Following our previous experience, the relative seriality model

was fitted to two different sets of clinical data for radiation myelitis concerning thoracic spinal cord after radiation treatment of 43 patients with lung carcinoma and cervical spinal cord after treating 248 patients for malignant disease of head and neck.

Individual treatment data were suitably fitted by the relative seriality model. The estimated radiobiological parameters of the model indicate that the probability of inducing this complication after radiation therapy is volume dependent only for the cervical part of spinal cord, whereas for the thoracic part no volume effect could be observed.

Two different statistical methods applied to the patient material showed that the radiobiological model and the estimated parameters can be used to closely predict the complication rates observed.

Background: Radiobiological models for normal tissue complication probability (NTCP) are more and more commonly used in order to estimate the clinical outcome of radiation therapy. A normal tissue complication probability model to be considered a good and reliable one should fulfill the following two requirements: (a) it should predict the sigmoid shape of the dose-response curve as well as possible and (b) it should duly handle the volume effect. In the work from 2005 (IJROBP 61(3):892-900, 2005) P. van Luijk et al. suggest that none of the existing NTCP models is able to describe the volume effects present in the rat spinal cord during irradiation with small proton beams and they indicate the need for developing such new models.

Methods: We have used the experimental data from H. Bijl et al. (IJROBP 52(1):205-211, 2002) to try explaining the change in the fifty percent effective dose (ED50) for different field sizes. We initiated this study to evaluate whether the induction of white matter necrosis in rat spinal cord after irradiation with small proton beams could be explained independent of used NTCP model. We therefore introduced a new concept of effective FSU dose, where a convolution of the original dose distribution with a function describing the effective size of a single FSU results in the average doses in a functional subunit. Such procedure allows determining the ED50 in an FSU of a certain size, within the irradiation field. We have also looked at non uniform dose distributions to see whether using a similar method we can explain the so called “bath and shower experiments” (IJROBP 57(1): 274-281, 2003).

Results: Using the least square method to compare the effective doses for different sizes of functional subunits with the experimental data we observe the best fit for about 8 mm length. It seems that this length could be understood as an effective size of functional subunits in rat spinal cord, explaining what is otherwise interpreted as a volume effect. For the non uniform dose distributions an effective FSU length of 5 mm gives the optimal fit with the Probit dose-response model.

Conclusions: The concept of an effective FSU length seems to explain at least part of the effects seen when small portions of the rat spinal cord are irradiated. The most likely FSU length for the shower and bath experiments is 5 mm according to these calculations.

The present thesis is focused on the development and application of dose response models for radiation therapy. Radiobiological models of tissue response to radiation are an integral part of the radiotherapeutic process and a powerful tool to optimize tumor control and minimize damage to healthy tissues for use in clinical trials. Ideally, the models could work as a historical control arm of a clinical trial eliminating the need to randomize patents to suboptimal therapies. In the thesis overview part, some of the basic properties of the dose response relation are reviewed and the most common radiobiological dose-response models are compared with regard to their ability to describe experimental dose response data for rat spinal cord using the maximum likelihood method. For vascular damage the relative seriality model was clearly superior to the other models, whereas for white matter necrosis all models were quite good except possibly the inverse tumor and critical element models. The radiation sensitivity, seriality and steepness of the dose-response relation of the spinal cord is found to vary considerably along its length. The cervical region is more radiation sensitive, more parallel, expressing much steeper dose-response relation and more volume dependent probability of inducing radiation myelitis than the thoracic part. The higher number of functional subunits (FSUs) consistent with a higher amount of white matter close to the brain may be responsible for these phenomena. With strongly heterogeneous dose delivery and due to the random location of FSUs, the effective size of the FSU and the mean dose deposited in it are of key importance and the radiation sensitivity distribution of the FSU may be an even better descriptor for the response of the organ. An individual optimization of a radiation treatment has the potential to increase the therapeutic window and improve cure for a subgroup of patients.

Background. Risk factors for development of a stricture of the upper esophagus after radiotherapy for head and neck cancer are poorly defined. Methods. This was a retrospective case-control study of patients diagnosed and treated for esophageal stricture after radiotherapy for head and neck cancer. Results. The incidence of esophageal stricture after external beam radiation therapy (EBRT) was 3.3%. Seventy patients with stricture and 66 patients without stricture were identified. A multivariate analysis showed that there was increased risk of stricture in receiving enteral feeding during EBRT or in receiving a mean dose of >45 By to the upper esophagus. Conclusions. Enteral feeding during EBRT is strongly associated with the development of stricture of the esophagus, as is a mean dose of >45 Gy to the upper esophagus. Treatment of the stricture with Savary-Gilliard bougienage or through scope balloon dilatation is safe and successful but often has to be repeated.

Background and purpose: Determination of the dose-response relations for oesophageal stricture after radiotherapy of the head and neck. Material and methods: In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992-2000 and 2001-2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model. Results: For the treatment period 1992-2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992-2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001-2005 were 49.8 and 21.4 Gy. For the period 2001-2005 the best estimates of the dose-response parameters are D-50 = 61.5 Gy (52.9-84.9 Gy), gamma = 1.4 (0.8-2.6) and s = 0.1 (0.01-0.3). Conclusions: Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001-2005. However, no dose response relation was found for the complete material.

