The main purpose of this thesis is to encourage the development of bioeffect planning as an experimental tool by which means bioeffect plans may be compared with standard isodose plans. This thesis also addresses the fundamental problems of the derivation of useful biological models for clinical application and the description of tumour and normal tissue parameter values and their variability. Particular emphasis has been placed on comparing the predictive value of the models and parameters against clinical results of fractionated and continuous irradiation either alone or combined.

Doctor of Health Science / It is well documented that for prostate cancer patients undergoing radiation therapy there is a correlation between target volume displacement and changes in bladder and rectal volumes. However, these studies have used a methodology that has captured only a subset of all treatment positions. This research used daily Computer Tomography (CT) imaging to comprehensively assess organ volumes, organ motion and their effect on dose, something that has never been performed previously, thus adding considerably to the understanding of the topic. Daily CT images were obtained using a Siemens Primus Linear Accelerator equipped with an in-room Somatom CT unit in the accelerator suite, marketed as ‘Primatom’, to accurately position the patient prior to treatment delivery. The internal structures of interest were contoured on the planning workstation by the investigator. The daily volume and location of the organs were derived from the computer to assess and analyse internal organ motion. The planned dose distribution was then imported onto the treatment CT datasets and used to compare the planned dose to i) the actual isocentre, where the isocentre was actually placed for that fraction, ii) the uncorrected isocentre, by un-doing any on-line corrections performed by the treatment staff prior to treatment delivery, and iii) the future isocentre, by placing the isocentre relative to internal organ motion on a daily basis. The results of this study did not confirm a statistically significant decrease in rectum volumes over time (hypothesis 1), however large fluctuations in bladder volume were confirmed (hypothesis 2). Internal organ motion for the rectum and bladder was demonstrated to be related to organ filling. Ideal planning volumes for these organs have been reported to minimise systematic and random uncertainty in the treatment volumes. An observed decrease in prostate volume over time, a systematic uncertainty in the location of the prostate at the time of the planning CT scan and a significant relationship between prostate centre of volume and rectum and bladder volumes has resulted in a recommendation that patients should be re-scanned during treatment to ensure appropriate clinical target volume coverage. A significant relationship between rectal and bladder volumes and the dose delivered to these organs was found (hypothesis 3). The dose delivered to the planning target volume was not related to the rectal or bladder volumes, although it was related to the motion of these organs. Despite these results only minimal effects on the dose delivered to any of the three isocentres occurred, indicating that the planned dose was accurately delivered using the methodology presented here (hypothesis 4). However the results do indicate that the patient preparation instructions need to be improved if margins are to be reduced in the future. It is unrealistic to assume that Image Guided Radiation Therapy will ever become routine practice due to infrastructure costs and time limitations. This research will inform radiation therapy centres of the variables associated with prostate cancer treatment on a daily basis, something that has never before been realistically achievable. As a result centres will be able to devise protocols to improve treatment outcomes.

In external beam radiotherapy quality assurance is carried out on the individual components of the treatment chain. The patient simulating device, planning system and linear accelerators are tested regularly according to set protocols developed by national and international organizations. Even though these individual systems are tested errors can be made in the transfer between systems. The best quality assurance for the system is at the end of the treatment planning chain. In-vivo dosimetry measures the dose to the target volume through indirect measures at the end of the treatment planning chain and is therefore the most likely method for picking up errors which might occur earlier in the chain. Metal Oxide Semiconductor Field Effect Transistors (MOSFETs) have been shown to have a similar error in estimating entrance dose for in-vivo dosimetry to diodes, but no studies have been done clinically with entrance dose in-vivo dosimetry with MOSFETs. The time savings for using MOSFETs makes them preferable to TLD's. Due to their small size and versatility in other applications they are useful as more than dedicated in-vivo dosimetry systems using diodes. Clinical implementation of external beam in-vivo dosimetry would add another use to the MOSFETs without purchasing more specialized equipment. My studies have shown that MOSFETs can be used clinically for external beam in-vivo dosimetry using entrance dose measurements. After the MOSFET measurement system was implemented using a custom built aluminium build up cap clinical measurements were performed. A total of 23 patients and 54 fields were studied. The mean for all clinical measurements was 1.3 %, with a standard deviation of 2.6 %. Results were normally distributed around a mean with skewness and kurtosis as -0.39 and 0.34 respectively. For breasts the mean was 1.8 %, with a standard deviation of 2.7 %. For prostates and hips the mean was 1.3 % with a standard deviation of 2.9 %. These results are similar to studies conducted with diodes and TLD's. From these results one can conclude that MOSFETs can be used for entrance dose in-vivo dosimetry and are no worse than diodes or TLD's in terms of their measurement accuracy. / Thesis (M.Sc.)--School of Chemistry and Physics, 2006.

