Distant metastases are a limiting factor in cancer patient survival as they are least accessible to conventional therapies. Effective therapy should treat primary tumours and metastatic disease. Use of image-guided radiation therapy (IGRx) enables high doses of radiation to be delivered for better tumour control while minimizing toxicity to healthy tissues. Systemic effects on distant non-irradiated tissues have been observed following IGRx. This phenomenon, termed the abscopal effect, is hypothesized to be mediated by the immune system. The inflammatory milieu generated following IGRx may activate immune cells to mount specific anti-tumour responses. The work described in this thesis aims to develop a model to study the abscopal effect, and evaluate the potential of combining IGRx and immunotherapy to enhance such distant tumour killing. Results from these studies may have clinical implications, where a combined IGRx and immunotherapy approach may prove useful in eliciting regression of local tumours and distant metastases.

Radiotherapy is one method of treating di erent diseases like cancer. It requires a treatment plan that clearly delineates target and non-target volumes, and the beams and their intensities to deliver the prescribed dose. Historical treatment plans often contain volume names that are unaccounted for. An approach is applied where desired volumes are detected and renamed to conform to current search standards. The mapped names provide an avenue for searching historical plans when performing outcomes analysis in the future to help improve quality in radiation therapy. A specific form known as intensity modulated radiation therapy is applied to total marrow irradiation, a method to remove all marrow in the body prior to bone marrow transplant. A set-covering approach is used, solved using heuristics and commercial packages to compare outcomes. Constraint programming is used in an attempt to better and to improve on the heuristic solutions.

Distant metastases are a limiting factor in cancer patient survival as they are least accessible to conventional therapies. Effective therapy should treat primary tumours and metastatic disease. Use of image-guided radiation therapy (IGRx) enables high doses of radiation to be delivered for better tumour control while minimizing toxicity to healthy tissues. Systemic effects on distant non-irradiated tissues have been observed following IGRx. This phenomenon, termed the abscopal effect, is hypothesized to be mediated by the immune system. The inflammatory milieu generated following IGRx may activate immune cells to mount specific anti-tumour responses. The work described in this thesis aims to develop a model to study the abscopal effect, and evaluate the potential of combining IGRx and immunotherapy to enhance such distant tumour killing. Results from these studies may have clinical implications, where a combined IGRx and immunotherapy approach may prove useful in eliciting regression of local tumours and distant metastases.

Radiotherapy is one method of treating di erent diseases like cancer. It requires a treatment plan that clearly delineates target and non-target volumes, and the beams and their intensities to deliver the prescribed dose. Historical treatment plans often contain volume names that are unaccounted for. An approach is applied where desired volumes are detected and renamed to conform to current search standards. The mapped names provide an avenue for searching historical plans when performing outcomes analysis in the future to help improve quality in radiation therapy. A specific form known as intensity modulated radiation therapy is applied to total marrow irradiation, a method to remove all marrow in the body prior to bone marrow transplant. A set-covering approach is used, solved using heuristics and commercial packages to compare outcomes. Constraint programming is used in an attempt to better and to improve on the heuristic solutions.

