Techniques médicales en plein essor suscitant d’importants espoirs thérapeutiques, les radiothérapies internes vectorisées (RIV) consistent à administrer un radiopharmaceutique pour traiter sélectivement les tumeurs. A l’heure actuelle, l’activité injectée au patient est généralement standardisée. Cependant, afin d’établir des relations dose-effet robustes et d’optimiser le traitement en préservant au mieux les tissus sains, une dosimétrie personnalisée doit être réalisée, à l’image des pratiques cliniques existant en radiothérapie externe. Dans ce cadre, l’objectif de la thèse était de développer, à l’aide du logiciel OEDIPE, une méthode de dosimétrie personnalisée reposant sur des calculs Monte Carlo directs. La méthode mise au point permet de calculer la distribution tridimensionnelle des doses absorbées en fonction de l’anatomie du patient, définie à l’aide d’images TDM ou IRM, ainsi que de la biodistribution de l’activité spécifique au patient, définie à partir de données d’émission TEMP ou TEP. Des aspects radiobiologiques, tels que les différences de radiosensibilité et de vitesse de réparation entre les tissus sains et les lésions tumorales, ont également été intégrés par l’intermédiaire du modèle linéaire-quadratique. Cette méthode a été appliquée à la radiothérapie interne sélective (SIRT) qui consiste à injecter des 90Y-microsphères pour traiter sélectivement les cancers hépatiques inopérables. Les distributions des doses absorbées et doses biologiques efficaces (BED) ainsi que les doses biologiques efficaces équivalentes uniformes (EUD) aux lésions hépatiques ont été calculées à partir des distributions d’activité de l’étape d’évaluation aux 99mTc-MAA pour 18 patients traités à l’hôpital européen Georges Pompidou. Ces résultats ont été comparés aux méthodes classiques utilisées en clinique et l’intérêt d’une dosimétrie précise et personnalisée pour la planification de traitement a été étudié. D’une part, la possibilité d’augmenter l’activité de manière personnalisée a été mise en évidence par le calcul de l’activité maximale injectable au patient en fonction de critères de tolérance donnés aux organes à risque. D’autre part, l’utilisation des grandeurs radiobiologiques a également permis d’évaluer l’apport potentiel de protocoles fractionnés en SIRT. L’outil développé peut donc être utilisé comme aide à l’optimisation des plans de traitement. En outre, une étude a été initiée en vue d’améliorer la reconstruction des données post-traitement de la TEMP-90Y. L’évaluation à partir de ces données des doses délivrées lors du traitement pourra permettre, d’une part, de prédire le contrôle tumoral et d’anticiper le risque de toxicité aux tissus sains et, d’autre part, d’établir des relations dose-effet précises pour ces traitements. / Medical techniques in full expansion arousing high therapeutic expectations, targeted radionuclide therapies (TRT) consist of administering a radiopharmaceutical to selectively treat tumors. Nowadays, the activity injected to the patient is generally standardized. However, in order to establish robust dose-effect relationships and to optimize treatments while sparing healthy tissues at best, a personalized dosimetry must be performed, just like actual clinical practice in external beam radiotherapy. In that context, this PhD main objective was to develop, using the OEDIPE software, a methodology for personalized dosimetry based on direct Monte Carlo calculations. The developed method enables to calculate the tridimensional distribution of absorbed doses depending on the patient anatomy, defined from CT or MRI data, and on the patient-specific activity biodistribution, defined from SPECT or PET data. Radiobiological aspects, such as differences in radiosensitivities and repair time constants between tumoral and healthy tissues, have also been integrated through the linear-quadratic model. This methodology has been applied to the selective internal radiation therapy (SIRT) which consists in the injection of 90Y-microspheres to selectively treat unresectable hepatic cancers. Distributions of absorbed doses and biologically effective doses (BED) along with the equivalent uniform biologically effective doses (EUD) to hepatic lesions have been calculated from 99mTc-MAA activity distributions obtained during the evaluation step for 18 patients treated at hôpital européen Georges Pompidou. Those results have been compared to classical methods used in clinics and the interest of accurate and personalized dosimetry for treatment planning has been investigated. On the one hand, the possibility to increase the activity in a personalized way has been highlighted with the calculation of the maximal activity that could be injected to the patient while meeting tolerance criteria on organs at risk. On the other hand, the use of radiobiological quantities has also enabled to evaluate the potential added value of fractionated protocols in SIRT. The developed tool can thus be used as a help for the optimization of treatment plans. Moreover, a study has been initiated to improve the reconstruction of post-treatment data from 90Y-SPECT. The estimation from those data of doses delivered during treatment could allow to predict tumoral control and to anticipate healthy tissues toxicity as well as to establish precise dose-effect relationships for those treatments.

