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Comparison of neutron organ and effective dose coefficients for PIMAL stylized phantom in bent postures in standard irradiation geometries

Neutron dose coefficients for standard irradiation geometries have been reported in International Commission on Radiological Protection (ICRP) Publication 116 for the ICRP Publication 110 adult reference phantoms. In the present paper, organ and effective dose coefficients have been calculated for a receptor in both upright and articulated (bent) postures representing more realistic working postures exposed to a mono-energetic neutron radiation field. This work builds upon prior work by Dewji and co-workers comparing upright and bent postures for exposure to mono-energetic photon fields. Simulations were conducted using the Oak Ridge National Laboratory’s articulated stylized adult phantom, “Phantom wIth Moving Arms and Legs” (PIMAL) software package, and the Monte Carlo N-Particle (MCNP) version 6.1.1 radiation transport code. Organ doses were compared for the upright and bent (45° and 90°) phantom postures for neutron energies ranging from 1 × 10 -9 to 20 MeV for the ICRP Publication 116 external exposure geometries—antero-posterior (AP), postero-anterior (PA), and left and right lateral (LLAT, RLAT). Using both male and female phantoms, effective dose coefficients were computed using ICRP Publication 103 methodology. The resulting coefficients for articulated phantoms were compared to those of the upright phantom. Computed organ and effective dose coefficients are discussed as a function of neutron energy, phantom posture, and source irradiation geometry. For example, it is shown here that for the AP and PA irradiation geometries, the differences in the organ coefficients between the upright and bent posture become more pronounced with increasing bending angle. In the AP geometry, the brain dose coefficients are expectedly higher in the bent postures than in the upright posture, while all other organs have lower dose coefficients, with the thyroid showing the greatest difference. Finally and overall, the effective dose estimated for the upright phantom is more conservative than that for the articulated phantom, which may have ramifications in the estimation or reconstruction of radiation doses.

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Evaluation of High Ipsilateral Subventricular Zone Radiation Therapy Dose in Glioblastoma: A Pooled Analysis

Purpose: Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. Methods and Materials: 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships between high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. Results: Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis. Conclusion: High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Radiation Dose to the Esophagus From Breast Cancer Radiation Therapy, 1943-1996: An International Population-Based Study of 414 Patients

Purpose: To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe. Methods and Materials: We abstracted the radiation therapy treatment parameters from each patient’s radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam types used were {sup 60}Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body. Results: Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus. Conclusions: Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses.

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Risk Factors for Neovascular Glaucoma After Proton Beam Therapy of Uveal Melanoma: A Detailed Analysis of Tumor and Dose–Volume Parameters

Purpose: To determine neovascular glaucoma (NVG) incidence and identify contributing tumor and dosing factors in uveal melanoma patients treated with proton beam radiation therapy (PBRT). Methods and Materials: A total of 704 PBRT patients treated by a single surgeon (DHC) for uveal melanoma (1996-2010) were reviewed for NVG in our prospectively maintained database. All patients received 56 GyE in 4 fractions. Median follow-up was 58.3 months. Analyses included the Kaplan-Meier method to estimate NVG distributions, univariate log–rank tests, and Cox's proportional hazards multivariate analysis using likelihood ratio tests to identify independent risk factors of NVG among patient, tumor, and dose–volume histogram parameters. Results: The 5-year PBRT NVG rate was 12.7% (95% confidence interval [CI] 10.2%-15.9%). The 5-year rate of enucleation due to NVG was 4.9% (95% CI 3.4%-7.2%). Univariately, the NVG rate increased significantly with larger tumor diameter (P<.0001), greater height (P<.0001), higher T stage (P<.0001), and closer proximity to the disc (P=.002). Dose–volume histogram analysis revealed that if >30% of the lens or ciliary body received ≥50% dose (≥28 GyE), there was a higher probability of NVG (P<.0001 for both). Furthermore, if 100% of the disc or macula received ≥28 GyE, the NVG rate was higher (P<.0001 and P=.03, respectively). If both anterior and posterior doses were above specified cut points, NVG risk was highest (P<.0001). Multivariate analysis confirmed significant independent risk factors to include tumor height (P<.0001), age (P<.0001), %disc treated to ≥50% Dose (<100% vs 100%) (P=.0007), larger tumor diameter (P=.01), %lens treated to ≥90% Dose (0 vs >0%-30% vs >30%) (P=.01), and optic nerve length treated to ≥90% Dose (≤1 mm vs >1 mm) (P=.02). Conclusions: Our current PBRT patients experience a low rate of NVG and resultant enucleation compared with historical data. The present analysis shows that tumor height, diameter, and anterior as well as posterior critical structure dose–volume parameters may be used to predict NVG risk.

