987 resultados para Health Sciences, Radiology|Physics, Radiation|Biophysics, Medical


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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. ^

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A three-dimensional model has been proposed that uses Monte Carlo and fast Fourier transform convolution techniques to calculate the dose distribution from a fast neutron beam. This method transports scattered neutrons and photons in the forward, lateral, and backward directions and protons, electrons, and positrons in the forward and lateral directions by convolving energy spread kernels with initial interaction available energy distributions. The primary neutron and photon spectrums have been derived from narrow beam attenuation measurements. The positions and strengths of the effective primary neutron, scattered neutron, and photon sources have been derived from dual ion chamber measurements. The size of the effective primary neutron source has been measured using a copper activation technique. Heterogeneous tissue calculations require a weighted sum of two convolutions for each component since the kernels must be invariant for FFT convolution. Comparisons between calculations and measurements were performed for several water and heterogeneous phantom geometries. ^

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The successful management of cancer with radiation relies on the accurate deposition of a prescribed dose to a prescribed anatomical volume within the patient. Treatment set-up errors are inevitable because the alignment of field shaping devices with the patient must be repeated daily up to eighty times during the course of a fractionated radiotherapy treatment. With the invention of electronic portal imaging devices (EPIDs), patient's portal images can be visualized daily in real-time after only a small fraction of the radiation dose has been delivered to each treatment field. However, the accuracy of human visual evaluation of low-contrast portal images has been found to be inadequate. The goal of this research is to develop automated image analysis tools to detect both treatment field shape errors and patient anatomy placement errors with an EPID. A moments method has been developed to align treatment field images to compensate for lack of repositioning precision of the image detector. A figure of merit has also been established to verify the shape and rotation of the treatment fields. Following proper alignment of treatment field boundaries, a cross-correlation method has been developed to detect shifts of the patient's anatomy relative to the treatment field boundary. Phantom studies showed that the moments method aligned the radiation fields to within 0.5mm of translation and 0.5$\sp\circ$ of rotation and that the cross-correlation method aligned anatomical structures inside the radiation field to within 1 mm of translation and 1$\sp\circ$ of rotation. A new procedure of generating and using digitally reconstructed radiographs (DRRs) at megavoltage energies as reference images was also investigated. The procedure allowed a direct comparison between a designed treatment portal and the actual patient setup positions detected by an EPID. Phantom studies confirmed the feasibility of the methodology. Both the moments method and the cross-correlation technique were implemented within an experimental radiotherapy picture archival and communication system (RT-PACS) and were used clinically to evaluate the setup variability of two groups of cancer patients treated with and without an alpha-cradle immobilization aid. The tools developed in this project have proven to be very effective and have played an important role in detecting patient alignment errors and field-shape errors in treatment fields formed by a multileaf collimator (MLC). ^

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The current standard for temperature sensitive imaging using magnetic resonance (MR) is 2-D, spoiled, fast gradient-echo (fGRE) phase-difference imaging exploiting temperature dependent changes in the proton resonance frequency (PRF). The echo-time (TE) for optimal sensitivity is larger than the typical repetition time (TR) of an fGRE sequence. Since TE must be less than TR in the fGRE sequence, this limits the technique's achievable sensitivity, spatial, and temporal resolution. This adversely affects both accuracy and volume coverage of the measurements. Accurate measurement of the rapid temperature changes associated with pulsed thermal therapies, such as high-intensity focused ultrasound (FUS), at optimal temperature sensitivity requires faster acquisition times than those currently available. ^ Use of fast MR acquisition strategies, such as interleaved echo-planar and spiral imaging, can provide the necessary increase in temporal performance and sensitivity while maintaining adequate signal-to-noise and in-plane spatial resolution. This research explored the adaptation and optimization of several fast MR acquisition methods for thermal monitoring of pulsed FUS thermal therapy. Temperature sensitivity, phase-difference noise and phase-difference to phase-difference-to noise ratio for the different pulse sequences were evaluated under varying imaging parameters in an agar gel phantom to establish optimal sequence parameters for temperature monitoring. The temperature sensitivity coefficient of the gel phantom was measured, allowing quantitative temperature extrapolations. ^ Optimized fast sequences were compared based on the ability to accurately monitor temperature changes at the focus of a high-intensity focused ultrasound unit, volume coverage, and contrast-to-noise ratio in the temperature maps. Operating parameters, which minimize complex phase-difference measurement errors introduced by use of the fast-imaging methods, were established. ^

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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. ^

