Mixed-Beam Approach for High-Risk Prostate Cancer Carbon-Ion Boost Followed by Photon Intensity-Modulated Radiotherapy: Preliminary Results of Phase II Trial AIRC-IG-14300

PurposeThis study represents a descriptive analysis of preliminary results of a Phase II trial on a novel mixed beam radiotherapy (RT) approach, consisting of carbon ions RT (CIRT) followed by intensity-modulated photon RT, in combination with hormonal therapy, for high-risk prostate cancer (HR PCa) with a special focus on acute toxicity.MethodsPrimary endpoint was the evaluation of safety in terms of acute toxicity. Secondary endpoints were early and long-term tolerability of treatment, quality of life (QoL), and efficacy. Data on acute and late toxicities were collected according to RTOG/EORTC. QoL of enrolled patients was assessed by IPSS, EORTC QLQ-C30, EORTC QLQ-PR25, and sexual activity by IIEF-5.ResultsTwenty-six patients were enrolled in the study, but only 15 completed so far the RT course and were included. Immediately after CIRT, no patients experienced GI/GU toxicity. At 1 and 3 months from the whole course RT completion, no GI/GU toxicities greater than grade 2 were observed. QoL scores were overall satisfactory.ConclusionsThe feasibility of the proposed mixed treatment schedule was assessed, and an excellent acute toxicity profile was recorded. Such findings instil confidence in the continuation of this mixed approach, with evaluation of long-term tolerability and efficacy.

Dosimetric Impact of Inter-Fraction Anatomical Changes in Carbon Ion Boost Treatment for High-Risk Prostate Cancer (AIRC IG 14300)

Rectum and bladder volumes play an important role in the dose distribution reproducibility in prostate cancer adenocarcinoma (PCa) radiotherapy, especially for particle therapy, where density variation can strongly affect the dose distribution. We investigated the reliability and reproducibility of our image-guided radiotherapy (IGRT) and treatment planning protocol for carbon ion radiotherapy (CIRT) within the phase II mixed beam study (AIRC IG 14300) for the treatment of high-risk PCa. In order to calculate the daily dose distribution, a set of synthetic computed tomography (sCT) images was generated from the cone beam computed tomography (CBCT) images acquired in each treatment session. Planning target volume (PTV) together with rectum and bladder volume variation was evaluated with sCT dose-volume histogram (DVH) metric deviations from the planning values. The correlations between the bladder and rectum volumes, and the corresponding DVH metrics, were also assessed. No significant difference in the bladder, rectum, and PTV median volumes between the planning computed tomography (pCT) and the sCT was found. In addition, no significant difference was assessed when comparing the average DVHs and median DVH metrics between pCT and sCT. Dose deviations determined by bladder and rectum filling variations demonstrated that dose distributions were reproducible in terms of both target coverage and organs at risk (OARs) sparing.

Effects of 5-Ion Beam Irradiation and Hindlimb Unloading on Metabolic Pathways in Plasma and Brain of Behaviorally Tested WAG/Rij Rats

A limitation of simulated space radiation studies is that radiation exposure is not the only environmental challenge astronauts face during missions. Therefore, we characterized behavioral and cognitive performance of male WAG/Rij rats 3 months after sham-irradiation or total body irradiation with a simplified 5-ion mixed beam exposure in the absence or presence of simulated weightlessness using hindlimb unloading (HU) alone. Six months following behavioral and cognitive testing or 9 months following sham-irradiation or total body irradiation, plasma and brain tissues (hippocampus and cortex) were processed to determine whether the behavioral and cognitive effects were associated with long-term alterations in metabolic pathways in plasma and brain. Sham HU, but not irradiated HU, rats were impaired in spatial habituation learning. Rats irradiated with 1.5 Gy showed increased depressive-like behaviors. This was seen in the absence but not presence of HU. Thus, HU has differential effects in sham-irradiated and irradiated animals and specific behavioral measures are associated with plasma levels of distinct metabolites 6 months later. The combined effects of HU and radiation on metabolic pathways in plasma and brain illustrate the complex interaction of environmental stressors and highlights the importance of assessing these interactions.

