Thoracic target volume delineation using various maximum-intensity projection computed tomography image sets for stereotactic body radiation therapy

The motion of lung tumors during respiration makes the accurate delivery of radiation therapy to the thorax difficult because it increases the uncertainty of target position. The adoption of four-dimensional computed tomography (4D-CT) has allowed us to determine how a tumor moves with respiration for each individual patient. Using information acquired during a 4D-CT scan, we can define the target, visualize motion, and calculate dose during the planning phase of the radiotherapy process. One image data set that can be created from the 4D-CT acquisition is the maximum-intensity projection (MIP). The MIP can be used as a starting point to define the volume that encompasses the motion envelope of the moving gross target volume (GTV). Because of the close relationship that exists between the MIP and the final target volume, we investigated four MIP data sets created with different methodologies (3 using various 4D-CT sorting implementations, and one using all available cine CT images) to compare target delineation. It has been observed that changing the 4D-CT sorting method will lead to the selection of a different collection of images; however, the clinical implications of changing the constituent images on the resultant MIP data set are not clear. There has not been a comprehensive study that compares target delineation based on different 4D-CT sorting methodologies in a patient population. We selected a collection of patients who had previously undergone thoracic 4D-CT scans at our institution, and who had lung tumors that moved at least 1 cm. We then generated the four MIP data sets and automatically contoured the target volumes. In doing so, we identified cases in which the MIP generated from a 4D-CT sorting process under-represented the motion envelope of the target volume by more than 10% than when measured on the MIP generated from all of the cine CT images. The 4D-CT methods suffered from duplicate image selection and might not choose maximum extent images. Based on our results, we suggest utilization of a MIP generated from the full cine CT data set to ensure a representative inclusive tumor extent, and to avoid geometric miss.

Is a 3-mm intrafractional margin sufficient for daily image-guided intensity-modulated radiation therapy of prostate cancer?

PURPOSE: To determine whether a 3-mm isotropic target margin adequately covers the prostate and seminal vesicles (SVs) during administration of an intensity-modulated radiation therapy (IMRT) treatment fraction, assuming that daily image-guided setup is performed just before each fraction. MATERIALS AND METHODS: In-room computed tomographic (CT) scans were acquired immediately before and after a daily treatment fraction in 46 patients with prostate cancer. An eight-field IMRT plan was designed using the pre-fraction CT with a 3-mm margin and subsequently recalculated on the post-fraction CT. For convenience of comparison, dose plans were scaled to full course of treatment (75.6 Gy). Dose coverage was assessed on the post-treatment CT image set. RESULTS: During one treatment fraction (21.4+/-5.5 min), there were reductions in the volumes of the prostate and SVs receiving the prescribed dose (median reduction 0.1% and 1.0%, respectively, p<0.001) and in the minimum dose to 0.1 cm(3) of their volumes (median reduction 0.5 and 1.5 Gy, p<0.001). Of the 46 patients, three patients' prostates and eight patients' SVs did not maintain dose coverage above 70 Gy. Rectal filling correlated with decreased percentage-volume of SV receiving 75.6, 70, and 60 Gy (p<0.02). CONCLUSIONS: The 3-mm intrafractional margin was adequate for prostate dose coverage. However, a significant subset of patients lost SV dose coverage. The rectal volume change significantly affected SV dose coverage. For advanced-stage prostate cancers, we recommend to use larger margins or improve organ immobilization (such as with a rectal balloon) to ensure SV coverage.

Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.