Bibliography: leaves 159-194 / xi, 194 leaves, [3] leaves of plates : ill. (2 col.) ; 31 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1986

<p>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).</p><p>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.</p><p>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.</p><p>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.</p>

<p>Idag ges strålbehandling som bot mot många olika cancerformer i hela världen. För en patient som ska genomgå, genomgår eller har genomgått en strålbehandling uppstår många tankar, känslor, smärtor och andra upplevelser som sjuksköterskan behöver känna till för att kunna bistå patienten. Strålbehandlingen ger många biverkningar som i värsta fall kan bli bestående livet ut. Syftet: Syftet med litteraturstudien var att beskriva patienters upplevelser i samband med strålbehandling. Metod: Studien genomfördes som en allmän litteraturstudie. Nio vetenskapliga artiklar med i huvudsak kvalitativ ansats valdes ut och analyserades efter en kvalitativ innehållsanalys. Resultat: Analysen resulterade i en process: före, under och efter strålbehandlingen, detta ledde till fem huvudkategorier, Rädd för att livet inte skall bli sig likt igen, Ensamhet i mörkret, Kraft att fortsätta kämpa, En känsla av skam, Bättre rustad inför framtidens utmaningar. Diskussion: Familj och närstående visade sig vara viktig för patienterna, även sjukvårdspersonal upplevdes som en trygghet i samband med behandlingen. Patienter upplever osäkerhet, maktlöshet och lidande inför behandlingen. Sjuksköterskan bör bidra till att patientens önskemål och omvårdnadsbehov blir tillgodosedda för att göra behandlingen så skonsam som möjligt. För att få ökad kunskap och förståelse för dessa patienters upplevelse av strålbehandling är fortsatt forskning inom detta område önskvärt.<em><em> </em></em></p> / <p> </p><p>Today, radiotherapy is given as cures for many different cancers worldwide. For a patient about to undergo, is undergoing or has undergone a radiation occurs many thoughts, feelings, pains and other experiences that the nurse should have knowledge of in order to assist the patients. The treatment brings many side-effects that are at worst likely, to continue throughout their lives. Aim: The aim of literature review was to describe patient experiences in connection with radiation therapy. Method: The review was conducted as a general literature review. Nine scientific articles with a qualitative approach were selected and analyzed by qualitative content analysis. Results: The analysis resulted in a process: before, during and after radiotherapy, this led to four main categories. <em>Fear that life is not to be the same again, Loneliness during a bothersome time, Strive to continue to struggle, An expectation that life should be the same again.</em> Discussion: Family and relatives proved to be important for patients health professionals also perceived as a security during the treatment. Patients experience insecurity, powerlessness and suffering about the treatment. The nurse should support the patient consider his or her wishes and needs in order to make the treatment as gentle as possible. In order to reach greater knowledge and understanding of these patients and their treatment continuing research in this area is desirable.</p><p> </p>