Microbeam Radiation Therapy (MRT) is an experimental form of radiation treatment which has the potential to improve the treatment of many types of cancer. In MRT, the radiation is applied as a grid by passing the collimated X-ray beam from a synchrotron through a microplane collimator, which is a stack of parallel plates of two materials with dramatically different X-ray transparencies. The peak-to-valley dose ratio (PVDR) is the difference between the dose in the microbeams and the dose delivered between the beams. It is the PVDR that is of biological importance in MRT. Therefore a dosimeter for MRT requires a combination of a large dynamic range for dose response into the kilo-Gray regime, and high spatial resolution on the micron scale. This project characterizes fluorophosphate glasses doped with trivalent samarium ions as a potential valency conversion dosimeter for MRT using the conversion of Sm3+→Sm2+ to measure the delivered dose. Samples irradiated at the Canadian Light Source synchrotron showed X-ray induced conversion that could be optically characterized by changes in the photoluminescence emission spectra to obtain irradiation dose. The conversion efficiency depends almost linearly on the irradiation dose up to 150 Gy and saturates at doses exceeding 1500 Gy. The conversion shows a strong correlation with an observed increase in absorbance of the glass in the range of 200-750 nm. The absorbance increases with X-ray dose and is related to the formation of phosphorous-oxygen hole centers (POHC) and POn electron centers. The presence of these defects within the irradiated glass was determined by examination of the induced optical absorbance and electron paramagnetic resonance (EPR) spectra. The formation of these hole centers along with the conversion of Sm3+→Sm2+ under X-ray irradiation suggests that the X-rays cause the formation of electron-hole pairs in the glass. The electrons are then primarily captured by the Sm3+ ions, becoming Sm2+ ions, with some of the electrons being captured by POn electron centers. The holes are captured by the POHCs. This process can be represented chemically as Sm3+ + e-→ Sm2+ and PO + h+→POHC. The stability of the Sm conversion under illumination was examined using photoluminescence spectra and the stability of the X-ray induced defects was examined via the induced optical absorbance and EPR spectra.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成11年1月22日 片桐浩久氏の博士論文として提出された

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.

Gold Nanoparticle-Aided Radiation Therapy (GNRT) is a new paradigm in radiation therapy which seeks to make a tumor more susceptible to radiation damage by modifying its photon interaction properties with an infusion of a high-atomic-number substance. The purpose of this study was to quantify the energy deposition due to secondary electrons from gold nanoparticles on a micrometer scale and to calculate the corresponding microscopic dose enhancement factor during GNRT. The Monte Carlo code EGSnrc was modified to obtain the spectra of secondary electrons from atoms of gold and molecules of water under photon irradiation of a tumor infused with 0.7 wt. % gold. Six different photon sources were used: 125I, 103Pd, 169Yb, 192Ir, 50kVp, and 6MV x-rays. Treating the scored electron spectra as point sources within an infinite medium of water, the event-by-event Monte Carlo code NOREC was used to quantify the radial dose distribution, giving rise to gold and water electron dose point kernels. These kernels were applied to a scanning electron microscope (SEM) image of a gold nanoparticle distribution in tissue. The dose at each point was then calculated, enabling the determination of the microscopic dose enhancement at each point. For the lower energy sources 125I, 103Pd, 169Yb, and 50 kVp, the secondary electron fluence was increased by as much as two orders of magnitude, leading to a one-to-two order of magnitude increase in the electron dose point kernel over radial distances up to 50 um. The dose was enhanced by 100% within 5 um of the nanoparticles, and by 5% as far away as 30 um. This study demonstrates a remarkable microscopic dose enhancement due to gold nanoparticles and low energy photon sources. Given that the dose enhancement exceeds 100% within very short distances from the nanoparticles, the maximum radiobiological benefit may be derived from active targeting strategies that concentrate nanoparticles in close proximity to the cancer cell and/or its nucleus.