Radiation therapy (RT) is commonly used to treat patients with lung cancer. One of the limitations of RT is that irradiation of the surrounding healthy lung tissues during RT may cause damage to the lungs. Radiation-induced pulmonary toxicity may be mitigated by minimizing doses to high-function lung tissues, which we refer to as functional avoidance RT. Lung function can be computed by image registration of treatment planning four-dimensional computed tomography (4DCT), which we refer to as CT ventilation imaging. However, the accuracy of functional avoidance RT is limited by lung function imaging accuracy and artifacts in 4DCT. The goal of this dissertation is to improve the accuracy of functional avoidance RT by overcoming those two limitations. A common method for estimating lung ventilation uses image registration to align the peak exhale and inhale 3DCT images. This approach called the 2-phase local expansion ratio is limited because it assumes no out-of-phase lung ventilation and may underestimate local lung ventilation. Out-of-phase ventilation occurs when regions of the lung reach their maximum (minimum) local volume in a phase other than the peak of inhalation (end of exhalation). This dissertation presents a new method called the N-phase local expansion ratio for detecting and characterizing locations of the lung that experience out-of-phase ventilation. The N-phase LER measure uses all 4DCT phases instead of two peak phases to estimate lung ventilation. Results show that out-of-phase breathing was common in the lungs and that the spatial distribution of out-of-phase ventilation varied from subject to subject. On average, 49% of the out-of-phase regions were mislabeled as low-function by the 2-phase LER. 4DCT and Xenon-enhanced CT (Xe-CT) of four sheep were used to evaluate the accuracy of 2-phase LER and N-phase LER. Results show that the N-phase LER measure was more correlated with the Xe-CT than the 2-phase LER measure. These results suggest that it may be better to use all 4DCT phases instead of the two peak phases to estimate lung function. The accuracy of functional avoidance RT may also be improved by reducing the impact of artifacts in 4DCT. In this dissertation, we propose a a geodesic density regression (GDR) algorithm to correct artifacts in one breathing phase by using artifact-free data in corresponding regions of the other breathing phases. Local tissue density change associated with CT intensity change during respiration is accommodated in the GDR algorithm. Binary artifact masks are used to exclude regions of artifacts from the regression, i.e., the GDR algorithm only uses artifact-free data. The GDR algorithm estimates an artifact-free CT template image and its time flow through a respiratory cycle. Evaluation of the GDR algorithm was performed using both 2D CT time-series images with simulated known motion artifacts and treatment planning 4DCT with real motion artifacts. The 2D results show that there is no significant difference (p-value = 0.95) between GDR regression of artifact data using artifact masks and regression of artifact-free data. In contrast, significant errors (p-value = 0.005) were present in the estimated Jacobian images when artifact masks were not used. We also demonstrated the effectiveness of the GDR algorithm for removing real duplication, misalignment, and interpolation artifacts in 4DCT. Overall this dissertation proposes methods that have the potential to improve functional avoidance RT by accommodating out-of-phase ventilation, and removing motion artifacts in 4DCT using geodesic image regression.

With the introduction of four dimensional-computed tomography (4DCT), treatment centers are now better able to account for respiration-induced uncertainty in radiation therapy treatment planning for lung cancer. We examined two practices in which 4DCT is used in radiotherapy. Our first study investigated the dosimetric uncertainty in four-dimensional (4D) dose calculation using three temporal probability distributions: 1) uniform distribution, 2) sinusoidal distribution, and 3) patient-specific distribution derived from the respiratory trace. Four-dimensional dose was evaluated in nine lung cancer patients. First, dose was computed for each of 10 binned CTs using 4DCT and deformable image registration. Next, the 10 deformed doses were summed together using one of three temporal probability distributions. To compare the two approximated 4D dose calculations to the 4D calculation derived using the patient's respiratory trace, 3D gamma analysis was performed using a tolerance criteria of 3% dose difference and 3mm distance to agreement. Additionally, mean lung dose (MLD), mean tumor dose (MTD), and lung V20 were used to assess clinical impact. For all patients, both uniform and sinusoidal dose distributions were found to have an average gamma passing rate >99% for both the lung and PTV volumes. Compared with 4D dose calculated using the patient respiratory trace, uniform distribution and sinusoidal distribution showed a percentage difference on average of -0.1±0.6% and -0.2±0.4% in MTD, -0.2±2.0% and -0.2±1.3% in MLD, 0.9±2.8% and -0.7±1.8% in lung V20, respectively. We concluded that 4D dose computed using either a uniform or sinusoidal temporal probability distribution is able to approximate 4D dose computed using the patient-specific respiratory trace. Our second study evaluated the dosimetric and temporal effects of respiratory gated radiation therapy using four different gating windows (20EX-20IN, 40EX-40IN, 60EX-60IN, and 80EX-80IN) and estimated the corresponding treatment delivery times for normal (500MU/min) and high (1500MU/min) dose rates. Five patients (3 non-gated, 2 gated 80EX-80IN) were retrospectively evaluated. For each patient, four individual treatment plans corresponding to the four different gating windows were created, and treatment delivery time for each plan was estimated using a MATLAB (MathWorks, Natick, MA) algorithm. Results showed that smaller gating windows reduced PTV volume, mean lung dose, and lung V20, while maintaining mean tumor dose and PTV coverage. Treatment times for gated plans were longer when dose rate was unchanged, however, increased dose rates were shown to achieve treatment times comparable to or faster than non-gated delivery times. We concluded that gated radiation therapy in lung cancer patients could potentially reduce lung toxicity, while as effectively treating the target volume. Furthermore, increased dose rates with gated radiation therapy are able to provide treatment times comparable to non-gated treatment.