Radiation treatment of arteriovenous malformations (AVMs) has a slow and progressive vaso-occlusive effect. Some studies suggested the possible role of vascular structure in this process. A detailed biomathematical model has been used, where the morphological, biophysical and hemodynamic characteristics of intracranial AVM vessels are faithfully reproduced. The effect of radiation on plexiform and fistulous AVM nidus vessels was simulated using this theoretical model. The similarities between vascular and electrical networks were used to construct this biomathematical AVM model and provide an accurate rendering of transnidal and intranidal hemodynamics. The response of different vessels to radiation and their obliteration probability as a function of different angiostructures were simulated and total obliteration was defined as the probability of obliteration of all possible vascular pathways. The dose response of the whole AVM is observed to depend on the vascular structure of the intra-nidus AVM. Furthermore, a plexiform AVM appears to be more prone to obliteration compared with an AVM of the same size but having more arteriovenous fistulas. Finally, a binomial model was introduced, which considers the number of crucial vessels and is able to predict the dose response behavior of AVMs with a complex vascular structure.

OBJECT:

Radiation treatment of large arteriovenous malformations (AVMs) remains difficult and not very effective, even though seemingly promising methods such as staged volume treatments have been proposed by some radiation treatment centers. In symptomatic patients harboring large intracranial AVMs not amenable to embolization or resection, single-session high-dose stereotactic radiation therapy is a viable option, and the special characteristics of high-ionization-density light-ion beams offer several treatment advantages over photon and proton beams. These advantages include a more favorable depth-dose distribution in tissue, an almost negligible lateral scatter of the beam, a sharper penumbra, a steep dose falloff beyond the Bragg peak, and a higher probability of vascular response due to high ionization density and associated induction of endothelial cell proliferation and/or apoptosis. Carbon ions were recently shown to be an effective treatment for skull-base tumors. Bearing that in mind, the authors postulate that the unique physical and biological characteristics of light-ion beams should convey considerable clinical advantages in the treatment of large AVMs. In the present meta-analysis the authors present a comparison between light-ion beam therapy and more conventional modalities of radiation treatment with respect to these lesions.

METHODS:

Dose-volume histograms and data on peripheral radiation doses for treatment of large AVMs were collected from various radiation treatment centers. Dose-response parameters were then derived by applying a maximum likelihood fitting of a binomial model to these data. The present binomial model was needed because the effective number of crucial blood vessels in AVMs (the number of vessels that must be obliterated to effect a cure, such as large fistulous nidus vessels) is low, making the Poisson model less suitable. In this study the authors also focused on radiobiological differences between various radiation treatments.

RESULTS:

Light-ion Bragg-peak dose delivery has the precision required for treating very large AVMs as well as for delivering extremely sharp, focused beams to irregular lesions. Stereotactic light-ion radiosurgery resulted in better angiographically defined obliteration rates, less white-matter necrosis, lower complication rates, and more favorable clinical outcomes. In addition, in patients treated by He ion beams, a sharper dose-response gradient was observed, probably due to a more homogeneous radiosensitivity of the AVM nidus to light-ion beam radiation than that seen when low-ionization-density radiation modalities, such as photons and protons, are used.

CONCLUSIONS:

Bragg-peak radiosurgery can be recommended for most large and irregular AVMs and for the treatment of lesions located in front of or adjacent to sensitive and functionally important brain structures. The unique physical and biological characteristics of light-ion beams are of considerable advantage for the treatment of AVMs: the densely ionizing beams of light ions create a better dose and biological effect distribution than conventional radiation modalities such as photons and protons. Using light ions, greater flexibility can be achieved while avoiding healthy critical structures such as diencephalic and brainstem nuclei and tracts. Treatment with the light ion He or Li is more suitable for AVMs <or= 10 cm(3), whereas treatment with the light ion Li, Be, or C may be more appropriate for larger AVMs. A binomial model based on the effective number of crucial vessels in the AVM may be used quite well to predict AVM obliteration probabilities for both small and large AVMs when therapies involving either photons or light ions are used.

This presentation briefly covers the ongoing development of a therapy center with multiple simultaneous radiation modalities at Karolinska university hospital. The hearth of the facility will most likely be a superconducting cyclotron capable of delivering around 400 MeV/u carbon ions simultaneously to two separate excentric gantries who service four treatment rooms each. A number of different stable ions will be available ranging from hydrogen to oxygen but also PET emitting C11 ions and possibly B8 the lightest existing PET emitter. Several treatment rooms will also be equipped for narrow scanned high energy photon and electron beam treatments and a light ion research facility for physics and biology studies will be set up on two separate beamlines. The centre will include an advanced PET-CT and MRSI based diagnostic centre on the same floor and close to both the ion treatment facility and the high energy photon and electron facility. By docking the stereotactic treatment coach both to the treatment units and before and after the treatment to the diagnostic PET-CT units, iso dose delivery can be rapidly examined by imaging the radiation induced C11 and O15 activity produced during the treatment.

One of the most used irradiation techniques in modern radiation therapy is step-and-shoot IMRT. The accuracy of this technique when delivering complex dose distributions strongly depends on the size of the subfields. The aims of this study is to determine the minimum size of subfields that can be used efficiently in Step-and-Shoot IMRT, to investigate the validation process for beam delivery and treatment planning dose calculations, and to find recommendations for practical clinical implementations.

