External radiotherapy is a common treatment technique for cancer. It has been shown that radiation therapy is a both clinically and economically effective treatment for many types of cancer, even though the equipment is expensive. The technology is in constant evolution and more and more sophisticated and complex techniques are introduced. One of the main tasks for physicists at a radiotherapy department is quality control, i.e. making sure that the treatments are delivered in accordance with the dosimetric intentions. Over dosage of radiation can lead to severe side effects, while under dosage reduces the probability for patient cure. The present thesis is mainly focused on the verification of the calculated dose. Requirements for independent dose calculation software are identified and the procedures using such software are described. In the publications included in the thesis an algorithm specially developed for verification of dose calculations is described and tested. The calculation uncertainties connected with the described algorithm are investigated and modeled. A brief analysis of the quality assurance procedures available and used in external radiotherapy is also included in the thesis. The main conclusion of the thesis is that independent verification of the dose calculations is feasible in an efficient and cost effective quality control system. The independent calculations do not only serve as a protection against accidents, but can also be the basis for comparisons of the dose calculation performance at different clinics.

The thesis concerns the epidemiology, current and possible future treatment of urothelial cancer of the urinary bladder. The Swedish National Quality Registry for Bladder Cancer 1997-2001 was used to explore epidemiology, current therapies and outcome. More common in men, the incidence for Ta and T1 tumours peaks in the age range 70-79 years. There were differences in treatment activity between the reporting regions. An increasing activity was seen. Older patients received less intravesical treatment, which was also a tendency for women. The five year relative survival for all stages (Ta-T4) was 70%; 93% for Ta and 75% for T1. For Ta or T1 survival did not differ significantly between regions. Because the registry has only been running since 1997 a long term follow-up (ten years) of 250 patients comparing Bacillus Calmette-Guerin and Mitomycin-C, was performed. No differences regarding complementary treatment, progression or survival (overall or disease specific) were shown. Looking for new drugs, gemcitabine was tried for intravesical instillations. Patients were randomised to one of three dose schedules. The effect on a marker tumour lesion was evaluated after nine weeks. The overall complete response rate was 31% (9/29). Side effects were more common in women but generally mild; the most common was nausea. One patient stopped instillations (nausea and fever). No patients were excluded due to pathological changes in laboratory parameters. For metastasised disease, over-expression of the growth factor receptor HER2 on urothelial cancer cells was explored in primary tumours and metastases, aiming at radionuclide target therapy. With a new antigen retrieval procedure and evaluation protocol 80% of primary tumours overexpressed the receptor and 72% remained so in the metastases. In conclusion current therapies were increasingly used by clinicians. Superiority for BCG could not be proven. Prerequisites for new therapies have been explored and the way has been paved for future studies.

Hypofractionated conformal stereotactic radiotherapy (HCSRT) has been used for the treatment of AVMs at the Umeå University Hospital since 1986. From this year and onwards an increasing number of patients with single or oligo brain metastases have also been treated using this technique. In paper I we have retrospectively evaluated our treatment results of AVMs in terms of obliteration and complications. The rates of obliteration and complications seem to be comparable with SRS even if the AVM volumes in our series were larger than in most series with SRS. In paper II we have retrospectively evaluated the results in terms of local control, survival and complications in two groups of patients with single or oligo brain metastases. One group was treated with HCSRT alone and the other group was treated with whole brain radiotherapy in combination with a stereotactic boost. Controversy still exists concerning the benefit of additional use of WBRT in combination with stereotactic irradiation. The survival times were equal in the two groups and no significant difference in local control was observed. The omission of WBRT seems to carry a higher risk for development new brain metastases distant from the irradiated area. In paper III we report the treatment results in a subgroup of AVMs treated with a combination of embolisation and HCSRT. We also focus on the reduction of vascular density within the nidus of an AVM and propose a method to digitally compare images and more objectively assess a reduction in vascular density following embolisation. Obliteration rates seem comparable with other series using a combination of SRS and embolisation even if our rate of complications was higher than what is usually reported. Using luminescence as measure of vascular density all AVMs seemed to be less dense after embolisation. Treatment accuracy in terms of reproducibility of the isocenter in consecutive treatment sessions is crucial in fractionated radiotherapy. In paper IV we have radiologically evaluated the reproducibility of the isocenter in successive treatment sessions using the non invasive relocatable Fixster frame. There was a high degree of reproducibility and only small errors that most likely is of no clinical importance. A reliable dose plan is equally important as a tool to predict the dose delivered inside and outside the target volume. In paper V we have evaluated the reliability of treatment plans in HCSRT for targets of different geometry and size. A liquid ion chamber and gel dosimeter was used for assessment of dose distribution and absorbed dose. The doseplanning system proved to be accurate in predicting the absorbed dose and dose distribution for the different targets.