Intensity-modulated brachytherapy techniques, compensator-based intensity modulated brachytherapy (CBT) and interstitial rotating shield brachytherapy (I-RSBT), are two novel conceptual radiation therapies for treating cervical and prostate cancer, respectively. Compared to conventional brachytherapy techniques for treating cervical cancer, CBT can potentially improve the dose conformity to the high-risk clinical target volume (CTV) of the cervix in a less invasive approach. I-RSBT can reduce the dose delivered to the prostate organ at risks (OARs) with the same radiation dose delivered to the prostate CTV. In this work, concepts and prototypes for CBT and I-RSBT were introduced and developed. Preliminary dosimetric measurements were performed for CBT and I-RSBT, respectively. A CBT prototype system was constructed and experimentally validated. A prototype cylindrical compensator with eight octants, each with different thicknesses, was designed. Direct metal laser sintering (DMLS) was used to construct CoCr and Ti compensator prototypes, and a 4-D milling technique was used to construct a Ti compensator prototype. Gafchromic EBT2 films, held by an acrylic quality assurance (QA) phantom, were irradiated to approximately 125 cGy with an electronic brachytherapy (eBT) source for both shielded and unshielded cases. The dose at each point on the films were calculated using a TG-43 calculation model that was modified to account for the presence of a compensator prototype by ray-tracing. With I-RSBT, a multi-pass dose delivery mechanism with prototypes was developed. Dosimetric measurements for a Gd-153 radioisotope was performed to demonstrate that using multiple partially shielded Gd-153 sources for I-RSBT is feasible. A treatment planning model was developed for applying I-RSBT clinically. A custom-built, stainless steel encapsulated 150 mCi Gd-153 capsule with an outer length of 12.8 mm, outer diameter of 2.10 mm, active length of 9.98 mm, and active diameter of 1.53 mm was used. A partially shielded catheter was constructed with a 500 micron platinum shield and a 500 micron aluminum emission window, both with 180° azimuthal coverage. An acrylic phantom was constructed to measure the dose distributions from the shielded catheter in the transverse plane using Gafchromic EBT3 films. Film calibration curves were generated from 50, 70, and 100 kVp x-ray beams with NIST-traceable air kerma values to account for energy variation. In conclusion, CBT, which is a non-invasive alternative to supplementary interstitial brachytherapy, is expected to improve dose conformity to bulky cervical tumors relative to conventional intracavitary brachytherapy. However, at the current stage, it would be time-consuming to construct a patient-specific compensator using DMLS, and the quality assurance of the compensator would be difficult. I-RSBT is a promising approach to reducing radiation dose delivered to prostate OARs. The next step in making Gd-153 based I-RSBT feasible in clinic is developing a Gd-153 source that is small enough such that the source, shield, and catheter all fit within a 16 guage needle, which has a 1.65 mm diameter.