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Dose–Volume Relationships Associated With Temporal Lobe Radiation Necrosis After Skull Base Proton Beam Therapy

Purpose: We evaluated patient and treatment parameters correlated with development of temporal lobe radiation necrosis. Methods and Materials: This was a retrospective analysis of a cohort of 66 patients treated for skull base chordoma, chondrosarcoma, adenoid cystic carcinoma, or sinonasal malignancies between 2005 and 2012, who had at least 6 months of clinical and radiographic follow-up. The median radiation dose was 75.6 Gy (relative biological effectiveness [RBE]). Analyzed factors included gender, age, hypertension, diabetes, smoking status, use of chemotherapy, and the absolute dose:volume data for both the right and left temporal lobes, considered separately. A generalized estimating equation (GEE) regression analysis evaluated potential predictors of radiation necrosis, and the median effective concentration (EC50) model estimated dose–volume parameters associated with radiation necrosis. Results: Median follow-up time was 31 months (range 6-96 months) and was 34 months in patients who were alive. The Kaplan-Meier estimate of overall survival at 3 years was 84.9%. The 3-year estimate of any grade temporal lobe radiation necrosis was 12.4%, and for grade 2 or higher radiation necrosis was 5.7%. On multivariate GEE, only dose–volume relationships were associated with the risk of radiation necrosis. In the EC50 model, all dose levels from 10 to 70 Gy (RBE) were highly correlated with radiation necrosis, with a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the absolute volume of a temporal lobe receiving 60 Gy (RBE) (aV60) exceeded 5.5 cm{sup 3}, or aV70 > 1.7 cm{sup 3}. Conclusions: Dose–volume parameters are highly correlated with the risk of developing temporal lobe radiation necrosis. In this study the risk of radiation necrosis increased sharply when the temporal lobe aV60 exceeded 5.5 cm{sup 3} or aV70 > 1.7 cm{sup 3}. Treatment planning goals should include constraints on the volume of temporal lobes receiving higher dose. The EC50 model provides suggested dose–volume temporal lobe constraints for conventionally fractionated high-dose skull base radiation therapy.

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A Contralateral Esophagus-Sparing Technique to Limit Severe Esophagitis Associated With Concurrent High-Dose Radiation and Chemotherapy in Patients With Thoracic Malignancies

Purpose: Severe (Radiation Therapy Oncology Group [RTOG] grade 3 or greater) esophagitis generally occurs in 15% to 25% of non–small cell lung cancer (NSCLC) patients undergoing concurrent chemotherapy and radiation therapy (CCRT), which may result in treatment breaks that compromise local tumor control and pose a barrier to dose escalation. Here, we report a novel contralateral esophagus-sparing technique (CEST) that uses intensity modulated radiation therapy (IMRT) to reduce the incidence of severe esophagitis. Methods and Materials: We reviewed consecutive patients with thoracic malignancies undergoing curative CCRT in whom CEST was used. The esophageal wall contralateral (CE) to the tumor was contoured as an avoidance structure, and IMRT was used to guide a rapid dose falloff gradient beyond the target volume in close proximity to the esophagus. Esophagitis was recorded based on the RTOG acute toxicity grading system. Results: We identified 20 consecutive patients treated with CCRT of at least 63 Gy in whom there was gross tumor within 1 cm of the esophagus. The median radiation dose was 70.2 Gy (range, 63-72.15 Gy). In all patients, ≥99% of the planning and internal target volumes was covered by ≥90% and 100% of prescription dose, respectively. Strikingly, no patient experienced grade ≥3 esophagitis (95% confidence limits, 0%-16%) despite the high total doses delivered. The median maximum dose, V45, and V55 of the CE were 60.7 Gy, 2.1 cc, and 0.4 cc, respectively, indicating effective esophagus cross-section sparing by CEST. Conclusion: We report a simple yet effective method to avoid exposing the entire esophagus cross-section to high doses. By using proposed CE dose constraints of V45 <2.5 cc and V55 <0.5 cc, CEST may improve the esophagus toxicity profile in thoracic cancer patients receiving CCRT even at doses above the standard 60- to 63-Gy levels. Prospective testing of CEST is warranted.