OBJECTIVE: Because studies suggest that ultraviolet (UV) radiation modulates the myositis phenotype and Mi-2 autoantigen expression, we conducted a retrospective investigation to determine whether UV radiation may influence the relative prevalence of dermatomyositis and anti-Mi-2 autoantibodies in the US. METHODS: We assessed the relationship between surface UV radiation intensity in the state of residence at the time of onset with the relative prevalence of dermatomyositis and myositis autoantibodies in 380 patients with myositis from referral centers in the US. Myositis autoantibodies were detected by validated immunoprecipitation assays. Surface UV radiation intensity was estimated from UV Index data collected by the US National Weather Service. RESULTS: UV radiation intensity was associated with the relative proportion of patients with dermatomyositis (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 0.9-5.8) and with the proportion of patients expressing anti-Mi-2 autoantibodies (OR 6.0, 95% CI 1.1-34.1). Modeling of these data showed that these associations were confined to women (OR 3.8, 95% CI 1.3-11.0 and OR 17.3, 95% CI 1.8-162.4, respectively) and suggests that sex influences the effects of UV radiation on autoimmune disorders. Significant associations were not observed in men, nor were UV radiation levels related to the presence of antisynthetase or anti-signal recognition particle autoantibodies. CONCLUSION: This first study of the distribution of myositis phenotypes and UV radiation exposure in the US showed that UV radiation may modulate the clinical and immunologic expression of autoimmune disease in women. Further investigation of the mechanisms by which these effects are produced may provide insights into pathogenesis and suggest therapeutic or preventative strategies.

Assessment of Collimator Jaw Optimization in Reducing Normal Tissue Irradiation with Intensity Modulated Radiation Therapy

Purpose: To evaluate normal tissue dose reduction in step-and-shoot intensity-modulated radiation therapy (IMRT) on the Varian 2100 platform by tracking the multileaf collimator (MLC) apertures with the accelerator jaws. Methods: Clinical radiation treatment plans for 10 thoracic, 3 pediatric and 3 head and neck patients were converted to plans with the jaws tracking each segment’s MLC apertures. Each segment was then renormalized to account for the change in collimator scatter to obtain target coverage within 1% of that in the original plan. The new plans were compared to the original plans in a commercial radiation treatment planning system (TPS). Reduction in normal tissue dose was evaluated in the new plan by using the parameters V5, V10, and V20 in the cumulative dose-volume histogram for the following structures: total lung minus GTV (gross target volume), heart, esophagus, spinal cord, liver, parotids, and brainstem. In order to validate the accuracy of our beam model, MLC transmission measurements were made and compared to those predicted by the TPS. Results: The greatest change between the original plan and new plan occurred at lower dose levels. The reduction in V20 was never more than 6.3% and was typically less than 1% for all patients. The reduction in V5 was 16.7% maximum and was typically less than 3% for all patients. The variation in normal tissue dose reduction was not predictable, and we found no clear parameters that indicated which patients would benefit most from jaw tracking. Our TPS model of MLC transmission agreed with measurements with absolute transmission differences of less than 0.1 % and thus uncertainties in the model did not contribute significantly to the uncertainty in the dose determination. Conclusion: The amount of dose reduction achieved by collimating the jaws around each MLC aperture in step-and-shoot IMRT does not appear to be clinically significant.

EVALUATION OF INTENSITY MODULATED RADIATION THERAPY (IMRT) DELIVERY ERROR DUE TO IMRT TREATMENT PLAN COMPLEXITY AND IMPROPERLY MATCHED DOSIMETRY DATA

