A 3-D CT assisted Monte Carlo evaluation of intracavitary brachytherapy implants

Intracavitary brachytherapy (ICB) combined with external beam irradiation for treatment of cervical cancer is highly successful in achieving local control. The M.D. Anderson Cancer Center employs Fletcher Suit Delclos (FSD) applicators. FSD applicators contain shields to limit dose to critical structures. Dosimetric evaluation of ICB implants is limited to assessing dose at reference points. These points serve as surrogates for treatment intensity and critical structure dose. Several studies have mentioned that the ICRU38 reference points inadequately characterize the dose distribution. Also, the ovoid shields are rarely considered in dosimetry. ^ The goal of this dissertation was to ascertain the influence of the ovoid shields on patient dose distributions. Monte Carlo dosimetry (MCD) was applied to patient computed tomography(CT) scans. These data were analyzed to determine the effect of the shields on dose to standard reference points and the bladder and rectum. The hypothesis of this work is that the ICRU38 bladder and rectal points computed conventionally are not clinically acceptable surrogates for the maximum dose points as determined by MCD. ^ MCD was applied to the tandem and ovoids. The FSD ovoids and tandem were modeled in a single input file that allowed dose to be calculated for any patient. Dose difference surface histograms(DDSH) were computed for the bladder and rectum. Reference point doses were compared between shielded and unshielded ovoids, and a commercial treatment planning system. ^ The results of this work showed the tandem tip screw caused a 33% reduction in dose. The ovoid shields reduced the dose by a maximum of 48.9%. DDSHs revealed on average 5% of the bladder surface area was spared 53 cGy and 5% of the rectal surface area was spared 195 cGy. The ovoid shields on average reduced the dose by 18% for the bladder point and 25% for the rectal point. The Student's t-test revealed the ICRU38 bladder and rectal points do not predict the maximum dose for these organs. ^ It is concluded that modeling the tandem and ovoid internal structures is necessary for accurate dose calculations, the bladder shielding segments may not be necessary, and that the ICRU38 bladder point is irrelevant. ^

Investigation of arterial spin labeling MRI for quantitative cerebral blood flow measurement

Arterial spin labeling (ASL) is a technique for noninvasively measuring cerebral perfusion using magnetic resonance imaging. Clinical applications of ASL include functional activation studies, evaluation of the effect of pharmaceuticals on perfusion, and assessment of cerebrovascular disease, stroke, and brain tumor. The use of ASL in the clinic has been limited by poor image quality when large anatomic coverage is required and the time required for data acquisition and processing. This research sought to address these difficulties by optimizing the ASL acquisition and processing schemes. To improve data acquisition, optimal acquisition parameters were determined through simulations, phantom studies and in vivo measurements. The scan time for ASL data acquisition was limited to fifteen minutes to reduce potential subject motion. A processing scheme was implemented that rapidly produced regional cerebral blood flow (rCBF) maps with minimal user input. To provide a measure of the precision of the rCBF values produced by ASL, bootstrap analysis was performed on a representative data set. The bootstrap analysis of single gray and white matter voxels yielded a coefficient of variation of 6.7% and 29% respectively, implying that the calculated rCBF value is far more precise for gray matter than white matter. Additionally, bootstrap analysis was performed to investigate the sensitivity of the rCBF data to the input parameters and provide a quantitative comparison of several existing perfusion models. This study guided the selection of the optimum perfusion quantification model for further experiments. The optimized ASL acquisition and processing schemes were evaluated with two ASL acquisitions on each of five normal subjects. The gray-to-white matter rCBF ratios for nine of the ten acquisitions were within ±10% of 2.6 and none were statistically different from 2.6, the typical ratio produced by a variety of quantitative perfusion techniques. Overall, this work produced an ASL data acquisition and processing technique for quantitative perfusion and functional activation studies, while revealing the limitations of the technique through bootstrap analysis. ^

