New methods of high dose delivery, such as intensity modulated radiation therapy (IMRT), stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS), hadron therapy, tomotherapy, etc., all make use of a few large fractions. To improve these treatments, there are three main directions: (i) improving physical dose distribution, (ii) optimizing radiosurgery dose-time scheme and (iii) modifying dose response of tumors or normal tissues. Different radiation modalities and systems have been developed to deliver the best possible physical dose to the target while keeping radiation to normal tissue minimum. Although applications of radiobiological findings to clinical practice are still at an early stage, many studies have shown that   sublethal radiation damage repair kinetics plays an important role in tissue response to radiation. The purpose of the present thesis is to show how the above-mentioned directions could be used to improve treatment outcomes with special interest in radiation modalities and dose-time scheme, as well as radiobiological modeling. Also for arteriovenous malformations (AVM), the possible impact of AVM network angiostructure in radiation response was studied. / Nya och förbättrade metoder för precisionsbestrålning, såsom intensitetsmodulerad strålbehandling (IMRT), stereotaktisk strålbehandling (SRT), stereotaktisk strålkirurgi (SRS) eller hadronterapi etc., gör det möjligt att leverera behandlingen i ett fåtal fraktioner med höga doser. Dessa behandlingmetoder kan ytterligare förbättras genom att (i) förbättra den fysikaliska dosfördelningen, (ii) optimera dosrater och fraktioneringsscheman eller (iii) modifiera dosresponsen hos tumörer eller normalvävnad. Olika strålmodaliteter och behandlingssystem har tagits fram för att kunna leverera bästa möjliga fysikaliska dosfördelning till targetvolymen samtidigt som dosen till frisk vävnad hålls så låg som möjligt. Även om användandet av radiobiologisk kunskap och modeller i klinisk rutin ännu är i sin linda så visar många studier att kinetiken för subletal reparation av strålskador har stor betydelse för strålresponsen. Syftet med denna avhandling är att visa hur dessa olika utvecklingsvägar kan användas för att förbättra behandlingsresultatet speciellt genom att studera vald strålmodalitet, dosrat och fraktioneringsschema samt radiobiologisk modellering. För arteriovenösa missbildningar (AVM) har även  studerats hur strukturen hos angionätverket påverkar strålresponsen. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.</p>

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Computed tomography (CT) is an imaging technique that uses x-ray and computers to create cross-sectional images of structures. Stereotactic CT-guided biopsy is defined as the use of a stable apparatus to direct and perform tissue biopsies under CT guidance. For the brain, the principal advantage of stereotactic CT guidance over other biopsy techniques is its high accuracy in getting a sample from deep-seated lesions. The objectives of this study were to create an inexpensive CT-guided stereotactic device adaptable to different canine head sizes and to test the accuracy of the device for needle placement in deep-seated brain targets. A biopsy device was created that consists of four main components: a CT table fixation device, a head fixture, a needle fixture , and motion control system. Accuracy was tested using 16 head and neck specimens obtained from dogs euthanitized for reasons unrelated to the brain. Deep-seated (caudate nucleus and pituitary gland) targets were identified on CT. After a 5 mm craniotomy, the biopsy needle, with CT monitoring, was progressively introduced into the target. The final needle track distance was measured on CT. The brain was removed and sliced to verify placement of the needle tip within the target and to measure the actual needle track distance. The total cost of materials and construction for the stereotactic CT-guided biopsy device was $785.00. No difference in needle placement accuracy was identified for caudate and pituitary targets. Based on assessments by 2 independent observers, the caudate target was successfully hit 75% of the time. Pituitary targets were successfully hit 96.8 % of the time. Actual needle track lengths were an average of 3.2 mm less that the track length measured on CT. This difference was most likely due to incomplete staining of the bevel part of the needle track on gross specimens. / Master of Science