Two different detectors, a CC04 ion chamber and a SFD stereotactic diode, have been used for measuring head scatter factors in air (Sc), total output factors (Scp) and dose profiles in water for a wide range of field sizes. The measurements were compared to calculations done with a pre-release version of the Nucletron MasterPlanTM v 3.1 treatment planning system that employs a novel, high resolution fluence modelling for both its pencil beam and collapsed cone dose calculation algorithms. Collimator settings were explicitly checked using FWHM film measurements with a build-up sheet of tungsten placed close to the treatment head to reduce the influence from lateral electron transport and geometrical penumbra. An analysis of the influence and sensitivity of Scp for small fields with respect to the linear accelerator source size and shape was also made.

The measurements with the ionization chamber and the stereotactic diode showed good agreements with each other and with the treatment planning system calculations for field sizes larger than 2×2 cm2. For small field sizes, measurements with different detectors yielded different results. Calculations showed agreements with measurements with the smallest detector, provided careful field size calibration and commissioning of calculation parameters. Uncertainties in collimator settings and source characteristics were shown to yield large uncertainties in Scp for fields smaller than 2×2 cm2.

The treatment planning system was found to properly handle small subfields but results were very sensitive to uncertainties in source size, as well as calibration and reproducibility of the collimator settings. Therefore if subfields smaller than 2×2 cm2 are to be used in IMRT extra care should be taken to determine the source characteristics and to calibrate the collimators. The volume of the detectors used for validation of such small fields and the loss of charged particle equilibrium conditions also have to be taken into consideration.

The dose distribution around brachytherapy (BT) sources is characterized by steep dose gradients and an energy spectrum varying rapidly with depth in water around the source. These two properties make experimental verification of the dose distribution difficult, and put high demands on the dosimetry system in use regarding precision, size and energy dependence. The American Association of Physicists in Medicine (AAPM) recommends lithium fluoride (LiF) thermo-luminescence dosimetry (TLD) to be used for verification measurements, as it is the only dosimetry system meeting the requirements, but still the total combined uncertainty in dose-rate determination is as high as 7-9 % (1 σ). Lithium formate is a new dosimetry material that is less energy dependent than LiF, but more sensitive than the most common EPR (electron paramagnetic resonance) dosimetry material, alanine. In order to evaluate lithium formate EPR for BT dosimetry, dosimeters were produced for experimental dose determination around BT source 192Ir. The dosimeters were calibrated against an ionization chamber in a high energy photon beam. Dose to water was determined at 1, 3 and 5 cm radial distance from the source, which was stepped along a straight line in a PMMA phantom. The experiments were performed twice using 4 dosimeters per distance and experiment. Methods to correct for energy dependence were developed and evaluated. The uncertainty in measured dose was estimated. The experimental dose values agreed with the values from the treatment planning system with a maximum deviation of 3.3 %, and an average 1 σ uncertainty of 3 % at 3 and 5 cm and 5 % at 1cm. Uncertainty in radial distance from the source as well as source calibration were the dominating contributions to the total combined uncertainty. Lithium formate EPR has been shown to be a promising alternative to LiF TLD for BT dosimetry.

Recently we challenged the view that arterial desaturation during hypergravity is caused by redistribution of blood flow to dependent lung regions by demonstrating a paradoxical redistribution of blood flow towards non-dependent regions. We have now quantified regional ventilation in 10 healthy supine volunteers at normal and three times normal gravity (1G and 3G). Regional ventilation was measured with Technegas (Tc-99m) and quantitative single photon emission computed tomography (SPECT). Hypergravity caused arterial desaturation, mean decrease 8%, p<0.05 vs. 1G. The ratio for mean ventilation per voxel for non-dependent and dependent lung regions was 0.81+/-0.12 during 1G and 1.63+/-0.35 during 3G (mean+/-SD), p<0.0001. Thus, regional ventilation was shifted from dependent to non-dependent regions. We suggest that arterial desaturation during hypergravity is caused by quantitatively different redistributions of blood flow and ventilation. To our knowledge, this is the first study presenting high-resolution measurements of regional ventilation in humans breathing normally during hypergravity.

Since 1986 patients with ocular malignant melanoma have been treated with Ru-106 plaques at S:t Erik Eye Hospital. In 1998 I-125 radioactive seed plaques was presented as an alternative to Ru-106 when treating tumors with an apical height greater than 7 mm. Until June 2005 the doseplanning of these plaques was based on a depth-dose curve made in the dose planning system Cadplan supplied by Varian Medical Systems. In the recent years the capabilities of computerized 3D dose planning system has increased greatly. The number of types of seeds on the market has also increased.

In order to implement the modern 3D dose planning system Brachy Vision 7.3.10 in planning the I-125 plaques, a review of the dose planning process have been done.

The ultra sound equipment used by the ophthalmologist to determine the apical height of the tumor has been investigated in terms of accuracy. A phantom has been developed for this task.

As new seeds entered the market a comparision have been made comparing the Amersham 6711 seed with the Bebig I25.S06 seed. A method for measuring the activity of the single seeds has also been developed.

The dose planning system Brachy Vision 7.3.10 have been compared to the old dose planning method, and an implementation of the plaques into Brachy Vision have been made.

The ultra sound equipment was accurate in the regions of interest. It was also discovered that the Bebig I25.S06 seed gave slightly higher dose compared to the Amersham 6711 with the same activity. The difference between the seeds is however small. The results indicate that the old dose planning method gave a slight underdosage.