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A Comparative Evaluation of Normal Tissue Doses for Patients Receiving Radiation Therapy for Hodgkin Lymphoma on the Childhood Cancer Survivor Study and Recent Children's Oncology Group Trials

Purpose: Survivors of pediatric Hodgkin lymphoma (HL) are recognized to have an increased risk of delayed adverse health outcomes related to radiation therapy (RT). However, the necessary latency required to observe these late effects means that the estimated risks apply to outdated treatments. We sought to compare the normal tissue dose received by children treated for HL and enrolled in the Childhood Cancer Survivor Study (CCSS) (diagnosed 1970-1986) with that of patients treated in recent Children's Oncology Group (COG) trials (enrolled 2002-2012). Methods and Materials: RT planning data were obtained for 50 HL survivors randomly sampled from the CCSS cohort and applied to computed tomography planning data sets to reconstruct the normal tissue dosimetry. For comparison, the normal tissue dosimetry data were obtained for all 191 patients with full computed tomography–based volumetric RT planning on COG protocols AHOD0031 and AHOD0831. Results: For early-stage patients, the mean female breast dose in the COG patients was on average 83.5% lower than that for CCSS patients, with an absolute reduction of 15.5 Gy. For advanced-stage patients, the mean breast dose was decreased on average by 70% (11.6 Gy average absolute dose reduction). The mean heart dose decreased on average by 22.9 Gy (68.6%) and 17.6 Gy (56.8%) for early- and advanced-stage patients, respectively. All dose comparisons for breast, heart, lung, and thyroid were significantly lower for patients in the COG trials than for the CCSS participants. Reductions in the prescribed dose were a major contributor to these dose reductions. Conclusions: These are the first data quantifying the significant reduction in the normal tissue dose using actual, rather than hypothetical, treatment plans for children with HL. These findings provide useful information when counseling families regarding the risks of contemporary RT.

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Verification of Dose Distribution in Carbon Ion Radiation Therapy for Stage I Lung Cancer

Purpose: To evaluate robustness of dose distribution of carbon-ion radiation therapy (C-ion RT) in non-small cell lung cancer (NSCLC) and to identify factors affecting the dose distribution by simulated dose distribution. Methods and Materials: Eighty irradiation fields for delivery of C-ion RT were analyzed in 20 patients with stage I NSCLC. Computed tomography images were obtained twice before treatment initiation. Simulated dose distribution was reconstructed on computed tomography for confirmation under the same settings as actual treatment with respiratory gating and bony structure matching. Dose-volume histogram parameters, such as %D95 (percentage of D95 relative to the prescribed dose), were calculated. Patients with any field for which the %D95 of gross tumor volume (GTV) was below 90% were classified as unacceptable for treatment, and the optimal target margin for such cases was examined. Results: Five patients with a total of 8 fields (10% of total number of fields analyzed) were classified as unacceptable according to %D95 of GTV, although most patients showed no remarkable change in the dose-volume histogram parameters. Receiver operating characteristic curve analysis showed that tumor displacement and change in water-equivalent pathlength were significant predictive factors of unacceptable cases (P<.001 and P=.002, respectively). The main cause of degradation of the dose distribution was tumor displacement in 7 of the 8 unacceptable fields. A 6-mm planning target volume margin ensured a GTV %D95 of >90%, except in 1 extremely unacceptable field. Conclusions: According to this simulation analysis of C-ion RT for stage I NSCLC, a few fields were reported as unacceptable and required resetting of body position and reconfirmation. In addition, tumor displacement and change in water-equivalent pathlength (bone shift and/or chest wall thickness) were identified as factors influencing the robustness of dose distribution. Such uncertainties should be regarded in planning.

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Preliminary Results of a Phase 1 Dose-Escalation Trial for Early-Stage Breast Cancer Using 5-Fraction Stereotactic Body Radiation Therapy for Partial-Breast Irradiation

Purpose: To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Methods and Materials: Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohort to 40 Gy. Results: In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Conclusion: Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for early-stage breast cancer in the adjuvant setting.