In-beam positron emission tomography (in-beam PET) is currently the only method for an in-situ monitoring of highly tumor-conformed charged hadron therapy. In such therapy, the clinical effect of deviations from treatment planning is highly minimized by implementing safety margins around the tumor and selecting proper beam portals. Nevertheless, in-beam PET is able to detect eventual, undesirable range deviations and anatomical modifications during fractionated irradiation, to verify the accuracy of the beam portal delivered and to provide the radiotherapist with an estimation of the difference in dosage if the treatment delivered differs from the planned one. In a first study within this work, a set of simulation and fully-3D reconstruction routines shows that minimizing the opening angle of a cylindrical camera is determinant for an optimum quality of the in-beam PET images. The study yields two favorite detector geometries: a closed ring or a dual-head tomograph with narrow gaps. The implementation of either detector geometry onto an isocentric, ion beam delivery (gantry) is feasible by mounting the PET scanner at the beam nozzle. The implementation of an in-beam PET scanner with the mentioned detector geometries at therapeutic sites with a fixed, horizontal beam line is also feasible. Nevertheless, knowing that previous in-beam PET research in Berkeley was abandoned due to detector activation (Bismuth Germanate, BGO), arising most probably from passive beam shaping contaminations, the proposed detector configurations had to be tested in-beam. For that, BGO was substituted with a state-of-the-art scintillator (lutetium oxyorthosilicate, LSO) and two position sensitive detectors were built. Each detector contains 32 pixels, consisting of LSO finger-like crystals coupled to avalanche photodiode arrays (APDA). In order to readout the two detectors operated in coincidence, either in standalone mode or at the GSI medical beam line, a multi-channel, zero-suppressing free, list mode data acquisition system was built.The APDA were chosen for scintillation detection instead of photomultiplier tubes (PMT) due to their higher compactness and magnetic field resistance. A magnetic field resistant detector is necessary if the in-beam PET scanner is operated close to the last beam bending magnet, due to its fringe magnetic field. This is the case at the isocentric, ion beam delivery planned for the dedicated, heavy ion hospital facility under construction in Heidelberg, Germany. In-beam imaging with the LSO/APDA detectors positioned at small target angles, both upbeam and downbeam from the target, was successful. This proves that the detectors provide a solution for the proposed next-generation, improved in-beam PET scanners. Further confirming this result are germanium-detector-based, spectroscopic gamma-ray measurements: no scintillator activation is observed in patient irradiation conditions. Although a closed ring or a dual-head tomograph with narrow gaps is expected to provide improved in-beam PET images, low count rates in in-beam PET represent a second problem to image quality. More importantly, new accelerator developments will further enhance this problem to the point of making impossible in-beam PET data taking if the present acquisition system is used. For these reasons, two random-suppression methods allowing to collect in-beam PET events even during particle extraction were tested. Image counts raised almost twofold. This proves that the methods and associated data acquisition technique provide a solution for next-generation, in-beam positron emission tomographs installed at synchrotron or cyclotron radiotherapy facilities.

The purpose of this study was to assess the prognostic significance and clinical correlations of cyclooxgenase-2 expression (COX) in a cohort of patients treated with radiation (RT) for post-mastectomy chest wall relapse (PMCWR). Between 1975 and 1999, 113 patients were treated for isolated PMCWR. All patients were treated with biopsy and/or excision of the CWR followed by RT. Median follow-up was 10 years. All clinical data including demographics, pathology, staging, receptor status, HER-2/neu status, and adjuvant therapy were entered into a computerized database. Paraffin-embedded CWR specimens were retrieved from 42 patients, of which 38 were evaluated, created into a tissue microarray, stained by immunohistochemical methods for COX, and graded 0-3+. A score of 2-3+ was considered positive. Overall survival from original diagnosis for the entire cohort was 44% at 10 years. Survival rate after chest wall recurrence was 28% at 10 years. The distant metastasis-free survival rate after CWR was 40% at 10 years. Local-regional control of disease was achieved in 79% at 10 years after CWR. COX was considered positive in 13 of 38 cases. COX was inversely correlated with ER (p= .045) and PR (p = .028), and positively correlated with HER-2/neu (p =.003). COX was also associated with a shorter time to PMCWR. The distant metastasis-free rate for COX negative patients was 70% at 10 years, compared with 31% at 10 years for COX-2 positive patients (p = 0.029). COX positive had a poorer local-regional progression-free rate of 19% at 10 years, compared with 81% at 10 years for COX negative (p = 0.003). Outcome following RT for PMCWR is relatively poor. Positive COX correlated with other markers of poor outcome including a shorter time to local relapse, negative ER/PR and positive Her-2/neu status. Positive COX correlated with higher distant metastasis and lower local-regional control of disease. If confirmed with larger studies, these data have implications with respect to the concurrent use of COX-2 inhibitors and radiation for PMCWR.