During the last 20 years, the field of cellular and not least molecular radiation biology has been developed substantially and can today describe the response of heterogeneous tumors and organized normal tissues to radiation therapy quite well. An increased understanding of the sub-cellular and molecular response is leading to a more general systems biological approach to radiation therapy and treatment optimization. It is interesting that most of the characteristics of the tissue infrastructure, such as the vascular system and the degree of hypoxia, have to be considered to get an accurate description of tumor and normal tissue responses to ionizing radiation. In the limited space available, only a brief description of some of the most important concepts and processes is possible, starting from the key functional genomics pathways of the cell that are not only responsible for tumor development but also responsible for the response of the cells to radiation therapy. The key mechanisms for cellular damage and damage repair are described. It is further more discussed how these processes can be brought to inactivate the tumor without severely damaging surrounding normal tissues using suitable radiation modalities like intensity-modulated radiation therapy (IMRT) or light ions. The use of such methods may lead to a truly scientific approach to radiation therapy optimization, particularly when invivo predictive assays of radiation responsiveness becomes clinically available at a larger scale. Brief examples of the efficiency of IMRT are also given showing how sensitive normal tissues can be spared at the same time as highly curative doses are delivered to a tumor that is often radiation resistant and located near organs at risk. This new approach maximizes the probability to eradicate the tumor, while at the same time, adverse reactions in sensitive normal tissues are as far as possible minimized using IMRT with photons and light ions.

An integral equation relating the lateral absorbed dose profile of a photon beam to the resultant absorbed dose distribution during single-turn rotating-beam therapy has been set up and solved for the case of a cylindrical phantom with the axis of rotation coinciding with the axis of symmetry of the cylinder. In the first approximation the results obtained are also valid when the axis of rotation is somewhat off-centred, even in a phantom that deviates from circular symmetry, provided the rotation is performed in both clockwise and counter clockwise directions. The calculated dose profiles indicate that improved dose uniformity can be achieved using a new type of non-linear wedge-shaped filter, which can easily be designed using the derived general analytic solution to the integral equation.

As carbon ions, at therapeutic energies, penetrate tissue, they undergo inelastic nuclear reactions and give rise to significant yields of secondary fragment fluences. Therefore, an accurate prediction of these fluences resulting from the primary carbon interactions is necessary in the patient's body in order to precisely simulate the spatial dose distribution and the resulting biological effect. In this paper, the performance of nuclear fragmentation models of the Monte Carlo transport codes, FLUKA and GEANT4, in tissue-like media and for an energy regime relevant for therapeutic carbon ions is investigated. The ability of these Monte Carlo codes to reproduce experimental data of charge-changing cross sections and integral and differential yields of secondary charged fragments is evaluated. For the fragment yields, the main focus is on the consideration of experimental approximations and uncertainties such as the energy measurement by time-of-flight. For GEANT4, the hadronic models G4BinaryLightIonReaction and G4QMD are benchmarked together with some recently enhanced de-excitation models. For non-differential quantities, discrepancies of some tens of percent are found for both codes. For differential quantities, even larger deviations are found. Implications of these findings for the therapeutic use of carbon ions are discussed.

Biological treatment optimization aim at improving radiation therapy by accounting for the radiobiological tumour and normal tissues response properties when optimizing the dose delivery. Generally traditional methods, using only dosimetrical measures, disregard the nonlinear radiation response of different tumours and normal tissues. The accumulated knowledge on tissue response to radiation, in the form of more accurate dose response relations, cell survival models and their associated biological parameters, alongside with the tools for biological treatment plan optimization, has allowed the present investigation on the potential merits of biologically based treatment optimization in radiation therapy.

With a more widespread implementation of intensity modulated radiation therapy in the clinic, there is an increasing demand for faster and safer treatment delivery techniques. In this thesis biological treatment plan optimization, using the probability to achieve complication free tumour control as the quantifier for treatment outcome, was applied to radiation therapy of early breast cancer and advanced cervix cancer. It is shown that very conformal dose distributions can generally be produced with 3 or 4 optimally orientated coplanar intensity modulated beams, without having clinically significant losses in treatment outcome from the optimal dose distribution.

By using exhaustive search methods, the optimal coplanar beam directions for intensity modulated photon beams for early breast cancer and the optimal non-coplanar directions for an advanced cervix cancer were investigated. Although time consuming, exhaustive search methods have the advantage of revealing most features involving interactions between a small number of beams and how this may influence the treatment outcome. Thus phase spaces may serve as a general database for selecting an almost optimal treatment configuration for similar patients. Previous knowledge acquired with physically optimized uniform beam radiation therapy may not apply when intensity modulated biological optimization is used. Thus unconventional treatment directions were sometimes found.

The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I–II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P₊), the biologically effective uniform dose (), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P₊ between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P₊ are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose–response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals.

The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I-II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P(+)), the biologically effective uniform dose (D), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P(+) between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P(+) are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose-response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals.

Tumour oxygenation could be investigated through several methods that use various measuring principles and can therefore highlight its different aspects. The results have to be subsequently correlated, but this might not be straightforward due to intrinsic limitations of the measurement methods. This study describes an analysis of the relationship between vascular and tissue oxygenations that may help the interpretation of results. Simulations have been performed with a mathematical model that calculates the tissue oxygenation for complex vascular arrangements by taking into consideration the oxygen diffusion into the tissue and its consumption at the cells. The results showed that while vascular and tissue oxygenations are deterministically related, the relationship between them is not unequivocal and this could lead to uncertainties when attempting to correlate them. However, theoretical simulation could bridge the gap between the results obtained with various methods.