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Predictors of Radiation Therapy–Related Gastrointestinal Toxicity From Anal Cancer Dose-Painted Intensity Modulated Radiation Therapy: Secondary Analysis of NRG Oncology RTOG 0529

Purpose: NRG Oncology RTOG 0529 assessed the feasibility of dose-painted intensity modulated radiation therapy (DP-IMRT) to reduce the acute morbidity of chemoradiation with 5-fluorouracil (5FU) and mitomycin-C (MMC) for T2-4N0-3M0 anal cancer. This secondary analysis was performed to identify patient and treatment factors associated with acute and late gastrointestinal (GI) adverse events (AEs). Methods and Materials: NRG Oncology RTOG 0529 treatment plans were reviewed to extract dose-volume data for tightly contoured small bowel, loosely contoured anterior pelvic contents (APC), and uninvolved colon outside the target volume (UC). Univariate logistic regression was performed to evaluate association between volumes of each structure receiving doses ≥5 to 60 Gy (V5-V60) in 5-Gy increments between patients with and without grade ≥2 acute and late GI AEs, and grade ≥3 acute GI AEs. Additional patient and treatment factors were evaluated in multivariate logistic regression (acute AEs) or Cox proportional hazards models (late AEs). Results: Among 52 evaluable patients, grade ≥2 acute, grade ≥2 late, and grade ≥3 acute GI AEs were observed in 35, 17, and 10 patients, respectively. Trends (P<.05) toward statistically significant associations were observed between grade ≥2 acute GI AEs and small bowel dose (V20-V40), grade ≥2 late GI AEs and APC dose (V60), grade ≥3 acute GI AEs and APC dose (V5-V25), increasing age, tumor size >4 cm, and worse Zubrod performance status. Small bowel volumes of 186.0 cc, 155.0 cc, 41.0 cc, and 30.4 cc receiving doses greater than 25, 30, 35, and 40 Gy, respectively, correlated with increased risk of acute grade ≥2 GI AEs. Conclusions: Acute and late GI AEs from 5FU/MMC chemoradiation using DP-IMRT correlate with radiation dose to the small bowel and APC. Such associations will be incorporated in the dose-volume normal tissue constraint design for future NRG oncology anal cancer studies.

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Combined photon-electron beams in the treatment of the supraclavicular lymph nodes in breast cancer: A novel technique that achieves adequate coverage while reducing lung dose

Radiation pneumonitis is a well-documented side effect of radiation therapy for breast cancer. The purpose of this study was to compare combined photon-electron, photon-only, and electron-only plans in the radiation treatment of the supraclavicular lymph nodes. In total, 13 patients requiring chest wall and supraclavicular nodal irradiation were planned retrospectively using combined photon-electron, photon-only, and electron-only supraclavicular beams. A dose of 50 Gy over 25 fractions was prescribed. Chest wall irradiation parameters were fixed for all plans. The goal of this planning effort was to cover 95% of the supraclavicular clinical target volume (CTV) with 95% of the prescribed dose and to minimize the volume receiving ≥ 105% of the dose. Comparative end points were supraclavicular CTV coverage (volume covered by the 95% isodose line), hotspot volume, maximum radiation dose, contralateral breast dose, mean total lung dose, total lung volume percentage receiving at least 20 Gy (V{sub 20} {sub Gy}), heart volume percentage receiving at least 25 Gy (V{sub 25} {sub Gy}). Electron and photon energies ranged from 8 to 18 MeV and 4 to 6 MV, respectively. The ratio of photon-to-electron fractions in combined beams ranged from 5:20 to 15:10. Supraclavicular nodal coverage was highest in photon-only (mean = 96.2 ± 3.5%) followed closely by combined photon-electron (mean = 94.2 ± 2.5%) and lowest in electron-only plans (mean = 81.7 ± 14.8%, p < 0.001). The volume of tissue receiving ≥ 105% of the prescription dose was higher in the electron-only (mean = 69.7 ± 56.1 cm{sup 3}) as opposed to combined photon-electron (mean = 50.8 ± 40.9 cm{sup 3}) and photon-only beams (mean = 32.2 ± 28.1 cm{sup 3}, p = 0.114). Heart V{sub 25} {sub Gy} was not statistically different among the plans (p = 0.999). Total lung V{sub 20} {sub Gy} was lowest in electron-only (mean = 10.9 ± 2.3%) followed by combined photon-electron (mean = 13.8 ± 2.3%) and highest in photon-only plans (mean = 16.2 ± 3%, p < 0.001). As expected, photon-only plans demonstrated the highest target coverage and total lung V{sub 20} {sub Gy}. The superiority of electron-only beams, in terms of decreasing lung dose, is set back by the dosimetric hotspots associated with such plans. Combined photon-electron treatment is a feasible technique for supraclavicular nodal irradiation and results in adequate target coverage, acceptable dosimetric hotspot volume, and slightly reduced lung dose.