Intensity modulated radiation therapy (IMRT) is a technique that delivers a highly conformal dose distribution to a target volume while attempting to maximally spare the surrounding normal tissues. IMRT is a common treatment modality used for treating head and neck (H&N) cancers, and the presence of many critical structures in this region requires accurate treatment delivery. The Radiological Physics Center (RPC) acts as both a remote and on-site quality assurance agency that credentials institutions participating in clinical trials. To date, about 30% of all IMRT participants have failed the RPC’s remote audit using the IMRT H&N phantom. The purpose of this project is to evaluate possible causes of H&N IMRT delivery errors observed by the RPC, specifically IMRT treatment plan complexity and the use of improper dosimetry data from machines that were thought to be matched but in reality were not. Eight H&N IMRT plans with a range of complexity defined by total MU (1460-3466), number of segments (54-225), and modulation complexity scores (MCS) (0.181-0.609) were created in Pinnacle v.8m. These plans were delivered to the RPC’s H&N phantom on a single Varian Clinac. One of the IMRT plans (1851 MU, 88 segments, and MCS=0.469) was equivalent to the median H&N plan from 130 previous RPC H&N phantom irradiations. This average IMRT plan was also delivered on four matched Varian Clinac machines and the dose distribution calculated using a different 6MV beam model. Radiochromic film and TLD within the phantom were used to analyze the dose profiles and absolute doses, respectively. The measured and calculated were compared to evaluate the dosimetric accuracy. All deliveries met the RPC acceptance criteria of ±7% absolute dose difference and 4 mm distance-to-agreement (DTA). Additionally, gamma index analysis was performed for all deliveries using a ±7%/4mm and ±5%/3mm criteria. Increasing the treatment plan complexity by varying the MU, number of segments, or varying the MCS resulted in no clear trend toward an increase in dosimetric error determined by the absolute dose difference, DTA, or gamma index. Varying the delivery machines as well as the beam model (use of a Clinac 6EX 6MV beam model vs. Clinac 21EX 6MV model), also did not show any clear trend towards an increased dosimetric error using the same criteria indicated above.

Patient classification system: An integrated method for measuring nursing intensity and optimizing resource allocation

A patient classification system was developed integrating a patient acuity instrument with a computerized nursing distribution method based on a linear programming model. The system was designed for real-time measurement of patient acuity (workload) and allocation of nursing personnel to optimize the utilization of resources.^ The acuity instrument was a prototype tool with eight categories of patients defined by patient severity and nursing intensity parameters. From this tool, the demand for nursing care was defined in patient points with one point equal to one hour of RN time. Validity and reliability of the instrument was determined as follows: (1) Content validity by a panel of expert nurses; (2) predictive validity through a paired t-test analysis of preshift and postshift categorization of patients; (3) initial reliability by a one month pilot of the instrument in a practice setting; and (4) interrater reliability by the Kappa statistic.^ The nursing distribution system was a linear programming model using a branch and bound technique for obtaining integer solutions. The objective function was to minimize the total number of nursing personnel used by optimally assigning the staff to meet the acuity needs of the units. A penalty weight was used as a coefficient of the objective function variables to define priorities for allocation of staff.^ The demand constraints were requirements to meet the total acuity points needed for each unit and to have a minimum number of RNs on each unit. Supply constraints were: (1) total availability of each type of staff and the value of that staff member (value was determined relative to that type of staff's ability to perform the job function of an RN (i.e., value for eight hours RN = 8 points, LVN = 6 points); (2) number of personnel available for floating between units.^ The capability of the model to assign staff quantitatively and qualitatively equal to the manual method was established by a thirty day comparison. Sensitivity testing demonstrated appropriate adjustment of the optimal solution to changes in penalty coefficients in the objective function and to acuity totals in the demand constraints.^ Further investigation of the model documented: correct adjustment of assignments in response to staff value changes; and cost minimization by an addition of a dollar coefficient to the objective function. ^

Verification of intensity modulated stereotactic radiotherapy using Monte Carlo calculations and EPID dosimetry

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. ^

The design and evaluation of a 2D dose verification system for intensity modulated radiotherapy