The interest in theoretical modelling of radiation response has grown steadily from a fast method to estimate the gain of new treatment strategies to an individualisation tool that may be used as part of the treatment planning algorithms. While the advantages of biological optimisation of plans are obvious, accurate theoretical models and realistic information about the micro-environmental conditions in tissues are needed. This paper aimed to investigate the clinical implications of taking into consideration the details of the tumour microenvironmental conditions. The focus was on the availability of oxygen and other nutrients to tumour cells and the relationship between cellular energy reserves and DNA repair ability as this is thought to influence the response of the various hypoxic cells. The choice of the theoretical models for predicting the response (the linear quadratic model or the inducible repair model) was also addressed. The modelling performed in this project has shown that the postulated radiobiological differences between acute and chronic hypoxia have some important clinical implications which may help to understand the mechanism behind the current success rates of radiotherapy. The results also suggested that it is important to distinguish between the two types of hypoxia in predictive assays and other treatment simulations.

Several methods exist for evaluating tumor oxygenation as hypoxia is an important prognostic factor for cancer patients. They use different measuring principles that highlight various aspects of oxygenation. The results could be empirically correlated, but it has been suspected that there could be discordances in some cases. This study describes an analysis of the relationship between vascular and tissue oxygenations. Theoretical simulation has been employed to characterize tissue oxygenations for a broad range of distributions of intervessel distances and vascular oxygenations. The results were evaluated with respect to the implications for practical measurements of tissue oxygenations. The findings showed that although the tissue oxygenation is deterministically related to vascular oxygenation, the relationship between them is not unequivocal. Variability also exists between the fractions of values below the sensitivity thresholds of various measurement methods which in turn could be reflected in the power of correlations between results from different methods or in the selection of patients for prognostic studies. The study has also identified potential difficulties that may be encountered at the quantitative evaluation of the results from oxygenation measurements. These could improve the understanding of oxygenation measurements and the interpretation of comparisons between results from various measurement methods.

PURPOSE: To study the clinically relevant relative biologic effectiveness (RBE) of fractionated treatments with high linear energy transfer (LET) radiation and to identify the important factors that might influence the transfer of tolerance and curative levels from low LET radiation. These are important questions in the light of the growing interest for the therapeutic use of radiation with higher LET than electrons or photons. METHODS AND MATERIALS: The RBE of various fractionated schedules was analyzed with theoretical models for radiation effect, and the resulting predictions were compared with the published clinical and experimental data regarding fractionated irradiation with high LET radiation. RESULTS: The clinically relevant RBE increased for greater doses per fraction, in contrast to the predictions from single-dose experiments. Furthermore, the RBE for late-reacting tissues appeared to modify more quickly than that for early-reacting tissues. These aspects have quite important clinical implications, because the increased biologic effectiveness reported for this type of radiation would otherwise support the use of hypofractionation. Thus, the differential between acute and late-reacting tissues could put the late-reacting normal tissues at more risk from high LET irradiation; however, at the same time, it could increase the therapeutic window for slow-growing tumors. CONCLUSIONS: The modification of the RBE with the dose per fraction must be carefully taken into consideration when devising fractionated treatments with high LET radiation. Neglecting to do so might result in an avalanche of complications that could obscure the potential advantages of the therapeutic use of this type of radiation.

PURPOSE: This study explores the implications for cancer induction of treatment details such as fractionation, planning target volume (PTV) definition, and interpatient variations, which are relevant for the radiation treatment of prostate carcinomas.

METHODS AND MATERIALS: Treatment planning data from 100 patients have been analyzed with a risk model based on the United Nations Scientific Committee on the Effects of Atomic Radiation competition model. The risk model can account for dose heterogeneity and fractionation effects characteristic for modern radiotherapy. Biologically relevant parameters from clinical and experimental data have been used with the model.

RESULTS: The results suggested that changes in prescribed dose could lead to a modification of the risks for individual organs surrounding the clinical target volume (CTV) but that the total risk appears to be less affected by changes in the target dose. Larger differences are observed for modifications of the margins between the CTV and the PTV because these have direct impact onto the dose level and dose heterogeneity in the healthy tissues surrounding the CTV. Interpatient anatomic variations also have to be taken into consideration for studies of the risk for cancer induction from radiotherapy.

CONCLUSIONS: The results have shown the complex interplay between the risk for secondary malignancies, the details of the treatment delivery, and the patient heterogeneity that may influence comparisons between the long-term effects of various treatment techniques. Nevertheless, absolute risk levels seem very small and comparable to mortality risks from surgical interventions, thus supporting the robustness of radiation therapy as a successful treatment modality for prostate carcinomas.