Quantification of Differential Response of Tumour and Normal Cells to Microbeam Radiation in the Absence of FLASH Effects

Microbeam radiotherapy (MRT) is a preclinical method of delivering spatially-fractionated radiotherapy aiming to improve the therapeutic window between normal tissue complication and tumour control. Previously, MRT was limited to ultra-high dose rate synchrotron facilities. The aim of this study was to investigate in vitro effects of MRT on tumour and normal cells at conventional dose rates produced by a bench-top X-ray source. Two normal and two tumour cell lines were exposed to homogeneous broad beam (BB) radiation, MRT, or were separately irradiated with peak or valley doses before being mixed. Clonogenic survival was assessed and compared to BB-estimated surviving fractions calculated by the linear-quadratic (LQ)-model. All cell lines showed similar BB sensitivity. BB LQ-model predictions exceeded the survival of cell lines following MRT or mixed beam irradiation. This effect was stronger in tumour compared to normal cell lines. Dose mixing experiments could reproduce MRT survival. We observed a differential response of tumour and normal cells to spatially fractionated irradiations in vitro, indicating increased tumour cell sensitivity. Importantly, this was observed at dose rates precluding the presence of FLASH effects. The LQ-model did not predict cell survival when the cell population received split irradiation doses, indicating that factors other than local dose influenced survival after irradiation.

Flow-Induced Vibration of a Candu Fuel String

A comprehensive vibration model is developed in this thesis to simulate the dynamical behaviour of a string of CANDU fuel bundles subjected to unsteady flow of coolant inside a pressure tube. The large-scale dynamical system of interest consists of several hundreds of solid and deformable components interacting with the coolant flow, with each other and with the pressure tube through frictional contact at various interfaces. In the first stage of this thesis, the three-node higher-order mixed beam finite elements and the nine-node thick plate finite elements are employed to model the fuel bundles. The equations of motion of the fuel string system are discretised in the time domain using the Newmark integration scheme. The CANDU fuel string behaviour is highly nonlinear and the total number of potential frictional contact exceeds thousand sets. In the second stage, a numerical scheme for efficiently handling three-dimensional friction and contact is developed. The incremental displacement is used to relate gaps with contact forces and the problem is formulated to be a linear complementarity problem (LCP). The accuracy and robustness of the presented method is tested against several numerical simulations and experimental results available in the literature. To find the unsteady fluid forces acting on the fuel string two comprehensive computational fluid dynamic (CFD) models that include endcaps and spacer pads are developed. The models are solved using the large eddy simulation (LES) scheme. The coolant unsteady pressure is integrated over fuel rods surfaces and unsteady fluid forces are found and used as the excitation sources for fuel string vibration. The power spectral density (PSD) of unsteady fluid forces are obtained and peak frequencies are identified. A FORTRAN code consisting of approximately 13000 lines is developed and validated at different stages for use in Canadian nuclear industry to simulate the vibrational behaviour of a 12-bundle fuel string and the material loss during reactor normal operations. Free vibration analyses of a CANDU fuel string are also performed and natural frequencies of the system are obtained.

Flow-Induced Vibration of a Candu Fuel String

A comprehensive vibration model is developed in this thesis to simulate the dynamical behaviour of a string of CANDU fuel bundles subjected to unsteady flow of coolant inside a pressure tube. The large-scale dynamical system of interest consists of several hundreds of solid and deformable components interacting with the coolant flow, with each other and with the pressure tube through frictional contact at various interfaces. In the first stage of this thesis, the three-node higher-order mixed beam finite elements and the nine-node thick plate finite elements are employed to model the fuel bundles. The equations of motion of the fuel string system are discretised in the time domain using the Newmark integration scheme. The CANDU fuel string behaviour is highly nonlinear and the total number of potential frictional contact exceeds thousand sets. In the second stage, a numerical scheme for efficiently handling three-dimensional friction and contact is developed. The incremental displacement is used to relate gaps with contact forces and the problem is formulated to be a linear complementarity problem (LCP). The accuracy and robustness of the presented method is tested against several numerical simulations and experimental results available in the literature. To find the unsteady fluid forces acting on the fuel string two comprehensive computational fluid dynamic (CFD) models that include endcaps and spacer pads are developed. The models are solved using the large eddy simulation (LES) scheme. The coolant unsteady pressure is integrated over fuel rods surfaces and unsteady fluid forces are found and used as the excitation sources for fuel string vibration. The power spectral density (PSD) of unsteady fluid forces are obtained and peak frequencies are identified. A FORTRAN code consisting of approximately 13000 lines is developed and validated at different stages for use in Canadian nuclear industry to simulate the vibrational behaviour of a 12-bundle fuel string and the material loss during reactor normal operations. Free vibration analyses of a CANDU fuel string are also performed and natural frequencies of the system are obtained.