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In a phase I clinical trial, six multiple myeloma patients, who were non-responsive to conventional therapy and were scheduled for bone marrow transplantation, received Holmium-166 ($\sp{166}$Ho) labeled to a bone seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid), for the purpose of bone marrow ablation. The specific aims of my research within this protocol were to evaluate the toxicity and efficacy of $\sp{166}$Ho DOTMP by quantifying the in vivo pharmacokinetics and radiation dosimetry, and by correlating these results to the biologic response observed. The reproducibility of pharmacokinetics from multiple injections of $\sp{166}$Ho DOTMP administered to these myeloma patients was demonstrated from both blood and whole body retention. The skeletal concentration of $\sp{166}$Ho DOTMP was heterogenous in all six patients: high in the ribs, pelvis, and lumbar vertebrae regions, and relatively low in the femurs, arms, and head.^ A novel technique was developed to calculate the radiation dose to the bone marrow in each skeletal ROI, and was applied to all six $\sp{166}$Ho DOTMP patients. Radiation dose estimates for the bone marrow calculated using the standard MIRD "S" factors were compared with the average values derived from the heterogenous distribution of activity in the skeleton (i.e., the regional technique). The results from the two techniques were significantly different; the average of the dose estimates from the regional technique were typically 30% greater. Furthermore, the regional technique provided a range of radiation doses for the entire marrow volume, while the MIRD "S" factors only provided a single value. Dose volume histogram analysis of data from the regional technique indicated a range of dose estimates that varied by a factor of 10 between the high dose and low dose regions. Finally, the observed clinical response of cells and abnormal proteins measured in bone marrow aspirates and peripheral blood samples were compared with radiation dose estimates for the bone marrow calculated from the standard and regional technique. The results showed the regional technique values correlated more closely to several clinical response parameters. (Abstract shortened by UMI.) ^

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Damage of the colorectum is the dose-limiting normal tissue complication following radiotherapy of prostate and cervical cancers. One approach for decreasing complications is to physically reduce the treatment volume. Mathematical models have been previously developed to describe the change in associated toxicity with a change in irradiated volume, i.e. the "volume effect", for serial-type normal tissues including the colorectum. The first goal of this thesis was to test the hypothesis that there would not be a threshold length in the development of obstruction after irradiation of mouse colorectum, as predicted by the Probability model of the volume effect. The second goal was to examine if there were differences in the threshold and in the incidence of colorectal obstruction after irradiation of two mouse strains, C57B1/6 (C57) and C3Hf/Kam (C3H), previously found to be fibrosis-prone and-resistant, respectively, after lung irradiation due, in part, to genetic differences. The hypothesis examined was that differences in incidence between strains were due to the differential expression of the fibrogenic cytokines $\rm TGF\beta$ and $\rm TNF\alpha.$ Various lengths of C57 and C3H mouse colorectum were irradiated and the incidence of colorectal obstruction was followed up to 15 months. A threshold length was observed for both mouse strains, in contradiction of model predictions. The mechanism of the threshold was epithelial regeneration after irradiation. C57 mice had significantly higher incidence of colorectal obstruction compared to C3H mice, especially at smaller irradiated lengths. Colorectal tissue was obtained at various times after irradiation and prepared for histology, immunohistochemistry and RNase protection assay for measurement of $\rm TGF\beta 1,$ 2, 3 and $\rm TNF\alpha$ mRNA. Distinct strain differences in the histological time of appearance and spatial locations of fibrosis were observed. However, there were no consistent strain difference in mRNA levels or immunolocalization for any of the cytokines examined. The data indicate the need for volume effect models that account for biologically important processes, such as the effect of epithelial regeneration after irradiation. As well, changes in fibrogenic cytokines at the mRNA level do not contribute to the strain difference in radiation-induced colorectal obstruction. ^

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We have developed an empirically based simulation system to create images equivalent in SNR and SPR to those that would be acquired with various possible SEDR configurations. This system uses a collection of spot collimated full-field images (SCFFIs) of an anthropomorphic chest phantom, taken at high exposure levels and rescaled in noise and intensity, then digitally collimated and combined to produce the simulated SEDR images. This system allows for the study of design trade-offs between different equalization feedback schemes and scatter rejection geometries in addition to estimating the clinical benefits of SEDR over traditional imaging techniques. Data from this simulation system has demonstrated that SEDR techniques offer potential significant improvements over currently used digital radiography techniques for chest imaging. ^

