Computer designed missing tissue and dose compensators have been produced and dosimetrically tested under a linear accelerator 6MV X-ray beam. Missing tissues compensators were developed to correct for patient external contour change only. Target dose compensators were developed to achieve a uniform dose throughout the target volume. With compensators present in the beam, data acquisition was repeated in a water phantom and an Anthropomorphic phantom. Clinically acceptable dose uniformity was achieved within these phantoms. For external contour compensation flat isodose curves were obtained giving an even dose in the region of interest. The dose difference found was within plus/minus 3% only. For the phantoms containing inhomogeneities dose uniformity to target volume was achieved within plus/minus 7%. Prediction of radiation dose was made using a GE Target Series 2 Treatment Planning Computer for each of the phantoms. Validation of the computer predicted dose was carried out using diode and TLD measurements. The measured data in the water tank was consistent with the computer data within plus/minus 2% for external contour changes and for inhomogeneities. The TLD measured results in the anthropomorphic phantom agreed with the planning computer results within 6%. Up to 4% of the difference is explainable due to supra-linearity and scatter effects / Master of Science (Hons) (Physics)

Object Rupture of intracranial arteriovenous malformations is a leading cause of stroke in children and young adults. Treatment options include surgery and highly focused radiation (stereotactic radiosurgery). For large and deep seated lesions, the risks of surgery may be prohibitively high, while radiosurgery has a disappointingly low efficacy and long latency. Radiosurgery carries the most promise for significant advances, however the process by which radiosurgery achieves obliteration is incompletely understood. Inflammation and thrombosis are likely to be important in the radiation response and may be amenable to pharmacological manipulation to improve radiosurgical efficacy. Materials and methods Immunohistochemistry and electron microscopy were used to study normal cerebral vessels, cavernous malformations and AVMs, some of which had previously been irradiated. An attempt was made to culture AVM endothelial cells to study the immediate response of AVM endothelium to radiosurgery. The effects of radiosurgery in a rat model of AVM were studied using immunohistochemistry and the results used to determine the choice of a pharmacological strategy to enhance the thrombotic effects of radiosurgery. Results Vascular malformations have a different endothelial inflammatory phenotype than normal cerebral vessels. Radiosurgery may cause long term changes in inflammatory molecule expression and leads to endothelial loss with exposure of pro-thrombotic molecules. Ultrastructural effects of irradiation include widespread cell loss, smooth muscle cell (SMC) proliferation and thrombosis. Endothelial culture from AVMs proved difficult due to SMC predominance in initial cultures. Radiosurgery upregulated several endothelial inflammatory molecules in the animal model and may induce pro-thrombotic cell membrane alterations. The administration of lipopolysaccharide and soluble tissue factor to rats following radiosurgery led to selective thrombosis of irradiated vessels. Conclusions Inflammation and thrombosis are important in the radiosurgical response of AVMs. Lumen obliteration appears to be mediated by proliferation of cells within the vessel wall and thrombosis. Upregulation of inflammatory molecules and perhaps disruption of the normal phospholipid asymmetry of the endothelial and SMC membranes are some of the earliest responses to radiosurgery. The alterations induced by radiation may be harnessed to selectively initiate thrombus formation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing treatable lesion size and reducing latency.

One of the main objectives of combining radiation treatment and chemotherapy is to obtain a therapeutic gain by an improved tumour control with less or no enhancement of normal tissue toxicity. The optimal schedule for the combined treatment of cisplatin-radiation is still under investigation. Neither the optimal time interval, nor the most adequate sequence of administration of cisplatin and radiation are known. The results of the trials are also inconclusive. Some trials showed a supra-additive effect from the administration of cisplatin before radiotherapy, others, on contrary, from the injection of drug after radiotherapy. The present work encompasses the major challenges brought by the combined modality treatment: cisplatin-radiotherapy. The major goal of this work was to investigate the optimal treatment sequencing between cisplatin and radiotherapy and also the optimal schedule for head and neck carcinomas. Therefore, a computer-based tumour model with literature-given biological parameters has been developed which has allowed the simulation of treatment with radiation and chemotherapy. Radiotherapy has been simulated on the virtual tumour and the effects of radiotherapy on tumour regression and regrowth have been analyzed. Also, the mechanisms of cisplatin's action on tumour have been implemented, and the phenomena of drug resistance and tumour repopulation during chemotherapy studied. Finally, the combined modality treatment has been simulated, and the effect of drug-radiation interaction on tumour behaviour evaluated. The current investigation has shown that cisplatin administered immediately before radiation gives similar tumour control to the post-radiation sequencing of the drug. Furthermore, the killing effect of the combined modality treatment on tumour increases with the increase in cell recruitment. The individual cell kill produced by cisplatin and radiation leads to an additive-only tumour response when the treatments are given concurrently, and for a synergistic effect cisplatin must potentiate the effect of radiation. The final conclusion, by which cisplatin administered on a daily basis leads to a better tumour control than cisplatin administered weekly, is in accordance with the latest trial results on head and neck cancers. Therefore, treatment regimens that correlate better with the pharmacokinetics and the radiobiological properties of the therapeutic agents result in better outcomes. / Thesis (Ph.D.)--School of Chemistry and Physics, 2004.

