Novel sequential methods in dose-finding designs : extensions of the continual reassessment method

Dose-finding trials are a form of clinical data collection process in which the primary objective is to estimate an optimum dose of an investigational new drug when given to a patient. This thesis develops and explores three novel dose-finding design methodologies. All design methodologies presented in this thesis are pragmatic. They use statistical models, incorporate clinicians' prior knowledge efficiently, and prematurely stop a trial for safety or futility reasons. Designing actual dose-finding trials using these methodologies will minimize practical difficulties, improve efficiency of dose estimation, be flexible to stop early and reduce possible patient discomfort or harm.

A simple method for EPID-based in vivo dosimetry for radiotherapy treatments of head-and-neck cancers

This study used a homogeneous water-equivalent model of an electronic portal imaging device (EPID), contoured as a structure in a radiotherapy treatment plan, to produce reference dose images for comparison with in vivo EPID dosimetry images. Head and neck treatments were chosen as the focus of this study, due to the heterogeneous anatomies involved and the consequent difficulty of rapidly obtaining reliable reference dose images by other means. A phantom approximating the size and heterogeneity of a typical neck, with a maximum radiological thickness of 8.5 cm, was constructed for use in this study. This phantom was CT scanned and a simple treatment including five square test fields and one off-axis IMRT field was planned. In order to allow the treatment planning system to calculate dose in a model EPID positioned a distance downstream from the phantom to achieve a source-to-detector distance (SDD) of 150 cm, the CT images were padded with air and the phantom’s “body” contour was extended to encompass the EPID contour. Comparison of dose images obtained from treatment planning calculations and experimental irradiations showed good agreement, with more than 90% of points in all fields passing a gamma evaluation, at γ (3%, 3mm )Similar agreement was achieved when the phantom was over-written with air in the treatment plan and removed from the experimental beam, suggesting that water EPID model at 150 cm SDD is capable of providing accurate reference images for comparison with clinical IMRT treatment images, for patient anatomies with radiological thicknesses ranging from 0 up to approximately 9 cm. This methodology therefore has the potential to be used for in vivo dosimetry during treatments to tissues in the neck as well as the oral and nasal cavities, in the head-and-neck region.

Electrocoagulation as a pre-treatment stage to reverse osmosis units

Reverse osmosis (RO) is used by coal seam gas (CSG) operators to treat produced water as it is a well-established and proven technology worldwide. Despite the suitability of RO, there are problems associated with RO technology such as membrane fouling which although not preventing use of RO does decrease effectiveness and increase operating costs. Hence, effective pre-treatment of water samples is essential. Electrocoagulation (EC) potentially can provide improved water purification compared to conventional coagulation prior to an RO unit. This paper provides the first reported study of EC for CSG water pre-treatment and compares the performance to a range of aluminium and iron based coagulants. It was found that EC was superior in terms of removal of silica, calcium, magnesium, barium and strontium in the produced water.

Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae

The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(ε-caprolactone) (PCL) scaffold with β-tricalcium phosphate microparticles (mPCL-TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL-TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP.

A Matlab toolbox for parametric identification of radiation-force models of ships and offshore structures

This article describes a Matlab toolbox for parametric identification of fluid-memory models associated with the radiation forces ships and offshore structures. Radiation forces are a key component of force-to-motion models used in simulators, motion control designs, and also for initial performance evaluation of wave-energy converters. The software described provides tools for preparing non-parmatric data and for identification with automatic model-order detection. The identification problem is considered in the frequency domain.

Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

A brief guide to synchrotron radiation-based microtomography in (structural) geology and rock mechanics

This contribution outlines Synchrotron-based X-ray micro-tomography and its potential use in structural geology and rock mechanics. The paper complements several recent reviews of X-ray microtomography. We summarize the general approach to data acquisition, post-processing as well as analysis and thereby aim to provide an entry point for the interested reader. The paper includes tables listing relevant beamlines, a list of all available imaging techniques, and available free and commercial software packages for data visualization and quantification. We highlight potential applications in a review of relevant literature including time-resolved experiments and digital rock physics. The paper concludes with a report on ongoing developments and upgrades at synchrotron facilities to frame the future possibilities for imaging sub-second processes in centimetre-sized samples.

Time- vs. frequency-domain identification of parametric radiation force models for marine structures at zero speed

The dynamics describing the motion response of a marine structure in waves can be represented within a linear framework by the Cummins Equation. This equation contains a convolution term that represents the component of the radiation forces associated with fluid memory effects. Several methods have been proposed in the literature for the identification of parametric models to approximate and replace this convolution term. This replacement can facilitate the model implementation in simulators and the analysis of motion control designs. Some of the reported identification methods consider the problem in the time domain while other methods consider the problem in the frequency domain. This paper compares the application of these identification methods. The comparison is based not only on the quality of the estimated models, but also on the ease of implementation, ease of use, and the flexibility of the identification method to incorporate prior information related to the model being identified. To illustrate the main points arising from the comparison, a particular example based on the coupled vertical motion of a modern containership vessel is presented.