Monte Carlo and analytical dose calculations for ocular proton therapy

Uveal melanoma is a rare but life-threatening form of ocular cancer. Contemporary treatment techniques include proton therapy, which enables conservation of the eye and its useful vision. Dose to the proximal structures is widely believed to play a role in treatment side effects, therefore, reliable dose estimates are required for properly evaluating the therapeutic value and complication risk of treatment plans. Unfortunately, current simplistic dose calculation algorithms can result in errors of up to 30% in the proximal region. In addition, they lack predictive methods for absolute dose per monitor unit (D/MU) values. ^ To facilitate more accurate dose predictions, a Monte Carlo model of an ocular proton nozzle was created and benchmarked against measured dose profiles to within ±3% or ±0.5 mm and D/MU values to within ±3%. The benchmarked Monte Carlo model was used to develop and validate a new broad beam dose algorithm that included the influence of edgescattered protons on the cross-field intensity profile, the effect of energy straggling in the distal portion of poly-energetic beams, and the proton fluence loss as a function of residual range. Generally, the analytical algorithm predicted relative dose distributions that were within ±3% or ±0.5 mm and absolute D/MU values that were within ±3% of Monte Carlo calculations. Slightly larger dose differences were observed at depths less than 7 mm, an effect attributed to the dose contributions of edge-scattered protons. Additional comparisons of Monte Carlo and broad beam dose predictions were made in a detailed eye model developed in this work, with generally similar findings. ^ Monte Carlo was shown to be an excellent predictor of the measured dose profiles and D/MU values and a valuable tool for developing and validating a broad beam dose algorithm for ocular proton therapy. The more detailed physics modeling by the Monte Carlo and broad beam dose algorithms represent an improvement in the accuracy of relative dose predictions over current techniques, and they provide absolute dose predictions. It is anticipated these improvements can be used to develop treatment strategies that reduce the incidence or severity of treatment complications by sparing normal tissue. ^

Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. ^ In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. ^ Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. ^ In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image-guided patient setup in conjunction with treatment delivery using respiratory gating reduces these uncertainties in tumor locations. In doing so, margins around the tumor used to generate the PTV can be reduced, which may allow for dose escalation to the tumor. ^

Electron intensity modulation for mixed-beam radiation therapy with an x-ray multi-leaf collimator

The current standard treatment for head and neck cancer at our institution uses intensity-modulated x-ray therapy (IMRT), which improves target coverage and sparing of critical structures by delivering complex fluence patterns from a variety of beam directions to conform dose distributions to the shape of the target volume. The standard treatment for breast patients is field-in-field forward-planned IMRT, with initial tangential fields and additional reduced-weight tangents with blocking to minimize hot spots. For these treatment sites, the addition of electrons has the potential of improving target coverage and sparing of critical structures due to rapid dose falloff with depth and reduced exit dose. In this work, the use of mixed-beam therapy (MBT), i.e., combined intensity-modulated electron and x-ray beams using the x-ray multi-leaf collimator (MLC), was explored. The hypothesis of this study was that addition of intensity-modulated electron beams to existing clinical IMRT plans would produce MBT plans that were superior to the original IMRT plans for at least 50% of selected head and neck and 50% of breast cases. Dose calculations for electron beams collimated by the MLC were performed with Monte Carlo methods. An automation system was created to facilitate communication between the dose calculation engine and the treatment planning system. Energy and intensity modulation of the electron beams was accomplished by dividing the electron beams into 2x2-cm2 beamlets, which were then beam-weight optimized along with intensity-modulated x-ray beams. Treatment plans were optimized to obtain equivalent target dose coverage, and then compared with the original treatment plans. MBT treatment plans were evaluated by participating physicians with respect to target coverage, normal structure dose, and overall plan quality in comparison with original clinical plans. The physician evaluations did not support the hypothesis for either site, with MBT selected as superior in 1 out of the 15 head and neck cases (p=1) and 6 out of 18 breast cases (p=0.95). While MBT was not shown to be superior to IMRT, reductions were observed in doses to critical structures distal to the target along the electron beam direction and to non-target tissues, at the expense of target coverage and dose homogeneity. ^