<p>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.</p>

<p>Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases.</p><p>Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of ¹²⁵I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking ¹²⁵I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter ⁷⁶Br by using NBI. Furthermore, it is shown that cellular uptake of ¹²⁵I can be modified by stimulating EGFR (HER-1) with EGF.</p><p>When labelled with the alpha emitter ²¹¹At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab.</p><p>Pertuzumab was radiolabelled with the low energy beta emitter ¹⁷⁷Lu without losing affinity or immunocompetence. [¹⁷⁷Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. </p><p>In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with ¹⁷⁷Lu, show promise as TRT agents.</p>

The cell survival curve is the only means by which to both qualitatively and quantitatively assess morphologic alterations directly resulting from in vitro irradiation of the cell. A ������Co cell survival curve experiment has successfully demonstrated the response of the AtT-20 clone mammalian cell line to the effects of gamma rays. With the results of this experiment, a low LET radiation cell survival curve now exists to be used as a comparative upon the completion of BNCT cell survival curves. / Graduation date: 1995

BACKGROUND : Radiation oncology was these 20 last years revolutionized by the 3-dimensional conformal radiotherapy (3D-CRT) and its technical evolution, the intensity modulated radiotherapy (IMRT). Thanks to steep dose gradient dose distribution, these techniques allow to conform the prescribed dose to the Planning Target Volume (PTV) while significantly decreasing the dose delivered to the Organs at Risk (OAR). One critical step remains the accurate definition of the Gross Tumor Volume (GTV). If the GTV is underestimated, there is a risk of missing part of the target. If the GTV is overestimated, the risk is to overirradiate normal tissues. Today's gold standard for GTV definition is the Computed Tomography (CT) scanner. We though know that its poor soft tissues contrast is a factor of variability for target definition purpose. AIMS : It can be hypothesized that, for Head and Neck Squamous Cell Carcinomas located in the oropharynx or the laryngo-hypopharynx, the use of other anatomical (like Magnetic Resonance Imaging – MRI) or functional (like positron emission tomography with either 11C-methionine – MET-PET- or 18F-fluorol-deoxy-glucose – FDG-PET) imaging modalities could complement CT for GTV delineation, and have an impact on subsequent CTV and PTV delineation and dose distribution to the non target tissues outside the PTV. RESULTS : We could demonstrate that, providing an adequate and controlled methodology concerning image coregistration and tumor volume delineation on functional images, differences were observed for the delineation of primary tumor volume or GTV according to the modality used. Moreover, the trends were the same for both locations studied (oropharyngeal and laryngo-hypopharyngeal) : CT, MRI and MET-PET volumes were not significantly different in absolute volumes, but there was no total overlap, each imaging modality having the tendency to visualize different types and relatively specific pathways of tumor extension (e.g. : cartilages in MRI). What was very interesting was the significantly smaller FDG-PET volume which could have a real impact on radiation oncology practice by (1) allowing to reduce dose distribution and (2) providing fast and reproducible GTV delineation based on its functional characteristic. Furthermore, we could demonstrate on the subset of operated patients that these smaller FDG-PET volumes were not the fact of a volume underestimating delineation algorithm but well the reflection of true tumor extension. But one must keep in mind that because of spatial resolution limitations, there was still a significant overestimate of this true GTV. Also, none of the imaging modalities was able to visualize very small tumor extensions. This last fact put in the light the need for strict guidelines for CTV prediction based on GTV extension. This is what was done with the help of both anatomical and histo-pathological literature data. These guidelines were used to delineate CTVs on our images, allowing to perform comparative planning on primary tumor. It could be concluded that differences in GTV had not only an