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The usage of intensity modulated radiotherapy (IMRT) treatments necessitates a significant amount of patient-specific quality assurance (QA). This research has investigated the precision and accuracy of Kodak EDR2 film measurements for IMRT verifications, the use of comparisons between 2D dose calculations and measurements to improve treatment plan beam models, and the dosimetric impact of delivery errors. New measurement techniques and software were developed and used clinically at M. D. Anderson Cancer Center. The software implemented two new dose comparison parameters, the 2D normalized agreement test (NAT) and the scalar NAT index. A single-film calibration technique using multileaf collimator (MLC) delivery was developed. EDR2 film's optical density response was found to be sensitive to several factors: radiation time, length of time between exposure and processing, and phantom material. Precision of EDR2 film measurements was found to be better than 1%. For IMRT verification, EDR2 film measurements agreed with ion chamber results to 2%/2mm accuracy for single-beam fluence map verifications and to 5%/2mm for transverse plane measurements of complete plan dose distributions. The same system was used to quantitatively optimize the radiation field offset and MLC transmission beam modeling parameters for Varian MLCs. While scalar dose comparison metrics can work well for optimization purposes, the influence of external parameters on the dose discrepancies must be minimized. The ability of 2D verifications to detect delivery errors was tested with simulated data. The dosimetric characteristics of delivery errors were compared to patient-specific clinical IMRT verifications. For the clinical verifications, the NAT index and percent of pixels failing the gamma index were exponentially distributed and dependent upon the measurement phantom but not the treatment site. Delivery errors affecting all beams in the treatment plan were flagged by the NAT index, although delivery errors impacting only one beam could not be differentiated from routine clinical verification discrepancies. Clinical use of this system will flag outliers, allow physicists to examine their causes, and perhaps improve the level of agreement between radiation dose distribution measurements and calculations. The principles used to design and evaluate this system are extensible to future multidimensional dose measurements and comparisons. ^

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The electron pencil-beam redefinition algorithm (PBRA) of Shiu and Hogstrom has been developed for use in radiotherapy treatment planning (RTP). Earlier studies of Boyd and Hogstrom showed that the PBRA lacked an adequate incident beam model, that PBRA might require improved electron physics, and that no data existed which allowed adequate assessment of the PBRA-calculated dose accuracy in a heterogeneous medium such as one presented by patient anatomy. The hypothesis of this research was that by addressing the above issues the PBRA-calculated dose would be accurate to within 4% or 2 mm in regions of high dose gradients. A secondary electron source was added to the PBRA to account for collimation-scattered electrons in the incident beam. Parameters of the dual-source model were determined from a minimal data set to allow ease of beam commissioning. Comparisons with measured data showed 3% or better dose accuracy in water within the field for cases where 4% accuracy was not previously achievable. A measured data set was developed that allowed an evaluation of PBRA in regions distal to localized heterogeneities. Geometries in the data set included irregular surfaces and high- and low-density internal heterogeneities. The data was estimated to have 1% precision and 2% agreement with accurate, benchmarked Monte Carlo (MC) code. PBRA electron transport was enhanced by modeling local pencil beam divergence. This required fundamental changes to the mathematics of electron transport (divPBRA). Evaluation of divPBRA with the measured data set showed marginal improvement in dose accuracy when compared to PBRA; however, 4% or 2mm accuracy was not achieved by either PBRA version for all data points. Finally, PBRA was evaluated clinically by comparing PBRA- and MC-calculated dose distributions using site-specific patient RTP data. Results show PBRA did not agree with MC to within 4% or 2mm in a small fraction (<3%) of the irradiated volume. Although the hypothesis of the research was shown to be false, the minor dose inaccuracies should have little or no impact on RTP decisions or patient outcome. Therefore, given ease of beam commissioning, documentation of accuracy, and calculational speed, the PBRA should be considered a practical tool for clinical use. ^

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In this investigation, bromine-77 was produced with a medical cyclotron and imaged with gamma cameras. Br-77 emits a 240 kev photon with a half life of 56 hours. The C-Br bond is stronger than the C-I bond and bromine is not collected in the thyroid. Bromine can be used to label many organic molecules by methods analogous to radioiodination. The only North American source of Br-77 in the 70's and 80's was Los Alamos National Laboratory, but it discontinued production in 1989. In this method, a p,3n reaction on Br-77 produces Kr-77 which decays with a 1.2 hour half life to Br-77. A cyclotron generated 40 MeV proton beam is incident on a nearly saturated NaBr or LiBr solution contained in a copper or titanium target. A cooling chamber through which helium gas is flowed separates the solution from the cyclotron beam line. Helium gas is also flowed through the solution to extract Kr-77 gas. The mixture flows through a nitrogen trap where Kr-77 freezes and is allowed to decay to Br-77. Eight production runs were performed, three with a copper target and five with a titanium target with yields of 40, 104, 180, 679, 1080, 685, 762 and 118 uCi respectively. Gamma ray spectroscopy has shown the product to be very pure, however corrosion has been a major obstacle, causing the premature retirement of the copper target. Phantom and in-vivo rat nuclear images, and an autoradiograph in a rat are presented. The quality of the nuclear scans is reasonable and the autoradiograph reveals high isotope uptake in the renal parenchyma, a more moderate but uniform uptake in pulmonary and hepatic tissue, and low soft tissue uptake. There is no isotope uptake in the brain or the gastric mucosa. ^