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Simple shielding reduces dose to the contralateral breast during prone breast cancer radiotherapy

Our goal was to design a prone breast shield for the contralateral breast and study its efficacy in decreasing scatter radiation to the contralateral breast in a prone breast phantom setup receiving radiation therapy designed for breast cancer. We constructed a prone breast phantom setup consisting of (1) A thermoplastic mask with a left-sided depression created by a water balloon for a breast shape; (2) 2 plastic bags to hold water in the thermoplastic mask depression; (3) 2000 mL of water to fill the thermoplastic mask depression to create a water-based false breast; (4) 1-cm thick bolus placed in the contralateral breast holder; (5) 2 lead (Pb) sheets, each 0.1-cm thick for blocking scatter radiation in the contralateral bolus-based false breast; (6) a prone breast board to hold the thermoplastic mask, water, bolus, and lead; (7) 9 cm solid water on top of the breast board to simulate body; (8) a diode was used to verify dose for each treatment field of the treated water-based breast; (9) metal–oxide–semiconductor-field effect transistor (MOSFET) dosimeters to measure dose to the contralateral bolus-based breast. The phantom prone breast setup was CT simulated and treatment was designed with 95% isodose line covering the treated breast. The maximum dose was 107.1%. Megavoltage (MV) port images ensured accurate setup. Measurements were done using diodes on the treated water-based breast and MOSFET dosimeters at the medial and lateral sides of the contralateral bolus-based breast without and with the Pb shield. Five treatments were done for each of the 3 data sets and recorded individually for statistical purposes. All treatments were completed with 6 MV photons at 200 cGy per treatment. The dose contributions from each of the 3 data sets including 15 treatments total without and with the prone lead shield to the medial and lateral portions of contralateral bolus-based breast were averaged individually. Unshielded dose means were 37.11 and 2.94 cGy, and shielded dose means were 12.68 and 1.54 cGy, respectively. When comparing medial and lateral portions of the contralateral bolus-based doses without and with Pb, the shield significantly reduced dose to both sides of the contralateral breast (medial p = 2.64 × 10{sup −14}, lateral p = 4.91 × 10{sup −6}). The prone 0.2-cm Pb shield significantly reduced scatter dose to the contralateral breast on the order of 2 to 3 times. Reductions may be clinically relevant for women younger than 45 years by decreasing the risk of contralateral radiation-induced breast cancer in patients receiving radiation therapy for breast cancer. This shield is simple as it would be a part of the prone breast board during treatments, but future studies are warranted for safety and efficacy clinically.

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Comparing probabilistic and descriptive analyses of time–dose–toxicity relationship for determining no-observed-adverse-effect level in drug development

The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; and then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between-study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation. - Highlights: • Simulations revealed issues with NOAEL concept, determination and application. • Probabilistic modelling was used to address these issues. • The model integrated time-dose-toxicity data from multiple studies. • The approach uses data efficiently and may allow more meaningful human translation.