The radiation dose in radiation therapy is mainly measured by ion chamber. The ion chamber measurement will not be accurate if there is not enough phantom material surrounding the ion chamber to provide the electron equilibrium condition. The lack of electron equilibrium will cause a reduction of dose. This may introduce problems in treatment planning. Because some planning algorithms cannot predict the reduction, they over estimate the dose in the region. Electron disequilibrium will happen when the radiation field size is too small or the density of irradiated material is too low to provide sufficient electrons going into the dose volume. The amount of tissue required to provide electron equilibrium in a 6MV photon beam by three methods: direct calculation from Klein-Nisina equation, measurement in low density material phantom and a Monte Carlo simulation is done to compare with the measurement, an indirect method from a planning algorithm which does not provide an accurate result under lateral electron disequilibrium. When the error starts to happen in such planning algorithm, we know that the electron equilibrium conditions does not exist. Only the 6MV photon beam is investigated. This is because in most cases, a 6MV small fields are used for head and neck (larynx cavity) and 6MV fields are commonly used for lung to minimise uncertainity due to lateral electron at higher energies. / Master of Science (Hons)

<p>Radiation quality is described by the RBE (relative biological effectiveness) that varies with the ionizing ability of the radiation. Microdosimetric quantities describe distributions of energy imparted to small volumes and can be related to RBE. This has made microdosimetry a powerful tool for radiation quality determinations in both radiation protection and radiation therapy. The variance-covariance method determines the dose-average of the distributions and has traditionally been used with two detectors to correct for beam intensity variations. Methods to separate dose components in mixed radiation fields and to correct for beam variations using only one detector have been developed in this thesis. Quality factor relations have been optimized for different neutron energies, and a new algorithm that takes single energy deposition events from densely ionizing radiation into account has been formulated. The variance-covariance technique and the new methodology have been shown to work well in the cosmic radiation field onboard aircraft, in the mixed photon and neutron fields in the nuclear industry and in pulsed fields around accelerators.</p><p>The method has also been used for radiation quality characterization in therapy beams. The biological damage is related to track-structure and ionization clusters and requires descriptions of the energy depositions in nanometre sized volumes. It was shown that both measurements and Monte Carlo simulation (condensed history and track-structure) are needed for a reliable nanodosimetric beam characterization. The combined experimental and simulated results indicate that the dose-mean of the energy imparted to an object in the nanometre region is related to the clinical RBE in neutron, proton and photon beams. The results suggest that the variance-covariance technique and the dose-average of the microdosimetric quantities could be well suited for describing radiation quality also in therapy beams.</p>

<p>The Swedish Cancer Register was used to determine the relative survival rate in colon and rectal cancer and to estimate the occurrence of second cancers related to radiation therapy for rectal cancer. The Swedish Hospital Discharge Register and hospital records were used to estimate the rate of late adverse effects due to radiation therapy for rectal cancer. The whole Swedish population was the source of the survival studies. Patients participating in the Uppsala Trial and the Swedish Rectal Cancer Trial on radiation therapy for rectal cancer constituted the subjects of the studies on late adverse effects and second cancers.</p><p>The main results of the survival analysis revealed a significant improvement in the 5-year relative survival rate for both colon and rectal cancer. During the time period 1960-1999, the survival improved from 39.6% to 57.2% in colon cancer and from 36.1% to 57.6% in rectal cancer.</p><p>Patients irradiated for rectal cancer, in addition to surgery, were at increased risk for a second cancer compared to those treated by surgery alone. This risk increase was mainly found for cancers developing in organs within or adjacent to the irradiated target (relative risk (RR) 2.04; 95% confidence interval (CI) 1.10–3.79). Furthermore, the most important late adverse effects of radiation therapy seem to be those on the gastrointestinal tract, in the form of small bowel obstruction (RR 1.88; 95%CI 1.10–3.20) and abdominal pain (RR 1.92; 95% CI 1.14–3.23). Overall, the benefit of radiation therapy was greater than its drawbacks, as a large reduction in local recurrences and better survival was noted in patients treated preoperatively with irradiation for rectal cancer.</p><p>In conclusion, significant improvements in the survival of patients with colon and rectal cancers have occurred in the last decades, especially in patients with rectal cancer. These improvements probably are related to advances in surgical and adjuvant treatment. The radiation therapy has several drawbacks, however, including an increased risk of second cancers and of bowel obstruction. This emphasises the need to further improve the radiation technique and to select only those patients for radiation therapy who are most likely to benefit from it.</p>

