantly lower treatment parameter values for CI (1.09 vs 1.49; p< .001) whereas, 3D-CRT showed lower Dmax (48.1Gy vs 49.2Gy; p< .001) and rectum (88.5% vs 96%). A reduced 3D-CRT dose was noted for bladder Dmax (47.4Gy vs 48.3Gy; p< .001). Conclusion: VMAT offered a superior dosimetric option, with better OAR dose sparing and optimal tumour dosimetry.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22038号 / 医博第4523号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 松村 由美, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The aim of this work is primarily to validate the advanced techniques for treatment planning and dosimetric verification for modern megavoltage x-ray radiotherapy. With the advent of modern radiotherapy techniques, there is a great need for assuring quality of the radiation dose distributions generated by the advanced intensity modulated treatments (IMRT/VMAT). This is typically accomplished by the assessment of the treatment plan quality at the planning stage and then verification of the dose distributions through measurements on the phantoms or independent dose calculations prior to the actual delivery of these plans to patients. The major focus of this work is to clinically evaluate the modern 2D and 3D dose verification techniques. The measurement-based dosimetry systems investigated were ArcCHECK/3DVH and SRS MapCHECK. AcrCHECK/3DVH system uses the measurement-guided dose reconstruction algorithm to correct the predicted dose in the patient dataset. The system was intended for VMAT/IMRT QA. SRS MapCHECK was investigated for SRS treatments. The independent dose calculation system was DoseCHECK which employed a GPU-accelerated convolution-superposition of algorithm for 3D dose reconstruction on the patient dataset. Next, a hybrid dose verification system (PerFRACTION) was evaluated, which takes input from both the treatment planning system and the linac EPID and produces a measurement-guided 3D dose distribution for comparison with the plan. This system was investigated for potential QA applications to a modern, efficient SRS technique, involving simultaneously treating multiple targets with a single isocenter. The performance of all dosimetry systems was validated against well-characterized independent dosimeters, such as ion chamber, film and scintillator detectors, or 3D arrays (Delta4), using stringent dose comparison criteria to test their limits for the intended clinical applications. For the initial plan quality evaluation of a novel tool (Feasibility DVH) was investigated. This tool a priori estimates best achievable dose volume histograms for a specific patient, based on the basic physics properties of the megavoltage x-rays, thus helping the planners to guide their efforts. All studied dosimetry systems showed an excellent agreement of the average gamma (a mathematical combination of DD and DTA) passing rates >98% for most of the plans. The 3% DD/2mm DTA criteria were used for extracranial plans and 3%/1mm for intracranial SRS plans. As dictated by the logic of the application, the comparisons were made against TPS calculations, a bi-planar array, or film measurements. Similarly the average percent point dose errors <2% were observed against the ion chambers or film. In the rare instances when the deviations were larger, intuitive explanations were provided, based on either the physics of the plans or inhomogeneous patient anatomy and resulting algorithm limitations. Feasibility DVH was shown to reliably predict the best possible organ sparing for clinical head-and-neck VMAT plans. Overall the investigated dosimetry systems were found reliable and feasible for their intended clinical use.

No description available.

High doses of 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") are known to reduce levels of various serotonergic markers outside of the raphe nuclei. To test the hypothesis that these deficits reflect a degeneration of distal axons/terminals, we investigated the effects of an MDMA binge (10mg/kg x 4) on the relative protein and genetic expression of several serotonergic markers in rats, as well as the effects of this compound on the quantity of serotonergic terminals in these animals. In experiment I, we examined whether MDMA alters serotonin transporter (SERT) levels as determined by lysate binding and immunoblotting analyses. Both methods of analysis revealed MDMA-induced reductions in regional SERT content. Experiment II investigated MDMA-induced changes in terminal-specific levels of SERT and the vesicular monoamine transporter 2 (VMAT-2) in the hippocampus, a region with sparse dopaminergic innervation, after lesioning noradrenergic input with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Animals were administered 100 mg/kg DSP-4 or saline 1 week prior to MDMA (or saline). As determined by immunoblotting of synaptosomal tissue, the DSP-4/MDMA group showed little change in hippocampal VMAT-2 protein expression compared to DSP-4/Saline controls, despite large reductions in SERT levels in all regions examined in the MDMA-treated animals. Experiment III examined whether MDMA alters genetic expression of SERT and VMAT-2. When compared to saline-treated controls, animals given MDMA showed a striking decrease in SERT gene expression (and a lesser effect on VMAT-2) in dorsal/median raphe as assessed by quantitative RT-PCR. Experiment IV(a) investigated the effects of MDMA on gene and protein expression of tryptophan hydroxylase (TPH) in the hippocampus. Levels of TPH protein were unchanged between treatment groups, while transcript levels were decreased 15-fold in the dorsal/median raphe. In experiment IV(b), flow cytometry was used to measure whether MDMA alters the quantity of serotonergic terminals in the hippocampus. MDMA-treated animals showed an increase in the number of serotonergic synaptosomes identified by co-labeling for synaptosome-associated protein of 25 kDa (SNAP-25) and TPH. These results demonstrate that MDMA causes substantial regulatory changes in the expression of serotonergic markers with no evidence for synaptic loss, questioning the need to invoke distal axotomy as an explanation of MDMA-related serotonergic deficits.