60 APPLIED LIFE SCIENCES↗

A low dose simulation tool for CT systems with energy integrating detectors

Purpose: This paper introduces a new strategy for simulating low-dose computed tomography (CT) scans using real scans of a higher dose as an input. The tool is verified against simulations and real scans and compared to other approaches found in the literature. Methods: The conditional variance identity is used to properly account for the variance of the input high-dose data, and a formula is derived for generating a new Poisson noise realization which has the same mean and variance as the true low-dose data. The authors also derive a formula for the inclusion of real samples of detector noise, properly scaled according to the level of the simulated x-ray signals. Results: The proposed method is shown to match real scans in number of experiments. Noise standard deviation measurements in simulated low-dose reconstructions of a 35 cm water phantom match real scans in a range from 500 to 10 mA with less than 5% error. Mean and variance of individual detector channels are shown to match closely across the detector array. Finally, the visual appearance of noise and streak artifacts is shown to match in real scans even under conditions of photon-starvation (with tube currents as low as 10 and 80 mA). Additionally, the proposed method is shown to be more accurate than previous approaches (1) in achieving the correct mean and variance in reconstructed images from pure-Poisson noise simulations (with no detector noise) under photon-starvation conditions, and (2) in simulating the correct noise level and detector noise artifacts in real low-dose scans. Conclusions: The proposed method can accurately simulate low-dose CT data starting from high-dose data, including effects from photon starvation and detector noise. This is potentially a very useful tool in helping to determine minimum dose requirements for a wide range of clinical protocols and advanced reconstruction algorithms.

60 APPLIED LIFE SCIENCES↗

Dose optimization in cardiac x-ray imaging

Purpose: The aim of this research was to optimize x-ray image quality to dose ratios in the cardiac catheterization laboratory. This study examined independently the effects of peak x-ray tube voltage (kVp), copper (Cu), and gadolinium (Gd) x-ray beam filtration on the image quality to radiation dose balance for adult patient sizes.Methods: Image sequences of polymethyl methacrylate (PMMA) phantoms representing two adult patient sizes were captured using a modern flat panel detector based x-ray imaging system. Tin and copper test details were used to simulate iodine-based contrast medium and stents/guide wires respectively, which are used in clinical procedures. Noise measurement for a flat field image and test detail contrast were used to calculate the contrast to noise ratio (CNR). Entrance surface dose (ESD) and effective dose measurements were obtained to calculate the figure of merit (FOM), CNR{sup 2}/dose. This FOM determined the dose efficiency of x-ray spectra investigated. Images were captured with 0.0, 0.1, 0.25, 0.4, and 0.9 mm Cu filtration and with a range of gadolinium oxysulphide (Gd{sub 2}O{sub 2}S) filtration.Results: Optimum x-ray spectra were the same for the tin and copper test details. Lower peak tube voltages were generally favored. For the 20 cm phantom, using 2 Lanex Fast Back Gd{sub 2}O{sub 2}S screens as x-ray filtration at 65 kVp provided the highest FOM considering ESD and effective dose. Considering ESD, this FOM was only marginally larger than that from using 0.4 mm Cu at 65 kVp. For the 30 cm phantom, using 0.25 mm copper filtration at 80 kVp was most optimal; considering effective dose the FOM was highest with no filtration at 65 kVp.Conclusions: These settings, adjusted for x-ray tube loading limits and clinically acceptable image quality, should provide a useful option for optimizing patient dose to image quality in cardiac x-ray imaging. The same optimal x-ray beam spectra were found for both the tin and copper details, suggesting that iodine contrast based imaging and visualization of interventional devices could potentially be optimized for dose using similar x-ray beam spectra.

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SU-E-P-03: Implementing a Low Dose Lung Screening CT Program Meeting Regulatory Requirements

Purpose: To provide information pertaining to IROC Houston QA Center's (RPC) credentialing process for institutions participating in NCI-sponsored clinical trials. Purpose: Provide guidance to the Radiology Departments with the intent of implementing a Low Dose CT Screening Program using different CT Scanners with multiple techniques within the framework of the required state regulations. Method: State Requirements for the purpose of implementing a Low Dose CT Lung Protocol required working with the Radiology and Pulmonary Department in setting up a Low Dose Screening Protocol designed to reduce the radiation burden to the patients enrolled. Radiation dose measurements (CTDIvol) for various CT manufacturers (Siemens16, Siemens 64, Philips 64, and Neusoft128) for three different weight based protocols. All scans were reviewed by the Radiologist. Prior to starting a low dose lung screening protocol, information had to be submitted to the state for approval. Performing a Healing Arts protocol requires extensive information. This not only includes name and address of the applicant but a detailed description of the disease, the x-ray examination and the population to be examined. The unit had to be tested by a qualified expert using the technique charts. The credentials of all the operators, the supervisors and the Radiologists had to be submitted to the state. Results: All the appropriate documentation was sent to the state for review. The measured results between the Low Dose Protocol versus the default Adult Chest Protocol showed that there was a dose reduction of 65% for small (100-150 lb.) patient, 75% for the Medium patient (151-250 lbs.), and a 55% reduction for the Large patient ( over 250 lbs.). Conclusion: Measured results indicated that the Low Dose Protocol indeed lowered the screening patient's radiation dose and the institution was able to submit the protocol to the State's regulators.