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. ^

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. ^

Use of light intensity, temperature, and humidity to verify exposure location

Research studies on the association between exposures to air contaminants and disease frequently use worn dosimeters to measure the concentration of the contaminant of interest. But investigation of exposure determinants requires additional knowledge beyond concentration, i.e., knowledge about personal activity such as whether the exposure occurred in a building or outdoors. Current studies frequently depend upon manual activity logging to record location. This study's purpose was to evaluate the use of a worn data logger recording three environmental parameters—temperature, humidity, and light intensity—as well as time of day, to determine indoor or outdoor location, with an ultimate aim of eliminating the need to manually log location or at least providing a method to verify such logs. For this study, data collection was limited to a single geographical area (Houston, Texas metropolitan area) during a single season (winter) using a HOBO H8 four-channel data logger. Data for development of a Location Model were collected using the logger for deliberate sampling of programmed activities in outdoor, building, and vehicle locations at various times of day. The Model was developed by analyzing the distributions of environmental parameters by location and time to establish a prioritized set of cut points for assessing locations. The final Model consisted of four "processors" that varied these priorities and cut points. Data to evaluate the Model were collected by wearing the logger during "typical days" while maintaining a location log. The Model was tested by feeding the typical day data into each processor and generating assessed locations for each record. These assessed locations were then compared with true locations recorded in the manual log to determine accurate versus erroneous assessments. The utility of each processor was evaluated by calculating overall error rates across all times of day, and calculating individual error rates by time of day. Unfortunately, the error rates were large, such that there would be no benefit in using the Model. Another analysis in which assessed locations were classified as either indoor (including both building and vehicle) or outdoor yielded slightly lower error rates that still precluded any benefit of the Model's use.^

Comparison of clinical and economic outcomes between high-intensity care and hospice care for the end-of-life melanoma patients

The intensity of care for patients at the end-of-life is increasing in recent years. Publications have focused on intensity of care for many cancers, but none on melanoma patients. Substantial gaps exist in knowledge about intensive care and its alternative, hospice care, among the advanced melanoma patients at the end of life. End-of-life care may be used in quite different patterns and induce both intended and unintended clinical and economic consequences. We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases to identify patients aged 65 years or older with metastatic melanoma who died between 2000 and 2007. We evaluated trends and associations between sociodemographic and health services characteristics and the use of hospice care, chemotherapy, surgery, and radiation therapy and costs. Survival, end-of-life costs, and incremental cost-effectiveness ratio were evaluated using propensity score methods. Costs were analyzed from the perspective of Medicare in 2009 dollars. In the first journal Article we found increasing use of surgery for patients with metastatic melanoma from 13% in 2000 to 30% in 2007 (P=0.03 for trend), no significant fluctuation in use of chemotherapy (P=0.43) or radiation therapy (P=0.46). Older patients were less likely to receive radiation therapy or chemotherapy. The use of hospice care increased from 61% in 2000 to 79% in 2007 (P =0.07 for trend). Enrollment in short-term (1-3 days) hospice care use increased, while long-term hospice care (≥ 4 days) remained stable. Patients living in the SEER Northeast and South regions were less likely to undergo surgery. Patients enrolled in long-term hospice care used significantly less chemotherapy, surgery and radiation therapy. In the second journal article, of 611 patients identified for this study, 358 (59%) received no hospice care after their diagnosis, 168 (27%) received 1 to 3 days of hospice care, and 85 (14%) received 4 or more days of hospice care. The median survival time was 181 days for patients with no hospice care, 196 days for patients enrolled in hospice for 1 to 3 days, and 300 days for patients enrolled for 4 or more days (log-rank test, P < 0.001). The estimated hazard ratios (HR) between 4 or more days hospice use and survival were similar within the original cohort Cox proportional hazard model (HR, 0.62; 95% CI, 0.49-0.78, P < 0.0001) and the propensity score-matched model (HR, 0.61; 95% CI, 0.47-0.78, P = 0.0001). Patients with ≥ 4 days of hospice care incurred lower end-of-life costs than the other two groups ($14,298 versus $19,380 for the 1- to 3-days hospice care, and $24,351 for patients with no hospice care; p < 0.0001). In conclusion, Surgery and hospice care use increased over the years of this study while the use of chemotherapy and radiation therapy remained consistent for patients diagnosed with metastatic melanoma. Patients diagnosed with advanced melanoma who enrolled in ≥ 4 days of hospice care experienced longer survival than those who had 1-3 days of hospice or no hospice care, and this longer overall survival was accompanied by lower end-of-life costs.^