impact on CTV and subsequent PTV, but also on dose distribution, either on total irradiated volume or -perhaps more important- on mean dose to parotid glands. No significant effect could be observed on maximal dose to spinal cord. Compared to planning performed on macroscopy-based volumes, no significant difference could be found with what was done on PET-derived planning. CONCLUSION : This research paves the way for the use of FDG-PET for GTV delineation in planning the patients with oropharyngeal and laryngo-hypopharyngeal squamous cell carcinomas. / INTRODUCTION : La radiothérapie moderne a terriblement évolué ces 20 dernières années grâce au développement de la radiothérapie conformationnelle tridimensionnelle (3D-CRT) et de son évolution technique, la radiothérapie par modulation d'intensité (IMRT). Grâce à la création de gradients de dose très raides, ces techniques permettent de conformer au mieux la distribution de la dose au “Planning Target Volume” (PTV) tout en diminuant de manière significative la dose délivrée aux Organes à Risque (OAR). La précision de la définition du “Gross Tumor Volume” (GTV) ou volume tumoral macroscopique reste une étape cruciale dans le sens où une sous-estimation du volume augmente le risque de sous-doser la dose délivrée à la tumeur. Dans l'autre sens, la surestimation du volume tumoral conduit immanquablement à une surirradiation des tissus sains. La tomographie computée par scanner (CT) est l'imagerie de référence pour la définition du GTV. Cependant, le manque de constraste entre tissus mous – à fortiori entre la tumeur et les tissus environnants- constitue un facteur de variabilité reconnu quant à la précision de délimitation du GTV. BUTS : Pour les cancers de la sphère cervico-maxillo-faciale, en particulier pour les tumeurs épithéliales oropharyngées et laryngo-hypopharyngées, démontrer que l'usage complémentaire d'une autre imagerie anatomique comme la résonance magnétique (IRM) ou fonctionnelle comme la tomographie par émission de positrons utilisant soit la méthionine marquée au carbone 11 (MET-TEP), soit le fluoro-déoxy-glucose marqué au fluor 18 (FDG-TEP) peut améliorer la précision de la délimitation GTV. Dans ce cas, démontrer également que cela a un impact sur la délimitation des CTV et PTV sous-jacents et, in fine, sur la distribution de la dose aux tissus sains extérieurs au PTV. RESULTATS : Moyennant l'utilisation adéquate et contrôlée de méthodes de corégistration des images et de délimitation automatique des volumes en imagerie fonctionnelle, nous avons pu démontrer des différences en terme de GTV délimité selon les différentes modalités d'imagerie, avec une tendance identique que l'on se situe au niveau oropharyngé ou laryngo-hypopharyngé. Les GTV délimités sur CT, IRM et MET-TEP n'étaient pas significativement différents en valeurs absolues, mais chaque modalité avait tendance, au-delà d'une zone de congruence s'élevant en moyenne à 50% du volume total, à visualiser des extensions vers des zones anatomiques lui étant propre (ex. : les cartilages en IRM). Les volumes délimités en FDG-TEP étaient significativement plus petits que ceux délimités sur les autres modalités d'imagerie. Nous pûmes de plus démontrer sur un ensemble de patients opérés par laryngectomie totale que le FDG-TEP était aussi la plus précise des modalités d'imagerie. Cependant, par manque de résolution spatiale, aucune des modalités d'imagerie ne fut en mesure de couvrir totalement le GTV. Ce fait met en lumière le besoin de recommendations claires pour la prédiction du CTV sur base de l'extension du GTV. Ce travail fut réalisé sur base des données de la littérature anatomique (normale et pathologique). Ces recommendations furent utilisées pour délimiter les CTV sur les images CT, FDG-TEP et du spécimen chirurgical (les imageries IRM et MET-TEP ne furent pas analysées puisque n'apportant rien en regard du CT). Les PTV furent ensuite générés et une planification tridimensionnelle réalisée. Tant les CTV que les PTV délimités sur le FDG-TEP restaient significativement plus petits que leurs homologues délimités sur CT. Cette réduction permettait une réduction de la dose délivrée aux glandes parotides en particulier, aux tissus hors PTV de manière plus générale. CONCLUSION : Cette recherche ouvre la voie à l'utilisation du FDG-TEP pour la délimitation du GTV chez les patients atteints de tumeurs épithéliales des sphères oropharyngée et laryngo-hypopharyngée.