<p>The energy dependent response of silicon diodes in photon beams is a known problem. A new approach to solve this problem is by correcting the response, a response model was suggested by Yin et al. (2002, 2004), and later refined by Eklund and Ahnesjö (2009). In this work a prototype software was developed to calculate correction factors for arbitrary measurement points in MLC shaped fields using fluence pencil beam kernels to calculate the spectra used by the model of Eklund and Ahnesjö (2009). This work investigate this approach for large field sizes. It was found that the relative dose measurements of the corrected unshielded diode agreed with ionization chamber measurements within 1% at the central axis. Measurements made off axis (square and irregular fields) agreed within 2%, better results were achieved within the fields when the off axis beam softening were taken into consideration. This work has also shown that this new approach is an alternitive to shielded diodes and that corrected diodes will in some cases provide more reliable results.</p>

<p>In this project several tests were performed to evaluate the performance of an On-Board Imager® (OBI) mounted on a clinical linear accelerator. The measurements were divided into three parts; geometric accuracy, image registration and couch shift accuracy, and image quality. A cube phantom containing a radiation opaque marker was used to study the agreement with treatment isocenter for both kV-images and cone-beam CT (CBCT) images. The long term stability was investigated by acquiring frontal and lateral kV images twice a week over a 3 month period. Stability in vertical and longitudinal robotic arm motion as well as the stability of the center-of-rotation was evaluated. Further, the agreement of kV image and CBCT center with MV image center was examined.</p><p>A marker seed phantom was used to evaluate and compare the three applications in image registration; 2D/2D, 2D/3D and 3D/3D. Image registration using kV-kV image sets were compared with MV MV and MV-kV image sets. Further, the accuracy in 2D/2D matches with images acquired at non-orthogonal gantry angles was evaluated. The image quality in CBCT images was evaluated using a Catphan® phantom. Hounsfield unit (HU) uniformity and linearity was compared with planning CT. HU accuracy is crucial for dose verification using CBCT data.</p><p>The geometric measurements showed good long term stability and accurate position reproducibility after robotic arm motions. A systematic error of about 1 mm in lateral direction of the kV-image center was detected. A small difference between kV and CBCT center was observed and related to a lateral kV detector offset. The vector disagreement between kV- and MV-image centers was  2 mm at some gantry angles. Image registration with the different match applications worked sufficiently. 2D/3D match was seen to correct more accurately than 2D/2D match for large translational and rotational shifts. CBCT images acquired with full-fan mode showed good HU uniformity but half fan images were less uniform. In the soft tissue region the HU agreement with planning CT was reasonable while a larger disagreement was observed at higher densities. This work shows that the OBI is robust and stable in its performance. With regular QC and calibrations the geometric precision of the OBI can be maintained within 1 mm of treatment isocenter.</p>

<p>At the University Hospital of Umeå, NUS, a new radiation treatment department is being built. The purpose of this master thesis is to evaluate the actual radiation protection outside three out of five treatment rooms in the building, including two Varian and one Siemens accelerator, and to verify that the radiation limits for the staff and the general public, stated by the Swedish Radiation Safety Authority, are obeyed.</p><p>The evaluation of the radiation protection shielding is made through measurements. The nominal photon beam energies 6 and 15 MV (dose rates up to 500 MU/min) can be used, which means that both photons and neutrons will contribute to the effective dose. For the photon measurements, two different GM counters have been used and for the neutron measurements a Neutron detector with a polyethylene moderator and a ³He recoil proton counter tube was applied. The thesis also includes a literature study of the photon and neutron energy spectra outside the treatment rooms in order to check that the measurement equipments are suitable to use.</p><p>The measured doses of the radiation shielding are below the radiation limits per week and year but the measurements indicate too high values per hour, i.e. momentary dose rate, at the height of isocenter of the primary walls and at the gap under the door for all three accelerators. The rooms with the Varian accelerators also show too high values per hour at the secondary wall where the door is attached. However, the limiting value per hour is only a recommendation and no extra reinforcement in therefore required. Nevertheless, one should avoid placing a workplace, for example a writing desk, close to the secondary and primary walls.</p>