The risk for radiation-induced cancers has become increasingly important as patient survival following radiotherapy has increased due to the advent of new methods for early detection and advanced treatment. Attempts have been made to quantify the risk of cancer that may be associated with various treatment approaches, but the accuracy of predictions is rather low due to the influence of many confounding factors. It is the aim of this paper to investigate the impact of dose heterogeneity and inter-patient anatomical heterogeneity that may be encountered in a population of patients undergoing radiotherapy and are thought to influence risk predictions. Dose volume histograms from patients treated with radiation for the carcinoma of the prostate have been used to calculate the risk for secondary malignancies using a competition dose-response model previously developed. Biologically-relevant parameters derived from clinical and experimental data have been used for the model. The results suggested that dose heterogeneity plays an important role in predicting the risk for secondary cancer and that it should be taken into account through the use of dose volume histograms. Consequently, dose-response relationships derived for uniform relationships should be used with care to predict the risk for secondary malignancies in heterogeneously irradiated tissues. Inter-patient differences could lead to considerable uncertainties in the shape of the relationship between predicted risk and average tissue dose, as seen in epidemiological studies. They also lead to rather weak correlations between the risk for secondary malignancies and target volumes. The results stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy for treatment plan evaluation or for retrospective analyses of the induction of secondary cancers. Nevertheless, the levels of risks are generally low and they could be regarded as the price of success for the advances in the radiotherapy of the prostate.

The interest in theoretical modelling of radiation response has grown steadily from a fast method to estimate the gain of new treatment strategies to an individualisation tool that may be used as part of the treatment planning algorithms. While the advantages of biological optimisation of plans are obvious, accurate theoretical models and realistic information about the micro-environmental conditions in tissues are needed. This paper aimed to investigate the clinical implications of taking into consideration the details of the tumour microenvironmental conditions. The focus was on the availability of oxygen and other nutrients to tumour cells and the relationship between cellular energy reserves and DNA repair ability as this is thought to influence the response of the various hypoxic cells. The choice of the theoretical models for predicting the response (the linear quadratic model or the inducible repair model) was also addressed. The modelling performed in this project has shown that the postulated radiobiological differences between acute and chronic hypoxia have some important clinical implications which may help to understand the mechanism behind the current success rates of radiotherapy. The results also suggested that it is important to distinguish between the two types of hypoxia in predictive assays and other treatment simulations.

Several methods exist for evaluating tumor oxygenation as hypoxia is an important prognostic factor for cancer patients. They use different measuring principles that highlight various aspects of oxygenation. The results could be empirically correlated, but it has been suspected that there could be discordances in some cases. This study describes an analysis of the relationship between vascular and tissue oxygenations. Theoretical simulation has been employed to characterize tissue oxygenations for a broad range of distributions of intervessel distances and vascular oxygenations. The results were evaluated with respect to the implications for practical measurements of tissue oxygenations. The findings showed that although the tissue oxygenation is deterministically related to vascular oxygenation, the relationship between them is not unequivocal. Variability also exists between the fractions of values below the sensitivity thresholds of various measurement methods which in turn could be reflected in the power of correlations between results from different methods or in the selection of patients for prognostic studies. The study has also identified potential difficulties that may be encountered at the quantitative evaluation of the results from oxygenation measurements. These could improve the understanding of oxygenation measurements and the interpretation of comparisons between results from various measurement methods.

The aim of this work is to characterize the beam of the 60Co therapy unit “Siemens Gammatron 1”, used at the Swedish Radiation Protection Authority (SSI) to calibrate therapy level ionization chambers. SSI wants to know the spectra in the laboratory’s reference points and a verified, virtual model of the 60Co unit to be able to compare current and future experiments to Monte Carlo simulations.

EGSnrc is a code for performing Monte Carlo simulations. By using BEAMnrc, which is an additional package that simplifies the building process of a geometry in the EGS-code, the whole Gammatron at SSI was defined virtually. In this work virtual models for two experimental setups were built: the Gammatron irradiating in air to simulate the air-kerma calibration geometry and the Gammatron irradiating a water phantom similar to that used for the absorbed dose to water calibrations.

The simulations are divided into two different substeps: one for the fixed part of the Gammatron and one for the variable part to be able to study different entities and to shorten simulation times.

The virtual geometries are verified by comparing Monte Carlo results with measurements. When it was verified that the virtual geometries were to be trusted, they were used to generate the Gammatron photon spectra in air and water with different field sizes and at different depths. The contributions to the photon spectra from different regions in the Gammatron were also collected. This is something that is easy to achieve with Monte Carlo calculations, but difficult to obtain with ordinary detectors in real life measurements.

The results from this work give SSI knowledge of the photon spectra in their reference points for calibrations in air and in water phantom. The first step of the virtual model (fixed part of Gammatron) can be used for future experimental setups at SSI.

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.

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.

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.

The technique of ESR-dosimetry and strategies for investigation of new materials as in regard to their applicability as ESR-dosimeters for radiotherapy has been reviewed. As an example six salts of formic and lactic acid has been evaluated. The applicability of the dosimeter has been judged by evaluating the tissue equivalence, radical yield, radical stability, spectral suitability, optimal readout parameters, dose response and sensitivity of the dosimetric system. Dependence of material characteristics and influence parameters has been analysed.

The reviewed methods have been successfully used for evaluation of the new materials. Lithium formate has been shown to be a good candidate relative to the state of the art dosimeter of alanine. Using optimal readout parameters lithium formate has been shown to be nine times as sensitive but even at moderate settings lithium formate is more sensitive. The results for lithium formate are in accordance to those of previous studies. The signal intensity of sodium formate has also proved to be high but unfortunately the signal fades rapidly.

Two new methods have been proposed as synthesis of the reviewed methods. The first allows flexible, effective and objective baseline correction of the ESR-spectrum. The second deals with dose response measurement by linear regression of the entire spectrum and was found to be successful in separating the spectral peaks of the induced radicals from the background signal.