Proton therapy versus intensity modulated x-ray therapy in the treatment of prostate cancer: Estimating secondary cancer risks

External beam radiation therapy is used to treat nearly half of the more than 200,000 new cases of prostate cancer diagnosed in the United States each year. During a radiation therapy treatment, healthy tissues in the path of the therapeutic beam are exposed to high doses. In addition, the whole body is exposed to a low-dose bath of unwanted scatter radiation from the pelvis and leakage radiation from the treatment unit. As a result, survivors of radiation therapy for prostate cancer face an elevated risk of developing a radiogenic second cancer. Recently, proton therapy has been shown to reduce the dose delivered by the therapeutic beam to normal tissues during treatment compared to intensity modulated x-ray therapy (IMXT, the current standard of care). However, the magnitude of stray radiation doses from proton therapy, and their impact on this incidence of radiogenic second cancers, was not known. ^ The risk of a radiogenic second cancer following proton therapy for prostate cancer relative to IMXT was determined for 3 patients of large, median, and small anatomical stature. Doses delivered to healthy tissues from the therapeutic beam were obtained from treatment planning system calculations. Stray doses from IMXT were taken from the literature, while stray doses from proton therapy were simulated using a Monte Carlo model of a passive scattering treatment unit and an anthropomorphic phantom. Baseline risk models were taken from the Biological Effects of Ionizing Radiation VII report. A sensitivity analysis was conducted to characterize the uncertainty of risk calculations to uncertainties in the risk model, the relative biological effectiveness (RBE) of neutrons for carcinogenesis, and inter-patient anatomical variations. ^ The risk projections revealed that proton therapy carries a lower risk for radiogenic second cancer incidence following prostate irradiation compared to IMXT. The sensitivity analysis revealed that the results of the risk analysis depended only weakly on uncertainties in the risk model and inter-patient variations. Second cancer risks were sensitive to changes in the RBE of neutrons. However, the findings of the study were qualitatively consistent for all patient sizes and risk models considered, and for all neutron RBE values less than 100. ^

In-vivo diffusion tensor imaging of rat spinal cord with a phased array coil at 7T

Magnetic resonance imaging (MRI) is a non-invasive technique that offers excellent soft tissue contrast for characterizing soft tissue pathologies. Diffusion tensor imaging (DTI) is an MRI technique that has shown to have the sensitivity to detect subtle pathology that is not evident on conventional MRI. ^ Rats are commonly used as animal models in characterizing the spinal cord pathologies including spinal cord injury (SCI), cancer, multiple sclerosis, etc. These pathologies could affect both thoracic and cervical regions and complete characterization of these pathologies using MRI requires DTI characterization in both the thoracic and cervical regions. Prior to the application of DTI for investigating the pathologic changes in the spinal cord, it is essential to establish DTI metrics in normal animals. ^ To date, in-vivo DTI studies of rat spinal cord have used implantable coils for high signal-to-noise ratio (SNR) and spin-echo pulse sequences for reduced geometric distortions. Implantable coils have several disadvantages including: (1) the invasive nature of implantation, (2) loss of SNR due to frequency shift with time in the longitudinal studies, and (3) difficulty in imaging the cervical region. While echo planar imaging (EPI) offers much shorter acquisition times compared to spin-echo imaging, EPI is very sensitive to static magnetic field inhomogeneities and the existing shimming techniques implemented on the MRI scanner do not perform well on spinal cord because of its geometry. ^ In this work, an integrated approach has been implemented for in-vivo DTI characterization of rat spinal cord in the thoracic and cervical regions. A three element phased array coil was developed for improved SNR and extended spatial coverage. A field-map shimming technique was developed for minimizing the geometric distortions in EPI images. Using these techniques, EPI based DWI images were acquired with optimized diffusion encoding scheme from 6 normal rats and the DTI-derived metrics were quantified. ^ The phantom studies indicated higher SNR and smaller bias in the estimated DTI metrics than the previous studies in the cervical region. In-vivo results indicated no statistical difference in the DTI characteristics of either gray matter or white matter between the thoracic and cervical regions. ^