Treatment plan complexity metrics for predicting IMRT pre-treatment quality assurance results

The planning of IMRT treatments requires a compromise between dose conformity (complexity) and deliverability. This study investigates established and novel treatment complexity metrics for 122 IMRT beams from prostate treatment plans. The Treatment and Dose Assessor software was used to extract the necessary data from exported treatment plan files and calculate the metrics. For most of the metrics, there was strong overlap between the calculated values for plans that passed and failed their quality assurance (QA) tests. However, statistically significant variation between plans that passed and failed QA measurements was found for the established modulation index and for a novel metric describing the proportion of small apertures in each beam. The ‘small aperture score’ provided threshold values which successfully distinguished deliverable treatment plans from plans that did not pass QA, with a low false negative rate.

A practical and theoretical definition of 'small field'

Introduction The consistency of measuring small field output factors is greatly increased by reporting the measured dosimetric field size of each factor, as opposed to simply stating the nominal field size [1] and therefore requires the measurement of cross-axis profiles in a water tank. However, this makes output factor measurements time consuming. This project establishes at which field size the accuracy of output factors are not affected by the use of potentially inaccurate nominal field sizes, which we believe establishes a practical working definition of a ‘small’ field. The physical components of the radiation beam that contribute to the rapid change in output factor at small field sizes are examined in detail. The physical interaction that dominates the cause of the rapid dose reduction is quantified, and leads to the establishment of a theoretical definition of a ‘small’ field. Methods Current recommendations suggest that radiation collimation systems and isocentre defining lasers should both be calibrated to permit a maximum positioning uncertainty of 1 mm [2]. The proposed practical definition for small field sizes is as follows: if the output factor changes by ±1.0 % given a change in either field size or detector position of up to ±1 mm then the field should be considered small. Monte Carlo modelling was used to simulate output factors of a 6 MV photon beam for square fields with side lengths from 4.0 to 20.0 mm in 1.0 mm increments. The dose was scored to a 0.5 mm wide and 2.0 mm deep cylindrical volume of water within a cubic water phantom, at a depth of 5 cm and SSD of 95 cm. The maximum difference due to a collimator error of ±1 mm was found by comparing the output factors of adjacent field sizes. The output factor simulations were repeated 1 mm off-axis to quantify the effect of detector misalignment. Further simulations separated the total output factor into collimator scatter factor and phantom scatter factor. The collimator scatter factor was further separated into primary source occlusion effects and ‘traditional’ effects (a combination of flattening filter and jaw scatter etc.). The phantom scatter was separated in photon scatter and electronic disequilibrium. Each of these factors was plotted as a function of field size in order to quantify how each affected the change in small field size. Results The use of our practical definition resulted in field sizes of 15 mm or less being characterised as ‘small’. The change in field size had a greater effect than that of detector misalignment. For field sizes of 12 mm or less, electronic disequilibrium was found to cause the largest change in dose to the central axis (d = 5 cm). Source occlusion also caused a large change in output factor for field sizes less than 8 mm. Discussion and conclusions The measurement of cross-axis profiles are only required for output factor measurements for field sizes of 15 mm or less (for a 6 MV beam on Varian iX linear accelerator). This is expected to be dependent on linear accelerator spot size and photon energy. While some electronic disequilibrium was shown to occur at field sizes as large as 30 mm (the ‘traditional’ definition of small field [3]), it has been shown that it does not cause a greater change than photon scatter until a field size of 12 mm, at which point it becomes by far the most dominant effect.

Monte Carlo simulations of small field output factors in solid phantoms

Introduction Total scatter factor (or output factor) in megavoltage photon dosimetry is a measure of relative dose relating a certain field size to a reference field size. The use of solid phantoms has been well established for output factor measurements, however to date these phantoms have not been tested with small fields. In this work, we evaluate the water equivalency of a number of solid phantoms for small field output factor measurements using the EGSnrc Monte Carlo code. Methods The following small square field sizes were simulated using BEAMnrc: 5, 6, 7, 8, 10 and 30 mm. Each simulated phantom geometry was created in DOSXYZnrc and consisted of a silicon diode (of length and width 1.5 mm and depth 0.5 mm) submersed in the phantom at a depth of 5 g/cm2. The source-to-detector distance was 100 cm for all simulations. The dose was scored in a single voxel at the location of the diode. Interaction probabilities and radiation transport parameters for each material were created using custom PEGS4 files. Results A comparison of the resultant output factors in the solid phantoms, compared to the same factors in a water phantom are shown in Fig. 1. The statistical uncertainty in each point was less than or equal to 0.4 %. The results in Fig. 1 show that the density of the phantoms affected the output factor results, with higher density materials (such as PMMA) resulting in higher output factors. Additionally, it was also calculated that scaling the depth for equivalent path length had negligible effect on the output factor results at these field sizes. Discussion and conclusions Electron stopping power and photon mass energy absorption change minimally with small field size [1]. Also, it can be seen from Fig. 1 that the difference from water decreases with increasing field size. Therefore, the most likely cause for the observed discrepancies in output factors is differing electron disequilibrium as a function of phantom density. When measuring small field output factors in a solid phantom, it is important that the density is very close to that of water.