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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. ^

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Introduction. Tissue engineering techniques offer a potential means to develop a tissue engineered construct (TEC) for the treatment of tissue and organ deficiencies. However, a lack of adequate vascularization is a limiting factor in the development of most viable engineered tissues. Vascular endothelial growth factor (VEGF) could aid in the development of a viable vascular network within TECs. The long-term goals of this research are to develop clinically relevant, appropriately vascularized TECs for use in humans. This project tested the hypothesis that the delivery of VEGF via controlled release from biodegradable microspheres would increase the vascular density and rate of angiogenesis within a model TEC. ^ Materials and methods. Biodegradable VEGF-encapsulated microspheres were manufactured using a novel method entitled the Solid Encapsulation/Single Emulsion/Solvent Extraction technique. Using a PLGA/PEG polymer blend, microspheres were manufactured and characterized in vitro. A model TEC using fibrin was designed for in vivo tissue engineering experimentation. At the appropriate timepoint, the TECs were explanted, and stained and quantified for CD31 using a novel semi-automated thresholding technique. ^ Results. In vitro results show the microspheres could be manufactured, stored, degrade, and release biologically active VEGF. The in vivo investigations revealed that skeletal muscle was the optimal implantation site as compared to dermis. In addition, the TECs containing fibrin with VEGF demonstrated significantly more angiogenesis than the controls. The TECs containing VEGF microspheres displayed a significant increase in vascular density by day 10. Furthermore, TECs containing VEGF microspheres had a significantly increased relative rate of angiogenesis from implantation day 5 to day 10. ^ Conclusions. A novel technique for producing microspheres loaded with biologically active proteins was developed. A defined concentration of microspheres can deliver a quantifiable level of VEGF with known release kinetics. A novel model TEC for in vivo tissue engineering investigations was developed. VEGF and VEGF microspheres stimulate angiogenesis within the model TEC. This investigation determined that biodegradable rhVEGF 165-encapsulated microspheres increased the vascular density and relative rate of angiogenesis within a model TEC. Future applications could include the incorporation of microvascular fragments into the model TEC and the incorporation of specific tissues, such as fat or bone. ^

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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. ^

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The purpose of this work was to develop a comprehensive IMSRT QA procedure that examined, using EPID dosimetry and Monte Carlo (MC) calculations, each step in the treatment planning and delivery process. These steps included verification of the field shaping, treatment planning system (RTPS) dose calculations, and patient dose delivery. Verification of each step in the treatment process is assumed to result in correct dose delivery to the patient. ^ The accelerator MC model was verified against commissioning data for field sizes from 0.8 × 0.8 cm 2 to 10 × 10 cm 2. Depth doses were within 2% local percent difference (LPD) in low gradient regions and 1 mm distance to agreement (DTA) in high gradient regions. Lateral profiles were within 2% LPD in low gradient regions and 1 mm DTA in high gradient regions. Calculated output factors were within 1% of measurement for field sizes ≥1 × 1 cm2. ^ The measured and calculated pretreatment EPID dose patterns were compared using criteria of 5% LPD, 1 mm DTA, or 2% of central axis pixel value with ≥95% of compared points required to pass for successful verification. Pretreatment field verification resulted in 97% percent of the points passing. ^ The RTPS and Monte Carlo phantom dose calculations were compared using 5% LPD, 2 mm DTA, or 2% of the maximum dose with ≥95% of compared points required passing for successful verification. RTPS calculation verification resulted in 97% percent of the points passing. ^ The measured and calculated EPID exit dose patterns were compared using criteria of 5% LPD, 1 mm DTA, or 2% of central axis pixel value with ≥95% of compared points required to pass for successful verification. Exit dose verification resulted in 97% percent of the points passing. ^ Each of the processes above verified an individual step in the treatment planning and delivery process. The combination of these verification steps ensures accurate treatment delivery to the patient. This work shows that Monte Carlo calculations and EPID dosimetry can be used to quantitatively verify IMSRT treatments resulting in improved patient care and, potentially, improved clinical outcome. ^