<p>The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. </p><p>The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses.</p><p>Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel.</p><p>A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning.</p><p>This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.</p>

<p>Conventional cancer treatment based on radiotherapy or chemotherapy affects all dividing cells. By directing the therapy specifically to the tumor cells, normal cells can be spared. Tumor targeting molecules carrying a cytotoxic moiety is then an attractive approach. </p><p>In this thesis, an affibody molecule with high affinity for the protein HER-2, that is strongly associated with aggressive forms of breast cancer, was selected. After radiolabeling with ¹²⁵I, the affibody molecule, in monovalent and bivalent form, was tested <i>in vitro</i> in HER-2 overexpressing tumor cells and in transplanted tumors in mice. </p><p>It was shown that the HER-2 targeting affibody molecule bound its target in a specific manner, both <i>in vitro</i> and <i>in vivo</i>. The small size of the affibody molecule resulted in fast clearance through the kidneys. An impressive tumor-to-blood ratio of 10 eight hours post injection was achieved and the tumors could easily be visualized in a gamma camera. </p><p>The biologic effects of the bivalent affibody molecule and a monovalent affinity maturated version was measured and compared with the effects of the monoclonal antibody trastuzumab. It was found that although all molecules target the same protein, the effects differed greatly.</p><p>The affibody molecule was also labeled with the alpha-emitting radionuclide ²¹¹At. Specific decrease in survival was seen in HER-2 overexpressing cells receiving the ²¹¹At labeled affibody molecule. The sensitivity to the treatment differed between cell lines, probably as a result of differences between the cell lines in internalization and nuclear size. The ²¹¹At labeled affibody molecules were also tested <i>in vivo</i>, where stability of the ²¹¹At label was a problem. To circumvent this problem, more stable conjugation chemistry was tested, as well as strategies to prevent uptake of released ²¹¹At by normal organs.</p><p>This thesis describes the selection and optimization of affibody molecules for medical use for the first time.</p>

Rectal cancer is the eight most common cancer diagnosis in Sweden in both men and women, with almost 2000 new cases per year. Radiotherapy, which is an important treatment modality for rectal cancer, has evolved during the past decades. Diagnostic tools have also improved, allowing better staging and offering information used to make well-founded decisions in multidisciplinary team conferences. In a retrospective study (n=46) with locally advanced rectal cancer (LARC) patients, unfit for chemoradiotherapy, patients were treated with short-course radiotherapy. Delayed surgery was done when possible. Radical surgery was possible in 89% of the patients who underwent surgery (80%). Grade IV diarrhoea affected three elderly patients. Target radiation volume should be reduced in elderly or metastatic patients. In a prospective study (n=68) with LARC patients, magnetic resonance imaging (MRI) and 2-18F-fluoro-2-D-deoxyglucose (FDG) positron emission tomography (PET) were used to determine if FDG-PET could provide extra treatment information. Information from FDG-PET changed the stage of 10 patients. Delineation with FDG-PET generally resulted in smaller target volumes than MRI only. Seven of the most advanced LARC patients in the above cohort were used for a methodological study to determine if dose escalation to peripheral, non-resectable regions was feasible. Simultaneous integrated boost plans with photons and protons were evaluated. While toxicity was acceptable in five patients with both protons and photons, two patients with very large tumours had unacceptable risk for intestinal toxicity regardless of modality. In the interim analysis of the Stockholm III Trial (n=303, studying radiotherapy-fractionation and timing of surgery in relation to radiotherapy) compliance was acceptable and severe acute toxicity was infrequent, irrespective of fractionation. Short-course radiotherapy with immediate surgery tended to give more postoperative complications, but only if surgery was delayed more than 10 days after the start of radiotherapy. Quality-of-life in the Stockholm III Trial was studied before, during and shortly after treatment using the EORTC QLQ-C30 and CR38 questionnaires. Surgery accounted for more adverse effects than radiotherapy in all groups. Postoperatively, the poorest quality-of-life was seen in patients given short-course radiotherapy followed by immediate surgery. No postoperative differences were seen between the two groups with delayed surgery.

The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses. Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel. A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning. This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.