A detailed characterization of the trapped-proton-induced radiation environment on board Columbus and the International Space Station (ISS) has been carried out using the Geant4 Monte Carlo particle transport toolkit. Dose and dose equivalent rates, as well as penetrating particle spectra are presented. These results are based on detailed Geant4 geometry models of Columbus and ISS, comprising a total of about 1000 geometry volumes.

Simulated trapped-proton dose rates are found to be strongly dependent on ISS altitude. Dose rates for different locations inside the Columbus cabin are presented, as well as for different models of the incident trapped-proton flux. Dose rates resulting from incident anisotropic trapped protons are found to be lower than, or equal to, those of omnidirectional models. The anisotropy induced by the asymmetric shielding distribution of Columbus/ISS is also studied. The simulated trapped-proton dose (equivalent) rates, averaged over different locations inside Columbus, are 120 Gy/d (154 Sv/d) and 79 Gy/d (102 Sv/d) for solar minimum and maximum conditions according to AP8 incident proton spectra and an ISS orbit of 380 km. The solar maximum dose rates are found to be of the same order as measurements in other modules in the present ISS.

A characterization of the Galactic Cosmic Ray (GCR) induced radiation environment on-board Columbus and the International Space Station (ISS) has been carried out using the Geant4 Monte Carlo particle transport toolkit and detailed geometry models of Columbus and ISS. Dose and dose equivalent rates, as well as penetrating particle spectra are presented. Simulation results indicate that the major part of the dose rates due to GCR protons are associated with secondary particles produced in the hull of ISS. Neutrons contribute about 15% of the GCR proton dose equivalent rate and mesons about 10%. More than 40% of the simulated GCR proton dose and dose equivalent rates are due to protons in the energy range above 10 GeV. Protons in the energy range above 50 GeV contribute only 5% to the dose rates. The total simulated dose and dose equivalent rates at solar maximum are 63 Gy/d and 123 Sv/d, respectively. The dose equivalent rate underestimates measurements made during the 2001 solar maximum. The discrepancy can be attributed to deficiencies in hadronic ion-nuclei interaction models for heavy ions and to the lack of such models above 10 GeV/N in Geant4.

The influence of geometry model approximations on Geant4 Monte Carlo simulation results of the radiation environment on-board the Columbus module of the International Space Station (ISS) has been investigated. Three geometry models of Columbus with different levels of detail and a geometry model of ISS have been developed. These geometries have been used for Geant4 simulations of the radiation environment inside Columbus induced by trapped protons and Galactic Cosmic Ray protons. Simulated dose rates and particle spectra on-board Columbus for each of the three Columbus models, with or without the ISS geometry model included, are presented and compared.

From comparisons of simulated dose rates and particle spectra for the three different geometry models it was found that the most detailed geometry model (750 volumes) produced results similar to a much less detailed model (23 volumes). The most detailed geometry model was concluded to be a sufficiently detailed approximation of the physical Columbus for the purpose of proton induced space radiation studies. The simulated dose rates are compatible with measurements on-board the ISS. The simulation results also show that an increase in shielding thickness decreases the simulated dose rate induced by trapped protons. For Galactic Cosmic Ray protons the dose rate remains unchanged or is slightly increased.

Patient dose in diagnostic radiology is usually expressed in terms of organ dose and effective dose. The latter is used as a measure of the stochastic risk. Determinations of these doses are obtained by measurements (Thermoluminescent dosemeters) or by calculations (Monte Carlo simulation).

Conversion factors for the calculation of effective dose from dose-area product (DAP) values are commonly used to determine radiation dose in conventional x-ray imaging to realize radiation risks for different investigations, and for different ages. The exposure can easily be estimated by converting the DAP into an effective dose.

The aim of this study is to determine the conversion factor in procedures by computing the ratio between effective dose and DAP for fluoroscopic cardiac procedures in adults and for conventional lung and urography examinations in children.

Thermoluminescent dosemeters (TLD) were placed in an anthropomorphic phantom (Alderson Rando phantom) and child phantom (one year old) in order to measure the organ dose and compute the effective dose. A DAP meter was used to measure dose-area product.

MC calculations of radiation transport in mathematical anthropomorphic phantoms were used to obtain the effective dose for the same conditions with DAP as input data.

The deviation between the measured and calculated data was less than 10 %. The conversion factor for cardiac procedures varies between 0.19 mSvGy-1 cm-2 and 0.18 mSvGy-1 cm-2, for TLD respective MC. For paediatric simulation of a one year old phantom the average conversion factor for urography was 1.34 mSvGy-1 cm-2 and 1,48 mSvGy-1cm-2 for TLD respective MC. This conversion factor will decrease to 1.07 mSvGy-1 cm-2 using the TLD method, if the new ICRP (ICRP Publication 103) weighting factors were used to calculate the effective dose.

For lung investigations, the conversion factor for children was 1.75 mSvGy-1 cm-2 using TLD, while this value was 1.62 mSvGy-1 cm-2 using MC simulation. The conversion value increased to 2.02 mSvGy-1 cm-2 using ICRP’s new recommendation for tissue weighting factors and child phantom.

Purpose: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications.

Methods: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis.

Results: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections.

Conclusions: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.