The daily uncertainty concerning tumor localization is one of the major problems during the course of radiation therapy. Image guided-radiation therapy (IGRT) can be used to improve the localization and adjustment of the planning target volume. The aim of this work was to evaluate both the IGRT technique used for prostate cancer patients at the department of the Karolinska University Hospital and an alternative on-line adaptive radiation therapy (ART) method with an On-Board Imager (OBI). In the first part of the thesis 2D and 3D image registration with an OBI were compared. Ten prostate cancer patients were involved in the analyses. Two different statistical tests were used to determine significant systematic deviations between the two methods. The second part concerns daily dose verifications and dose plan reoptimization of one intensity modulated radiation therapy (IMRT) prostate cancer patient treated with IGRT. The study was based on cone-beam computed tomography (CBCT) images acquired at 6 different treatment fractions. The risk of developing late rectal and bladder toxicity was quantified using normal tissue complication probability (NTCP) calculations. Additional measurements on an Alderson phantom were performed to verify the accuracy of using the CBCT images for dose calculations. A statistically significant difference between the 2D-2D and the 3D-3D match applications could be observed in lateral and longitudinal direction. However, the effect differed among the patients. The phantom measurements showed small dose deviations between the CT and CBCT image, with a mean dose increase to the prostate and seminal vesicles (SV) of 2.5 %. The daily dose to the prostate and SV of the IMRT patient showed to be satisfactory. The daily dose to the rectum did not exceed the prescribed rectal dose except at one treatment fraction and the highest risk of developing late rectal toxicity was about 10.4 %. Large daily bladder dose variations were observed and at two treatment fractions the bladder dose restrictions were exceeded. With a reoptimization process of the dose plan, the dose to the bladder could be reduced while conserving the dose to the target. This work shows that for these specific patient cases appropriate doses to the prostate and SV can be delivered with IGRT. However, introducing a suitable ART method could lead to a reduction of inter-fractional rectal and bladder dose variations.

