DUAL ENERGY COMPUTED TOMOGRAPHY FOR PROTON THERAPY TREATMENT PLANNING

Proton radiation therapy is gaining popularity because of the unique characteristics of its dose distribution, e.g., high dose-gradient at the distal end of the percentage-depth-dose curve (known as the Bragg peak). The high dose-gradient offers the possibility of delivering high dose to the target while still sparing critical organs distal to the target. However, the high dose-gradient is a double-edged sword: a small shift of the highly conformal high-dose area can cause the target to be substantially under-dosed or the critical organs to be substantially over-dosed. Because of that, large margins are required in treatment planning to ensure adequate dose coverage of the target, which prevents us from realizing the full potential of proton beams. Therefore, it is critical to reduce uncertainties in the proton radiation therapy. One major uncertainty in a proton treatment is the range uncertainty related to the estimation of proton stopping power ratio (SPR) distribution inside a patient. The SPR distribution inside a patient is required to account for tissue heterogeneities when calculating dose distribution inside the patient. In current clinical practice, the SPR distribution inside a patient is estimated from the patient’s treatment planning computed tomography (CT) images based on the CT number-to-SPR calibration curve. The SPR derived from a single CT number carries large uncertainties in the presence of human tissue composition variations, which is the major drawback of the current SPR estimation method. We propose to solve this problem by using dual energy CT (DECT) and hypothesize that the range uncertainty can be reduced by a factor of two from currently used value of 3.5%. A MATLAB program was developed to calculate the electron density ratio (EDR) and effective atomic number (EAN) from two CT measurements of the same object. An empirical relationship was discovered between mean excitation energies and EANs existing in human body tissues. With the MATLAB program and the empirical relationship, a DECT-based method was successfully developed to derive SPRs for human body tissues (the DECT method). The DECT method is more robust against the uncertainties in human tissues compositions than the current single-CT-based method, because the DECT method incorporated both density and elemental composition information in the SPR estimation. Furthermore, we studied practical limitations of the DECT method. We found that the accuracy of the DECT method using conventional kV-kV x-ray pair is susceptible to CT number variations, which compromises the theoretical advantage of the DECT method. Our solution to this problem is to use a different x-ray pair for the DECT. The accuracy of the DECT method using different combinations of x-ray energies, i.e., the kV-kV, kV-MV and MV-MV pair, was compared using the measured imaging uncertainties for each case. The kV-MV DECT was found to be the most robust against CT number variations. In addition, we studied how uncertainties propagate through the DECT calculation, and found general principles of selecting x-ray pairs for the DECT method to minimize its sensitivity to CT number variations. The uncertainties in SPRs estimated using the kV-MV DECT were analyzed further and compared to those using the stoichiometric method. The uncertainties in SPR estimation can be divided into five categories according to their origins: the inherent uncertainty, the DECT modeling uncertainty, the CT imaging uncertainty, the uncertainty in the mean excitation energy, and SPR variation with proton energy. Additionally, human body tissues were divided into three tissue groups – low density (lung) tissues, soft tissues and bone tissues. The uncertainties were estimated separately because their uncertainties were different under each condition. An estimate of the composite range uncertainty (2s) was determined for three tumor sites – prostate, lung, and head-and-neck, by combining the uncertainty estimates of all three tissue groups, weighted by their proportions along typical beam path for each treatment site. In conclusion, the DECT method holds theoretical advantages in estimating SPRs for human tissues over the current single-CT-based method. Using existing imaging techniques, the kV-MV DECT approach was capable of reducing the range uncertainty from the currently used value of 3.5% to 1.9%-2.3%, but it is short to reach our original goal of reducing the range uncertainty by a factor of two. The dominant source of uncertainties in the kV-MV DECT was the uncertainties in CT imaging, especially in MV CT imaging. Further reduction in beam hardening effect, the impact of scatter, out-of-field object etc. would reduce the Hounsfeld Unit variations in CT imaging. The kV-MV DECT still has the potential to reduce the range uncertainty further.

A novel treatment planning methodology for high dose 166Ho-DOTMP therapy in patients with multiple myeloma

Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone-seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. ^ Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho-DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the patient without irrigation, will not significantly reduce the bladder wall dose. ^ The results from this work will produce the most advanced treatment planning methodology for bone marrow ablation therapy using radioisotopes currently available. Treatments can be tailored specifically for each patient, including the addition of concomitant total body irradiation for patients with unfavorable dose distributions, to deliver a desired patient disease response, while minimizing the dose or toxicity to non-target organs. ^

THE IMPLEMENTATION OF FEDERAL FAMILY PLANNING POLICY: AN ANALYSIS OF FACTORS AFFECTING STATE EXPENDITURES, FISCAL YEARS 1976-1981 (WOMEN, BUDGET, POPULATION)