Improved Techniques for Acquisition and Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Detecting Vascular Permeability in the Central Nervous System

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique for quantitative assessment of the integrity of blood-brain barrier and blood-spinal cord barrier (BSCB) in the presence of central nervous system pathologies. However, the results of DCE-MRI show substantial variability. The high variability can be caused by a number of factors including inaccurate T1 estimation, insufficient temporal resolution and poor contrast-to-noise ratio. My thesis work is to develop improved methods to reduce the variability of DCE-MRI results. To obtain fast and accurate T1 map, the Look-Locker acquisition technique was implemented with a novel and truly centric k-space segmentation scheme. In addition, an original multi-step curve fitting procedure was developed to increase the accuracy of T1 estimation. A view sharing acquisition method was implemented to increase temporal resolution, and a novel normalization method was introduced to reduce image artifacts. Finally, a new clustering algorithm was developed to reduce apparent noise in the DCE-MRI data. The performance of these proposed methods was verified by simulations and phantom studies. As part of this work, the proposed techniques were applied to an in vivo DCE-MRI study of experimental spinal cord injury (SCI). These methods have shown robust results and allow quantitative assessment of regions with very low vascular permeability. In conclusion, applications of the improved DCE-MRI acquisition and analysis methods developed in this thesis work can improve the accuracy of the DCE-MRI results.

Evaluation of PRESAGE® dosimeters for brachytherapy sources and the 3D dosimetry and characterization of the new AgX100 125I seed model

With continuous new improvements in brachytherapy source designs and techniques, method of 3D dosimetry for treatment dose verifications would better ensure accurate patient radiotherapy treatment. This study was aimed to first evaluate the 3D dose distributions of the low-dose rate (LDR) Amersham 6711 OncoseedTM using PRESAGE® dosimeters to establish PRESAGE® as a suitable brachytherapy dosimeter. The new AgX100 125I seed model (Theragenics Corporation) was then characterized using PRESAGE® following the TG-43 protocol. PRESAGE® dosimeters are solid, polyurethane-based, 3D dosimeters doped with radiochromic leuco dyes that produce a linear optical density response to radiation dose. For this project, the radiochromic response in PRESAGE® was captured using optical-CT scanning (632 nm) and the final 3D dose matrix was reconstructed using the MATLAB software. An Amersham 6711 seed with an air-kerma strength of approximately 9 U was used to irradiate two dosimeters to 2 Gy and 11 Gy at 1 cm to evaluate dose rates in the r=1 cm to r=5 cm region. The dosimetry parameters were compared to the values published in the updated AAPM Report No. 51 (TG-43U1). An AgX100 seed with an air-kerma strength of about 6 U was used to irradiate two dosimeters to 3.6 Gy and 12.5 Gy at 1 cm. The dosimetry parameters for the AgX100 were compared to the values measured from previous Monte-Carlo and experimental studies. In general, the measured dose rate constant, anisotropy function, and radial dose function for the Amersham 6711 showed agreements better than 5% compared to consensus values in the r=1 to r=3 cm region. The dose rates and radial dose functions measured for the AgX100 agreed with the MCNPX and TLD-measured values within 3% in the r=1 to r=3 cm region. The measured anisotropy function in PRESAGE® showed relative differences of up to 9% with the MCNPX calculated values. It was determined that post-irradiation optical density change over several days was non-linear in different dose regions, and therefore the dose values in the r=4 to r=5 cm regions had higher uncertainty due to this effect. This study demonstrated that within the radial distance of 3 cm, brachytherapy dosimetry in PRESAGE® can be accurate within 5% as long as irradiation times are within 48 hours.