<p>Background: This is a retrospective study of patients treated with stereotactic body radiation therapy (SBRT) with the stereotactic body frame for centrally located lung tumours. The purpose was to investigate the doses to the different structures of the tracheobronchial tree and to relate these doses to the incidence of atelectasis. The goal was to estimate a tolerance dose for the bronchi. Materials: The patient material consisted of 71 patient treated at the Karolinska University Hospital for a total of 102 tumours between November 1993 and March 2004. The patient group consisted of 36 men and 35 women with a mean age at the treatment of 67 years (range 34-87). The group was a mixture of patients with primary lung cancer and pulmonary metastases. Methods: After rereading and reactivating the dose plans for the patients in the treatment planning system (TPS) the different tracheobronchial structures (trachea, right mainstem bronchus, right superior bronchus, right intermedius bronchus, right medius bronchus, right inferior bronchus, left mainstem bronchus, left superior bronchus, left intermedius bronchus, left inferior bronchus) were outlined. The dose distribution in each structure was calculated and a dose-volume histogram (DVH) was created. Patients were allocated to four groups, i.e. patients with right sided tumours (22), left sided tumours (14), mediastinal tumours (23) and bilateral tumours (10). After that the maximum and mean doses to all structures were analysed. An oncologist reviewed the medical records for the patients and especially looked for atelectasis. The doses were related to the incidence of atelectasis.</p><p>Results and Conclusions: For the patient group with right sided tumours it seems like the maximum doses to the bronchi are higher for the patients with atelectasis in comparison with patients without atelectasis. A better correlation between atelectasis and maximum doses rather than mean doses was observed for these patients. At this moment the results are too preliminary, so it is not possible to suggest a tolerance dose for the bronchi. What can be said is that the maximum doses to the bronchi for patients with right sided tumours without atelectasis are below 250 Gy3 expressed in biologically equivalent dose (BED) with α/β=3Gy, while at least one bronchi structure in the atelectasis patients received a maximum dose above 250 Gy3.</p>

<p>Background: Stereotactic body radiation therapy (SBRT) is a relatively new method which has been employed e.g. in the treatment of liver tumours. Little dosimetric data has been published for SBRT in the liver. The aim of this retrospective study was to quantify the dosimetric parameters that influence the toxicity of the healthy liver, and the effect on the tumour, for SBRT to liver tumours in patients treated at Karolinska University Hospital. A comparison was made to relating published studies.</p><p>Patients and Methods: The patient group to be studied were treated at Karolinska University Hospital for liver metastases with SBRT between July 1993 and October 2004. There were 64 patients treated with 71 treatment plans for 81 tumours. Differential dose volume histograms were collected for the clinical target volume (CTV), the planning target volume (PTV) and the liver excluding the CTV, from all dose plans. Since different fractionation schedules were used, the doses were normalised using the linear quadratic model, to be comparable. The doses to the uninvolved liver were evaluated with the mean liver dose, the Lyman-Kutcher-Burman (LKB) effective volume normal tissue complication probability (NTCP) model as well as the critical volume NTCP-model. A comparison was made to the studies of Dawson et al (2002) and Schefter et al (2005). The doses to the CTV were evaluated using the equivalent uniform dose tumour control probability (TCP) model, and related to target size and date of treatment.</p><p>Results: When the mean doses to the uninvolved liver (the liver volume without tumour tissue) were compared to Dawson and Ten Haken’s results (2005), 20 treatments out of 71 were predicted to give a risk of radiation induced liver disease (RILD) higher than 50%. The effective volume calculations predicted that 18 treatments gave a risk of RILD higher than 50%, when compared to the results of Dawson et al (2002). According to the critical volume model and the parameter values of Schefter et al (2005), our data predict that 10 of the treatments gave a risk of liver function failure, to an unspecified risk level. Treatments of large tumours resulted in higher doses to the liver. The doses to the CTV showed that the maximum prescribed dose decreased with increasing CTV.</p><p>Discussion and Conclusions: An evaluation of clinical data is necessary to make a full analysis of the treatments of this study. Such an analysis is planned for the future.</p>