The purpose of this study was to analyze the implementation of national family planning policy in the United States, which was embedded in four separate statutes during the period of study, Fiscal Years 1976-81. The design of the study utilized a modification of the Sabatier and Mazmanian framework for policy analysis, which defined implementation as the carrying out of statutory policy. The study was divided into two phases. The first part of the study compared the implementation of family planning policy by each of the pertinent statutes. The second part of the study identified factors that were associated with implementation of federal family planning policy within the context of block grants.^ Implemention was measured here by federal dollars spent for family planning, adjusted for the size of the respective state target populations. Expenditure data were collected from the Alan Guttmacher Institute and from each of the federal agencies having administrative authority for the four pertinent statutes, respectively. Data from the former were used for most of the analysis because they were more complete and more reliable.^ The first phase of the study tested the hypothesis that the coherence of a statute is directly related to effective implementation. Equity in the distribution of funds to the states was used to operationalize effective implementation. To a large extent, the results of the analysis supported the hypothesis. In addition to their theoretical significance, these findings were also significant for policymakers insofar they demonstrated the effectiveness of categorical legislation in implementing desired health policy.^ Given the current and historically intermittent emphasis on more state and less federal decision-making in health and human serives, the second phase of the study focused on state level factors that were associated with expenditures of social service block grant funds for family planning. Using the Sabatier-Mazmanian implementation model as a framework, many factors were tested. Those factors showing the strongest conceptual and statistical relationship to the dependent variable were used to construct a statistical model. Using multivariable regression analysis, this model was applied cross-sectionally to each of the years of the study. The most striking finding here was that the dominant determinants of the state spending varied for each year of the study (Fiscal Years 1976-1981). The significance of these results was that they provided empirical support of current implementation theory, showing that the dominant determinants of implementation vary greatly over time. ^

COMPREHENSIVE CALCULATION-BASED IMRT QA USING R&V DATA, TREATMENT RECORDS, AND A SECOND TREATMENT PLANNING SYSTEM

Purpose: Traditional patient-specific IMRT QA measurements are labor intensive and consume machine time. Calculation-based IMRT QA methods typically are not comprehensive. We have developed a comprehensive calculation-based IMRT QA method to detect uncertainties introduced by the initial dose calculation, the data transfer through the Record-and-Verify (R&V) system, and various aspects of the physical delivery. Methods: We recomputed the treatment plans in the patient geometry for 48 cases using data from the R&V, and from the delivery unit to calculate the “as-transferred” and “as-delivered” doses respectively. These data were sent to the original TPS to verify transfer and delivery or to a second TPS to verify the original calculation. For each dataset we examined the dose computed from the R&V record (RV) and from the delivery records (Tx), and the dose computed with a second verification TPS (vTPS). Each verification dose was compared to the clinical dose distribution using 3D gamma analysis and by comparison of mean dose and ROI-specific dose levels to target volumes. Plans were also compared to IMRT QA absolute and relative dose measurements. Results: The average 3D gamma passing percentages using 3%-3mm, 2%-2mm, and 1%-1mm criteria for the RV plan were 100.0 (σ=0.0), 100.0 (σ=0.0), and 100.0 (σ=0.1); for the Tx plan they were 100.0 (σ=0.0), 100.0 (σ=0.0), and 99.0 (σ=1.4); and for the vTPS plan they were 99.3 (σ=0.6), 97.2 (σ=1.5), and 79.0 (σ=8.6). When comparing target volume doses in the RV, Tx, and vTPS plans to the clinical plans, the average ratios of ROI mean doses were 0.999 (σ=0.001), 1.001 (σ=0.002), and 0.990 (σ=0.009) and ROI-specific dose levels were 0.999 (σ=0.001), 1.001 (σ=0.002), and 0.980 (σ=0.043), respectively. Comparing the clinical, RV, TR, and vTPS calculated doses to the IMRT QA measurements for all 48 patients, the average ratios for absolute doses were 0.999 (σ=0.013), 0.998 (σ=0.013), 0.999 σ=0.015), and 0.990 (σ=0.012), respectively, and the average 2D gamma(5%-3mm) passing percentages for relative doses for 9 patients was were 99.36 (σ=0.68), 99.50 (σ=0.49), 99.13 (σ=0.84), and 98.76 (σ=1.66), respectively. Conclusions: Together with mechanical and dosimetric QA, our calculation-based IMRT QA method promises to minimize the need for patient-specific QA measurements by identifying outliers in need of further review.