Real time image guided radiotherapy has been proposed by integrating an in-line 6 MV linear accelerator (linac) to a magnetic resonance (MR) imager in either a parallel or transverse configuration. In either configuration, magnetic interference in the linac is caused by its immersion in the magnetic fringe fields of the MR imager. Thus in order to minimize the effect of the magnetic interference, investigations on linac performance in external magnetic fields was completed through various simulations. Finite difference and finite element methods as well as particle simulations were performed in order to design an electron gun and an in-line 6 MV linac waveguide. Monte Carlo simulations provided calculations of dose distributions in a water tank from the derived electron phase space at the linac target. The entire simulation was validated against measurements taken from a commercial medical in-line 6 MV linac, other simulation programs, and theory. The validated linac simulation was used to investigate linac performance in external magnetic fields. The results of this investigation showed that the linac had a much lower tolerance to transverse magnetic fields compared to longitudinal fields. While transverse magnetic fields caused a global deflection of the electron beam away from the central axis of the waveguide, longitudinal fields changed the optics of the electron gun in a suboptimal way. Both transverse and longitudinal magnetic fields caused excessive beam loss if the field strength was large enough. Heating caused by excessive beam loss in external magnetic fields was shown to have little effect on the resonant frequency of the waveguide, and any change in dosimetry, if it existed, was shown to be easily corrected using the jaws or multileaf collimators (MLCs). It was determined that the low-field parallel configuration linac-MR system investigated did not require any magnetic shielding, so the focus was on shielding the transverse configuration. Using beam loss, MLC motor tolerance to magnetic fields, and MR imager homogeneity as constraints, passive and active magnetic shielding was designed and optimized. Thus through the parallel configuration, or using magnetic shielding, magnetic interference has been reduced to within the linac operational tolerance. / Medical Physics

The Swedish Cancer Register was used to determine the relative survival rate in colon and rectal cancer and to estimate the occurrence of second cancers related to radiation therapy for rectal cancer. The Swedish Hospital Discharge Register and hospital records were used to estimate the rate of late adverse effects due to radiation therapy for rectal cancer. The whole Swedish population was the source of the survival studies. Patients participating in the Uppsala Trial and the Swedish Rectal Cancer Trial on radiation therapy for rectal cancer constituted the subjects of the studies on late adverse effects and second cancers. The main results of the survival analysis revealed a significant improvement in the 5-year relative survival rate for both colon and rectal cancer. During the time period 1960-1999, the survival improved from 39.6% to 57.2% in colon cancer and from 36.1% to 57.6% in rectal cancer. Patients irradiated for rectal cancer, in addition to surgery, were at increased risk for a second cancer compared to those treated by surgery alone. This risk increase was mainly found for cancers developing in organs within or adjacent to the irradiated target (relative risk (RR) 2.04; 95% confidence interval (CI) 1.10–3.79). Furthermore, the most important late adverse effects of radiation therapy seem to be those on the gastrointestinal tract, in the form of small bowel obstruction (RR 1.88; 95%CI 1.10–3.20) and abdominal pain (RR 1.92; 95% CI 1.14–3.23). Overall, the benefit of radiation therapy was greater than its drawbacks, as a large reduction in local recurrences and better survival was noted in patients treated preoperatively with irradiation for rectal cancer. In conclusion, significant improvements in the survival of patients with colon and rectal cancers have occurred in the last decades, especially in patients with rectal cancer. These improvements probably are related to advances in surgical and adjuvant treatment. The radiation therapy has several drawbacks, however, including an increased risk of second cancers and of bowel obstruction. This emphasises the need to further improve the radiation technique and to select only those patients for radiation therapy who are most likely to benefit from it.

Radiation quality is described by the RBE (relative biological effectiveness) that varies with the ionizing ability of the radiation. Microdosimetric quantities describe distributions of energy imparted to small volumes and can be related to RBE. This has made microdosimetry a powerful tool for radiation quality determinations in both radiation protection and radiation therapy. The variance-covariance method determines the dose-average of the distributions and has traditionally been used with two detectors to correct for beam intensity variations. Methods to separate dose components in mixed radiation fields and to correct for beam variations using only one detector have been developed in this thesis. Quality factor relations have been optimized for different neutron energies, and a new algorithm that takes single energy deposition events from densely ionizing radiation into account has been formulated. The variance-covariance technique and the new methodology have been shown to work well in the cosmic radiation field onboard aircraft, in the mixed photon and neutron fields in the nuclear industry and in pulsed fields around accelerators. The method has also been used for radiation quality characterization in therapy beams. The biological damage is related to track-structure and ionization clusters and requires descriptions of the energy depositions in nanometre sized volumes. It was shown that both measurements and Monte Carlo simulation (condensed history and track-structure) are needed for a reliable nanodosimetric beam characterization. The combined experimental and simulated results indicate that the dose-mean of the energy imparted to an object in the nanometre region is related to the clinical RBE in neutron, proton and photon beams. The results suggest that the variance-covariance technique and the dose-average of the microdosimetric quantities could be well suited for describing radiation quality also in therapy beams.