Background: This is a retrospective study of patients treated with stereotactic body radiation therapy (SBRT) with the stereotactic body frame for centrally located lung tumours. The purpose was to investigate the doses to the different structures of the tracheobronchial tree and to relate these doses to the incidence of atelectasis. The goal was to estimate a tolerance dose for the bronchi. Materials: The patient material consisted of 71 patient treated at the Karolinska University Hospital for a total of 102 tumours between November 1993 and March 2004. The patient group consisted of 36 men and 35 women with a mean age at the treatment of 67 years (range 34-87). The group was a mixture of patients with primary lung cancer and pulmonary metastases. Methods: After rereading and reactivating the dose plans for the patients in the treatment planning system (TPS) the different tracheobronchial structures (trachea, right mainstem bronchus, right superior bronchus, right intermedius bronchus, right medius bronchus, right inferior bronchus, left mainstem bronchus, left superior bronchus, left intermedius bronchus, left inferior bronchus) were outlined. The dose distribution in each structure was calculated and a dose-volume histogram (DVH) was created. Patients were allocated to four groups, i.e. patients with right sided tumours (22), left sided tumours (14), mediastinal tumours (23) and bilateral tumours (10). After that the maximum and mean doses to all structures were analysed. An oncologist reviewed the medical records for the patients and especially looked for atelectasis. The doses were related to the incidence of atelectasis. Results and Conclusions: For the patient group with right sided tumours it seems like the maximum doses to the bronchi are higher for the patients with atelectasis in comparison with patients without atelectasis. A better correlation between atelectasis and maximum doses rather than mean doses was observed for these patients. At this moment the results are too preliminary, so it is not possible to suggest a tolerance dose for the bronchi. What can be said is that the maximum doses to the bronchi for patients with right sided tumours without atelectasis are below 250 Gy3 expressed in biologically equivalent dose (BED) with α/β=3Gy, while at least one bronchi structure in the atelectasis patients received a maximum dose above 250 Gy3.

Background: Stereotactic body radiation therapy (SBRT) is a relatively new method which has been employed e.g. in the treatment of liver tumours. Little dosimetric data has been published for SBRT in the liver. The aim of this retrospective study was to quantify the dosimetric parameters that influence the toxicity of the healthy liver, and the effect on the tumour, for SBRT to liver tumours in patients treated at Karolinska University Hospital. A comparison was made to relating published studies. Patients and Methods: The patient group to be studied were treated at Karolinska University Hospital for liver metastases with SBRT between July 1993 and October 2004. There were 64 patients treated with 71 treatment plans for 81 tumours. Differential dose volume histograms were collected for the clinical target volume (CTV), the planning target volume (PTV) and the liver excluding the CTV, from all dose plans. Since different fractionation schedules were used, the doses were normalised using the linear quadratic model, to be comparable. The doses to the uninvolved liver were evaluated with the mean liver dose, the Lyman-Kutcher-Burman (LKB) effective volume normal tissue complication probability (NTCP) model as well as the critical volume NTCP-model. A comparison was made to the studies of Dawson et al (2002) and Schefter et al (2005). The doses to the CTV were evaluated using the equivalent uniform dose tumour control probability (TCP) model, and related to target size and date of treatment. Results: When the mean doses to the uninvolved liver (the liver volume without tumour tissue) were compared to Dawson and Ten Haken’s results (2005), 20 treatments out of 71 were predicted to give a risk of radiation induced liver disease (RILD) higher than 50%. The effective volume calculations predicted that 18 treatments gave a risk of RILD higher than 50%, when compared to the results of Dawson et al (2002). According to the critical volume model and the parameter values of Schefter et al (2005), our data predict that 10 of the treatments gave a risk of liver function failure, to an unspecified risk level. Treatments of large tumours resulted in higher doses to the liver. The doses to the CTV showed that the maximum prescribed dose decreased with increasing CTV. Discussion and Conclusions: An evaluation of clinical data is necessary to make a full analysis of the treatments of this study. Such an analysis is planned for the future.

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.

Prostate cancer is prevalent among men and one of the few cancer sites where local therapies currently target the entire organ instead of tumour. MRI holds promise in accurately depicting regions of cancer burden within the prostate gland and guiding tumour-targeted diagnostics and therapeutics. The clinical performance of a novel stereotactic MRI-guided needle navigation system for prostate cancer targeting was evaluated. Mean absolute in-plane stereotactic needle-targeting error for 10 patients was 2.2 mm and mean absolute depth error was 6.5 mm, highlighting a need to improve technical accuracy of the system. Consequently, alternative stereotactic registration techniques were investigated. Metrics of performance were in-plane stereotactic needle-targeting error, depth error, and registration time. A Z-shaped fiducial motif using automated registration performed best in phantom experiments with an in-plane error of 2.0 mm and depth error of 1.0 mm. These results will guide further software and hardware development to improve clinical performance.