Prostate radiotherapy treatment plan quality : effects of hip prostheses

Introduction This study aimed to examine the geometric and dosimetric results when radiotherapy treatment plans are designed for prostate cancer patients with hip prostheses. Methods Ten EBRT treatment plans for localised prostate cancer, in the presence of hip prostheses, were analysed and compared with a reference set of 196 treatment plans for localised prostate cancer in patients without prostheses. Crowe et al.’s TADA code [1] was used to extract treatment plan parameters and evaluate doses to target volumes and critical structures against recommended goals [2] and constraints [3, 4]. Results The need to avoid transmitting the radiation beam through the hip prostheses limited the range of gantry angles available for use in both the rotational (VMAT) and the non-rotational (3DCRT and IMRT) radiotherapy treatments. This geometric limitation (exemplified in the VMAT data shown in Fig. 1) reduced the overall quality of the treatment plans for patients with prostheses compared to the reference plans. All plans with prostheses failed the PTV dose homogeneity requirement [2], whereas only 4 % of the plans without prostheses failed this test. Several treatment plans for patients with hip prostheses also failed the QUANTEC requirements that less than 50 % of the rectum receive 50 Gy and less than 35 % of the rectum receive 60 Gy to keep the grade 3 toxicity rate below 10 % [3], or the Hansen and Roach requirement that less than 25 % of the bladder receive 75 Gy [4]. Discussion and conclusions The results of this study exemplify the difficulty of designing prostate radiotherapy treatment plans, where beams provide adequate doses to targeted tissues while avoiding nearby organs at risk, when the presence of hip prostheses limits the available treatment geometries. This work provides qualitative evidence of the compromised dose distributions that can result, in such cases.

Development of a dose assessment tool for the auditing of radiotherapy treatment dosimetric quality

The reporting and auditing of patient dose is an important component of radiotherapy quality assurance. The manual extraction of dose-volume metrics is time consuming and undesirable when auditing the dosimetric quality of a large cohort of patient plans. A dose assessment application was written to overcome this, allowing the calculation of various dose-volume metrics for large numbers of plans exported from treatment planning systems. This application expanded on the DICOM-handling functionality of the MCDTK software suite. The software extracts dose values in the volume of interest by using a ray casting point-in-polygon algorithm, where the polygons have been defined by the contours in the RTSTRUCT file...

Origins of the observed asymmetry in out-of-field dose from a linac fitted with an external micro-MLC

Objective Recently, Taylor et al. reported that use of the BrainLAB m3 microMLC, for stereotactic radiosurgery, results in a decreased out-of-field dose in the direction of leaf-motion compared to the outof- field dose measured in the direction orthogonal to leaf-motion [1]. It was recommended that, where possible, patients should be treated with their superior–inferior axes aligned with the microMLCs leafmotion direction, to minimise out-of-field doses [1]. This study aimed, therefore, to examine the causes of this asymmetry in outof- field dose and, in particular, to establish that a similar recommendation need not be made for radiotherapy treatments delivered by linear accelerators without external micro-collimation systems. Methods Monte Carlo simulations were used to study out-of-field dose from different linear accelerators (the Varian Clinacs 21iX and 600C and the Elekta Precise) with and without internal MLCs and external microMLCs [2]. Results Simulation results for the Varian Clinac 600C linear accelerator with BrainLAB m3 microMLC confirm Taylor et als [1] published experimental data. The out-of-field dose in the leaf motion direction is deposited by lower energy (more obliquely scattered) photons than the out-of-field dose in the orthogonal direction. Linear accelerators without microMLCs produce no asymmetry in out-offield dose. Conclusions The asymmetry in out-of-field dose previously measured by Taylor et al. [1] results from the shielding characteristics of the BrainLAB m3 microMLC device and is not produced by the linear accelerator to which it is attached.

Skill development in first year law students : an evaluation of peer assisted learning across two law units

Universities no longer equip graduates solely with the content knowledge of their discipline, but also with prospective employment skills. Professions also seek graduates who can ‘collaborate, share skills and knowledge, and communicate their ideas effectively’ (Kruck and Reif, 2001, p 37). However, as admission to university does not always guarantee that one is well equipped for the task, first year students also need guidance in the development of academic skills. This session describes two models of peer assisted learning embedded within the Torts and Legal Foundations B units at the Faculty of Law, Queensland University of Technology, and how they are used to supplement student understanding of substantive law with the development of academic and work-related skills. Student perceptions of the programs developed are considered, together with the challenges faced. Session participants will be asked to contribute to a discussion of these challenges and to offer ideas on their redress.