DEVELOPMENT OF A BEAM-SPECIFIC PLANNING TARGET VOLUME AND A ROBUST PLAN ANALYSIS TOOL FOR PROTON THERAPY

Proton therapy is growing increasingly popular due to its superior dose characteristics compared to conventional photon therapy. Protons travel a finite range in the patient body and stop, thereby delivering no dose beyond their range. However, because the range of a proton beam is heavily dependent on the tissue density along its beam path, uncertainties in patient setup position and inherent range calculation can degrade thedose distribution significantly. Despite these challenges that are unique to proton therapy, current management of the uncertainties during treatment planning of proton therapy has been similar to that of conventional photon therapy. The goal of this dissertation research was to develop a treatment planning method and a planevaluation method that address proton-specific issues regarding setup and range uncertainties. Treatment plan designing method adapted to proton therapy: Currently, for proton therapy using a scanning beam delivery system, setup uncertainties are largely accounted for by geometrically expanding a clinical target volume (CTV) to a planning target volume (PTV). However, a PTV alone cannot adequately account for range uncertainties coupled to misaligned patient anatomy in the beam path since it does not account for the change in tissue density. In order to remedy this problem, we proposed a beam-specific PTV (bsPTV) that accounts for the change in tissue density along the beam path due to the uncertainties. Our proposed method was successfully implemented, and its superiority over the conventional PTV was shown through a controlled experiment.. Furthermore, we have shown that the bsPTV concept can be incorporated into beam angle optimization for better target coverage and normal tissue sparing for a selected lung cancer patient. Treatment plan evaluation method adapted to proton therapy: The dose-volume histogram of the clinical target volume (CTV) or any other volumes of interest at the time of planning does not represent the most probable dosimetric outcome of a given plan as it does not include the uncertainties mentioned earlier. Currently, the PTV is used as a surrogate of the CTV’s worst case scenario for target dose estimation. However, because proton dose distributions are subject to change under these uncertainties, the validity of the PTV analysis method is questionable. In order to remedy this problem, we proposed the use of statistical parameters to quantify uncertainties on both the dose-volume histogram and dose distribution directly. The robust plan analysis tool was successfully implemented to compute both the expectation value and its standard deviation of dosimetric parameters of a treatment plan under the uncertainties. For 15 lung cancer patients, the proposed method was used to quantify the dosimetric difference between the nominal situation and its expected value under the uncertainties.

Comparison of Tumor Shrinkage and Cumulative Dose Distribution for Lung Cancers

Background: The physical characteristic of protons is that they deliver most of their radiation dose to the target volume and deliver no dose to the normal tissue distal to the tumor. Previously, numerous studies have shown unique advantages of proton therapy over intensity-modulated radiation therapy (IMRT) in conforming dose to the tumor and sparing dose to the surrounding normal tissues and the critical structures in many clinical sites. However, proton therapy is known to be more sensitive to treatment uncertainties such as inter- and intra-fractional variations in patient anatomy. To date, no study has clearly demonstrated the effectiveness of proton therapy compared with the conventional IMRT under the consideration of both respiratory motion and tumor shrinkage in non-small cell lung cancer (NSCLC) patients. Purpose: This thesis investigated two questions for establishing a clinically relevant comparison of the two different modalities (IMRT and proton therapy). The first question was whether or not there are any differences in tumor shrinkage between patients randomized to IMRT versus passively scattered proton therapy (PSPT). Tumor shrinkage is considered a standard measure of radiation therapy response that has been widely used to gauge a short-term progression of radiation therapy. The second question was whether or not there are any differences between the planned dose and 5D dose under the influence of inter- and intra-fractional variations in the patient anatomy for both modalities. Methods: A total of 45 patients (25 IMRT patients and 20 PSPT patients) were used to quantify the tumor shrinkage in terms of the change of the primary gross tumor volume (GTVp). All patients were randomized to receive either IMRT or PSPT for NSCLC. Treatment planning goals were identical for both groups. All patients received 5 to 8 weekly repeated 4-dimensional computed tomography (4DCT) scans during the course of radiation treatments. The original GTVp contours were propagated to T50 of weekly 4DCT images using deformable image registration and their absolute volumes were measured. Statistical analysis was performed to compare the distribution of tumor shrinkage between the two population groups. In order to investigate the difference between the planned dose and the 5D dose with consideration of both breathing motion and anatomical change, we re-calculated new dose distributions at every phase of the breathing cycle for all available weekly 4DCT data sets which resulted 50 to 80 individual dose calculations for each of the 7 patients presented in this thesis. The newly calculated dose distributions were then deformed and accumulated to T50 of the planning 4DCT for comparison with the planned dose distribution. Results: At the end of the treatment, both IMRT and PSPT groups showed mean tumor volume reductions of 23.6% ( 19.2%) and 20.9% ( 17.0 %) respectively. Moreover, the mean difference in tumor shrinkage between two groups is 3% along with the corresponding 95% confidence interval, [-8%, 14%]. The rate of tumor shrinkage was highly correlated with the initial tumor volume size. For the planning dose and 5D dose comparison study, all 7 patients showed a mean difference of 1 % in terms of target coverage for both IMRT and PSPT treatment plans. Conclusions: The results of the tumor shrinkage investigation showed no statistically significant difference in tumor shrinkage between the IMRT and PSPT patients, and the tumor shrinkage between the two modalities is similar based on the 95% confidence interval. From the pilot study of comparing the planned dose with the 5D dose, we found the difference to be only 1%. Overall impression of the two modalities in terms of treatment response as measured by the tumor shrinkage and 5D dose under the influence of anatomical change that were designed under the same protocol (i.e. randomized trial) showed similar result.