Las investigaciones en relación al fraccionamiento de la dosis y la administración de varias sesiones diarias, iniciadas de forma totalmente empírica por H. Coutard en 1919 (Regato, 1987), han alcanzado a partir del final de los años 60 (Abbatucci, 1968; Montague, 1968) y, gracias a la aportación de la Radiobiología, carácter científico, consolidando uno de los caminos de actualidad en Radioterapia Clínica. El doble mecanismo de acción del multlfraccionamiento, por un lado, como agente de sincronización al acumular a las células tumorales en “G2”, donde no pueden dividirse; y por otro lado, como agente terapéutico al actuar sobre células sincronizadas en M, preservando de lesiones irreparables a los tejidos normales y ocasionando una redistribución máxima de células tumorales, ha permitido depositar en esta estrategia de tratamiento radioterápico fundadas esperanzas de lograr mejorar los resultados en cierto tipo de tumores y determinadas localizaciones. En la esfera de las neoplasias de O.R.L, sobre todo en las fases mas avanzadas de la enfermedad, los resultados obtenidos con las estrategias clásicas de tratamiento son más bien mediocres (Fletcher, 1975), lo cual las convierte en un grupo de elección para ensayar los fraccionamientos no convencionales (Bernier, 1986). La aparición más temprana de las reacciones agudas, el acortamiento de su duración y la disminución del número de días de tratamiento, permite augurar una menor Incidencia de complicaciones y una respuesta inicial espectacular, que redundará en una mayor confianza y colaboración de los pacientes. Para enfocar adecuadamente el desarrollo de la presente tesis doctoral, parece oportuno efectuar inicialmente una breve revisión histórica tanto de la terapéutica radiológica como de la dosimetría, haciendo especial hincapié en aquellos acontecimientos que han puesto de manifiesto la importancia del factor tiempo en Radioterapia Clínica. La redacción escueta ordenada por años permite ponderar y remarcar los hechos narrados sin alargar demasiado la introducción de la cuestión fundamental a analizar. Posteriormente, se plantea una revisión de la problemática actual sobre la que fundamentamos el manejo de estrategias de multifraccionamiento, indicando las bases teóricas que permiten su utilización en clínica. En éste punto conviene introducir dos premisas que se utilizarán a lo largo de la presente tesis y que han de permitir aclarar conceptos a veces un tanto confusos en la bibliografía consultada: por un lado, es necesario definir el concepto de sesión como aquella acción mediante la cual se administra la irradiación en un determinado tiempo y utilizando todas las puertas de acceso de la misma, previstas teóricamente; por otro lado, equiparamos el concepto de fraccionamiento de la dosis a su administración mediante sesiones de igual duración repartidas a lo largo de un periodo de tiempo previamente determinado. Por último, se expone la experiencia clínica obtenida del tratamiento mediante una estrategia multifraccionada de un grupo de pacientes afectos de neoplasias localmente avanzadas de la esfera O.R.L, confirmando mediante la discusión y las conclusiones, la conveniencia de profundizar en el desarrollo del binomio dosis-tiempo en Radioterapia Clínica. Nuestra impresión, en relación a las estrategias convencionales anteriormente utilizadas en el Servicio de Radioterapia del Hospital Clínico y Provincial de Barcelona, para el tratamiento de las neoplasias loco-regionalmente avanzadas de la esfera O.R.L, es que el multifraccionamlento aumenta la probabilidad de control de estas neoplasias, con un aumento remarcable pero controlable de la toxicidad aguda y un ligero aumento tolerable de la toxicidad tardía. Las diferencias significativas encontradas en diversos parámetros deben enmarcarse dentro de las limitaciones propias de la estadística aplicada a una muestra pequeña, aunque corroboran los hallazgos publicados en la bibIiografía internacional. Nos encontramos pues ante una estrategia de tratamiento radioterápico válida, y que nos estimula para continuar buscando un camino que mejore la calidad de vida de nuestros pacientes. / Radiobiological considerations establish the use of non usual techniques in Radiotherapy treatments, in patients with Head and Neck neoplasms where the special economical and working characteristics allow develop a new perspective in Oncological Radiotherapy. The aim of this work was: I) A bibliographic research of the Radiotherapic basis, Dosimetric aspects and Radiobiological studies, to measure the influence of multiple fractions per day in Radiotherapic treatments. 2) To compare the results of three a day fractions versus conventional fractionation in patients with Head and Neck neoplasms. 3) Evaluation and analysis of toxicity, survival and response depending of the different treatment schedule. The results and conclusions of this study were analysed, deducing that the survival and response with respect to fractionation schedule were significant, being more elevated In patients treated with three a day fractionation.

School of Nursing

For over a century, physicians have prescribed x-ray radiation to destroy or impede the growth of cancerous tumours. Modern radiation therapy machines shape the radiation beam to balance the competing goals of maximizing irradiation of cancerous tissue and minimizing irradiation of healthy tissue, an objective complicated by tumour motion during the treatment and errors positioning the patient to align the tumour with the radiation beam. Recent medical imaging advances have motivated interest in using feedback during radiation therapy to track the tumour in real time and mitigate these complications. This thesis investigates how real-time feedback control can be used to track the tumour and focus the radiation beam tightly around the tumour. Improving on these results, a feedback control system is proposed for intensity modulated radiation therapy which allows a non-uniform radiation dose to be applied to the tumour. Motivated by the results of the proposed control systems, this thesis also examines two theoretical control problems: estimating the output of an unknown system when a sensor delay prevents its direct measurement, and designing a controller to provide an arbitrarily fast nonovershooting step response.

No description available.

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.