60 APPLIED LIFE SCIENCES↗

SU-E-J-97: Pretreatment Test and Post-Treatment Evaluation for Iso-NTCP Dose Guided Adapive Radiotherapy (DGART), Experience with Prostate Cancer Patients Treated with Rectal Balloons

Purpose: To explore the feasibility of pretreatment test for iso-NTCP DGART and to compare the pretreatment test results with post-treatment evaluations. Methods: NTCP here refers to late rectal wall toxicity only and is calculated with the ring rectal wall DVH. Simulation for one time iso- NTCP DGART starts after half of the total dose was done for 10 patients to investigate if TCP gains could be achieved. Six patients were treated using a 12-fraction 4.3Gy technique and four using 16-fraction 3.63Gy technique. For each of the 12-fraction cases a VMAT plan was generated in Pinnacle3™ using the daily CT obtained prior to the 6th fraction. A pretreatment simulation was performed using only the first 6 daily CTs. The idea is to add the 6 original plan delivered doses with 6 DGART plan delivered doses by deformable dose accumulation (DDA) on each of the first 6 CTs, resulting in 6 rectal wall doses (RWDs) and NTCPs. The 95% confidence interval (95%CI) for the 6 NTCPs were computed.The posttreatment evaluation was done by: a) copy the DGART plan to 6 CTs for fraction 7–12 and calculate the 6 actual DGART delivered fractional doses; b) sum the 6 actual DGART doses with the 6 original plan delivered doses by DDA on each of the 12 CTs resulting in 12 post-treatment RWDs and NTCPs; c) boxplot the 12 post-treatment NTCPs. Results: Target dose gain is 0.76–1.93 Gy. The 95%CI widths of the pretreatment tests NTCPs were 1.1–2.7%. For 5 patients, the planned NTCP fell within the 95%CI. For 4 patients, the planned NTCP was lower than the 95%CI lines. Post-treatment results show that for 7 patients, the upper quartile was within the 95%CI; for 2 patients, the upper quartile were higher than the 95%CI. Conclusion: The pretreatment test yields conservative prediction of the actual delivered NTCP.

60 APPLIED LIFE SCIENCES↗

SU-E-J-174: Adaptive PET-Based Dose Painting with Tomotherapy

Purpose: PET imaging can be converted into dose prescription directly. Due to the variability of the intensity of PET the image, PET prescription maybe superior over uniform dose prescription. Furthermore, unlike the case in image reconstruction of not knowing the image solution in advance, the prescribed dose is known from a PET image a priori. Therefore, optimum beam orientations are derivable. Methods: We can assume the PET image to be the prescribed dose and invert it to determine the energy fluence. The same method used to reconstruct tissue images from projections could be used to solve the inverse problem of determining beam orientations and modulation patterns from a dose prescription [10]. Unlike standard tomographic reconstruction of images from measured projection profiles, the inversion of the prescribed dose results in photon fluence which may be negative and therefore unphysical. Two-dimensional modulated beams can be modelled in terms of the attenuated or exponential radon transform of the prescribed dose function (assumed to be the PET image in this case), an application of a Ram-Lak filter, and inversion by backprojection. Unlike the case in PET processing, however, the filtered beam obtained from the inversion represents a physical photon fluence. Therefore, a positivity constraint for the fluence (setting negative fluence to zero) must be applied (Brahme et al 1982, Bortfeld et al 1990) Results: Truncating the negative profiles from the PET data results in an approximation of the derivable energy fluence. Backprojection of the deliverable fluence is an approximation of the dose delivered. The deliverable dose is comparable to the original PET image and is similar to the PET image. Conclusion: It is possible to use the PET data or image as a direct indicator of deliverable fluence for cylindrical radiotherapy systems such as TomoTherapy.

60 APPLIED LIFE SCIENCES↗