Development of a SPECT -based three-dimensional treatment planner for radionuclide therapy with iodine -131

Accurate calculation of absorbed dose to target tumors and normal tissues in the body is an important requirement for establishing fundamental dose-response relationships for radioimmunotherapy. Two major obstacles have been the difficulty in obtaining an accurate patient-specific 3-D activity map in-vivo and calculating the resulting absorbed dose. This study investigated a methodology for 3-D internal dosimetry, which integrates the 3-D biodistribution of the radionuclide acquired from SPECT with a dose-point kernel convolution technique to provide the 3-D distribution of absorbed dose. Accurate SPECT images were reconstructed with appropriate methods for noise filtering, attenuation correction, and Compton scatter correction. The SPECT images were converted into activity maps using a calibration phantom. The activity map was convolved with an $\sp{131}$I dose-point kernel using a 3-D fast Fourier transform to yield a 3-D distribution of absorbed dose. The 3-D absorbed dose map was then processed to provide the absorbed dose distribution in regions of interest. This methodology can provide heterogeneous distributions of absorbed dose in volumes of any size and shape with nonuniform distributions of activity. Comparison of the activities quantitated by our SPECT methodology to true activities in an Alderson abdominal phantom (with spleen, liver, and spherical tumor) yielded errors of $-$16.3% to 4.4%. Volume quantitation errors ranged from $-$4.0 to 5.9% for volumes greater than 88 ml. The percentage differences of the average absorbed dose rates calculated by this methodology and the MIRD S-values were 9.1% for liver, 13.7% for spleen, and 0.9% for the tumor. Good agreement (percent differences were less than 8%) was found between the absorbed dose due to penetrating radiation calculated from this methodology and TLD measurement. More accurate estimates of the 3-D distribution of absorbed dose can be used as a guide in specifying the minimum activity to be administered to patients to deliver a prescribed absorbed dose to tumor without exceeding the toxicity limits of normal tissues. ^

Dynamic contrast agent -enhanced magnetic resonance imaging assessment of tumor microvasculature

Dynamic contrast agent-enhanced magnetic resonance imaging (DCE MRI) data, when analyzed with the appropriate pharmacokinetic models, have been shown to provide quantitative estimates of microvascular parameters important in characterizing the angiogenic activity of malignant tissue. These parameters consist of the whole blood volume per unit volume of tissue, v b, transport constant from the plasma to the extravascular, extracellular space (EES), k1 and the transport constant from the EES to the plasma, k2. Parameters vb and k1 are expected to correlate with microvascular density (MVD) and vascular permeability, respectively, which have been suggested to serve as surrogate markers for angiogenesis. In addition to being a marker for angiogenesis, vascular permeability is also useful in estimating tumor penetration potential of chemotherapeutic agents. ^ Histological measurements of the intratumoral microvascular environment are limited by their invasiveness and susceptibility to sampling errors. Also, MVD and vascular permeability, while useful for characterizing tumors at a single time point, have shown less utility in longitudinal studies, particularly when used to monitor the efficacy of antiangiogenic and traditional chemotherapeutic agents. These limitations led to a search for a non-invasive means of characterizing the microvascular environment of an entire tumor. ^ The overall goal of this project was to determine the utility of DCE MRI for monitoring the effect of antiangiogenic agents. Further applications of a validated DCE MRI technique include in vivo measurements of tumor microvascular characteristics to aid in determining prognosis at presentation and in estimating drug penetration. DCE MRI data were generated using single- and dual-tracer pharmacokinetic models with different molecular-weight contrast agents. The resulting pharmacokinetic parameters were compared to immunohistochemical measurements. The model and contrast agent combination yielding the best correlation between the pharmacokinetic parameters and histological measures was further evaluated in a longitudinal study to evaluate the efficacy of DCE MRI in monitoring the intratumoral microvascular environment following antiangiogenic treatment. ^