Purpose: To quantify the radiobiological advantages obtained by an Improved Forward Planning technique (IFP) and two IMRT techniques using different fractionation schemes for the irradiation of head and neck tumours. The conventional radiation therapy technique (CONVT) was used here as a benchmark. Methods: Seven patients with head and neck tumours were selected for this retrospective planning study. The PTV1 included the primary tumour, PTV2 the high risk lymph nodes and PTV3 the low risk lymph nodes. Except for the conventional technique where a maximum dose of 64.8 Gy was prescribed to the PTV1, 70.2 Gy, 59.4 Gy and 50.4 Gy were prescribed respectively to PTV1, PTV2 and PTV3. Except for IMRT2, all techniques were delivered by three sequential phases. The IFP technique used five to seven directions with a total of 15 to 21 beams. The IMRT techniques used five to nine directions and around 80 segments. The first, IMRT1, was prescribed with the conventional fractionation scheme of 1.8 Gy per fraction delivered in 39 fractions by three treatment phases. The second, IMRT2, simultaneously irradiated the PTV2 and PTV3 with 59.4 Gy and 50.4 Gy in 28 fractions, respectively, while the PTV1 was boosted with six subsequent fractions of 1.8 Gy. Tissue response was calculated using the relative seriality model and the Poisson Linear-Quadratic-Time model to simulate repopulation in the primary tumour. Results: The average probability of total tumour control increased from 38% with CONVT to 80% with IFP, to 85% with IMRT1 and 89% with IMRT2. The shorter treatment time and larger dose per fraction obtained with IMRT2 resulted in an 11% increase in the probability of control in the PTV1 with respect to IFP and 7% relatively to IMRT1 (p < 0.05). The average probability of total patient complications was reduced from 80% with CONVT to 61% with IFP and 31% with IMRT. The corresponding probability of complications in the ipsilateral parotid was 63%, 42% and 20%; in the contralateral parotid it was 50%, 20% and 9%; in the oral cavity it was 2%, 15% and 4% and in the mandible it was 1%, 5% and 3%, respectively. Conclusions: A significant improvement in treatment outcome was obtained with IMRT compared to conventional radiation therapy. The practical and biological advantages of IMRT2, employing a shorter treatment time, may outweigh the small differences obtained in the organs at risk between the two IMRT techniques. This technique is therefore presently being used in the clinic for selected patients with head and neck tumours. A significant improvement in the quality of the dose distribution was obtained with IFP compared to CONVT. Thus, this beam arrangement is used in the clinical routine as an alternative to IMRT.

The protection of the unborn child in pregnant women from ionizing radiation is very important because the foetus is particularly sensitive to the effects of radiation. In case of pregnant members of staff working with ionising radiation, the unborn child is treated as a member of the general public, and a dose limit of 1 mSv during pregnancy is applied in order to protect the foetus.

The purpose of this work was to collect relevant information on exposure conditions and entrance doses of occupationally exposed workers in diagnostic radiology and nuclear medicine, and to give guidelines on how to estimate foetal doses for pregnant staff in such workplaces.

With X-ray procedures, an accumulated dose of 2 mSv during pregnancy, measured on the trunk (breast or waist) and behind a lead apron, is sufficient to ensure a foetal dose below 1 mSv. For staff working with nuclear medicine, the corresponding limit is 1.5 mSv taking into account external exposure from 99mTc. When internal contamination cannot be neglected, additional precautions need to be considered.

Purpose: The purpose of this work was to study the feasibility of a new inverse planning technique based on the generalized equivalent uniform dose for image-guided high dose rate (HDR) prostate cancer brachytherapy in comparison to conventional dose-volume based optimization. Methods: The quality of 12 clinical HDR brachytherapy implants for prostate utilizing HIPO (Hybrid Inverse Planning Optimization) is compared with alternative plans, which were produced through inverse planning using the generalized equivalent uniform dose (gEUD). All the common dose-volume indices for the prostate and the organs at risk were considered together with radiobiological measures. The clinical effectiveness of the different dose distributions was investigated by comparing dose volume histogram and gEUD evaluators. Results: Our results demonstrate the feasibility of gEUD-based inverse planning in HDR brachytherapy implants for prostate. A statistically significant decrease in D-10 or/and final gEUD values for the organs at risk (urethra, bladder, and rectum) was found while improving dose homogeneity or dose conformity of the target volume. Conclusions: Following the promising results of gEUD-based optimization in intensity modulated radiation therapy treatment optimization, as reported in the literature, the implementation of a similar model in HDR brachytherapy treatment plan optimization is suggested by this study. The potential of improved sparing of organs at risk was shown for various gEUD-based optimization parameter protocols, which indicates the ability of this method to adapt to the user's preferences.

A method to establish the boundaries of the sensitive volume for a chosen detector to within 50µm (as specified by Elekta Instuments AB) was investigated and is presented in this project. The detector studied was fixed to a positioning system with possibility to move with sub micrometer increments, and scanned in a narrow photon field. The detectors used for the experiment were silicon diodes and a pair of diamond detectors. The silicon diodes showed great promise for future study; two radiotherapy silicon diodes and one electrical component silicon diode were used. The electrical component silicon diode produced a surprisingly sharp dose profile compared with the medical silicon diodes. The diamond detectors gave no stable results at all.

As a radiation source 60Co proved most feasible, but a diagnostic x-ray source was also tested as well as a 99mTc source. These radiation sources were also examined with a modified Penelope code, i.e. Monte Carlo simulations. What became very obvious with the Monte Carlo simulations was the importance of the line up, which was never satisfactory.

To limit the sensitive volume of these detectors to within the desired boundaries showed great difficulty and was not achieved in this project.