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At least 487 records · Page 27

SU-E-T-218: Investigating the Differences in Out-Of-Field Dose Between An Inherently Uniform Beam and a Flattening Filter Free Beam Made Uniform Through Inverse Modulation

Purpose: To characterize with physical measurements the out-of-field dose for flattening filter free (FFF) and IMRT flattened FFF photon beams less than 10 MV from a Siemens Artiste LINAC, field size dependence, thereof, and comparison with the Pinnacle planning system calculation. Methods: Single field plans were developed for 5×5cm{sup 2} and 20×20cm{sup 2} field sizes for 6MV and 7MV-FFF. An additional 7MV-FFF plan was developed for each field size with the purpose of delivering a uniform dose (7MV-FFFUniform), similar to 6MV, utilizing inverse modulation. The calculated and measured dose was normalized to achieve equivalence at 10cm depth in water. Out-of-field dose measurements were acquired with a farmer-type ionization chamber in solid water at incremental distances up to 90cm from the field edge at physical depths of 1.5cm and 5.0cm. The dose contribution from head leakage was determined by closing the jaws symmetrically and the MLC off-axis Results: Data collected show that the out-of-field dose for 6MV is generally greater than 7MV-FFF and 7MV-FFF-Uniform. The 7MV-FFF-Uniform dose is less than 7MV-FFF for the small field size, but similar for the larger field and may be attributed to the small IMRT segments of the 5x5 field developing narrow beam geometry with reduced scatter. The out-of-field dose from 7MV-FFF-Uniform for the 20×20 field was greater than 6MV and 7MV-FFF beyond 50cm from the field edge. Head leakage from the 7MV-FFF-Uniform segmental MU modulation was greater than the un-modulated beams. The calculated out-of-field dose was consistently −200% different than measured for a subset of points considered. Conclusion: The modulation required to deliver a uniform large field dose with 7MV-FFF will increase the peripheral dose to the patient in comparison to already physically flattened fields; however, the dose near the field edge will be reduced. If reliable out-of-field doses are needed physical measurements should be used.

60 APPLIED LIFE SCIENCES↗

TU-F-BRF-03: Effect of Radiation Therapy Planning Scan Registration On the Dose in Lung Cancer Patient CT Scans

Purpose: To characterize the effect of deformable registration of serial computed tomography (CT) scans on the radiation dose calculated from a treatment planning scan. Methods: Eighteen patients who received curative doses (≥60Gy, 2Gy/fraction) of photon radiation therapy for lung cancer treatment were retrospectively identified. For each patient, a diagnostic-quality pre-therapy (4–75 days) CT scan and a treatment planning scan with an associated dose map calculated in Pinnacle were collected. To establish baseline correspondence between scan pairs, a researcher manually identified anatomically corresponding landmark point pairs between the two scans. Pre-therapy scans were co-registered with planning scans (and associated dose maps) using the Plastimatch demons and Fraunhofer MEVIS deformable registration algorithms. Landmark points in each pretherapy scan were automatically mapped to the planning scan using the displacement vector field output from both registration algorithms. The absolute difference in planned dose (|ΔD|) between manually and automatically mapped landmark points was calculated. Using regression modeling, |ΔD| was modeled as a function of the distance between manually and automatically matched points (registration error, E), the dose standard deviation (SD-dose) in the eight-pixel neighborhood, and the registration algorithm used. Results: 52–92 landmark point pairs (median: 82) were identified in each patient's scans. Average |ΔD| across patients was 3.66Gy (range: 1.2–7.2Gy). |ΔD| was significantly reduced by 0.53Gy using Plastimatch demons compared with Fraunhofer MEVIS. |ΔD| increased significantly as a function of E (0.39Gy/mm) and SD-dose (2.23Gy/Gy). Conclusion: An average error of <4Gy in radiation dose was introduced when points were mapped between CT scan pairs using deformable registration. Dose differences following registration were significantly increased when the Fraunhofer MEVIS registration algorithm was used, spatial registration errors were larger, and dose gradient was higher (i.e., higher SD-dose). To our knowledge, this is the first study to directly compute dose errors following deformable registration of lung CT scans.

60 APPLIED LIFE SCIENCES↗

TH-A-19A-06: Site-Specific Comparison of Analytical and Monte Carlo Based Dose Calculations

Purpose: To investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict dose distributions and to verify currently used uncertainty margins in proton therapy. Methods: Dose distributions predicted by an analytical pencilbeam algorithm were compared with Monte Carlo simulations (MCS) using TOPAS. 79 complete patient treatment plans were investigated for 7 disease sites (liver, prostate, breast, medulloblastoma spine and whole brain, lung and head and neck). A total of 508 individual passively scattered treatment fields were analyzed for field specific properties. Comparisons based on target coverage indices (EUD, D95, D90 and D50) were performed. Range differences were estimated for the distal position of the 90% dose level (R90) and the 50% dose level (R50). Two-dimensional distal dose surfaces were calculated and the root mean square differences (RMSD), average range difference (ARD) and average distal dose degradation (ADD), the distance between the distal position of the 80% and 20% dose levels (R80- R20), were analyzed. Results: We found target coverage indices calculated by TOPAS to generally be around 1–2% lower than predicted by the analytical algorithm. Differences in R90 predicted by TOPAS and the planning system can be larger than currently applied range margins in proton therapy for small regions distal to the target volume. We estimate new site-specific range margins (R90) for analytical dose calculations considering total range uncertainties and uncertainties from dose calculation alone based on the RMSD. Our results demonstrate that a reduction of currently used uncertainty margins is feasible for liver, prostate and whole brain fields even without introducing MC dose calculations. Conclusion: Analytical dose calculation algorithms predict dose distributions within clinical limits for more homogeneous patients sites (liver, prostate, whole brain). However, we recommend treatment plan verification using Monte Carlo simulations for patients with complex geometries.

60 APPLIED LIFE SCIENCES↗

TU-G-204-09: The Effects of Reduced- Dose Lung Cancer Screening CT On Lung Nodule Detection Using a CAD Algorithm

Purpose: While Lung Cancer Screening CT is being performed at low doses, the purpose of this study was to investigate the effects of further reducing dose on the performance of a CAD nodule-detection algorithm. Methods: We selected 50 cases from our local database of National Lung Screening Trial (NLST) patients for which we had both the image series and the raw CT data from the original scans. All scans were acquired with fixed mAs (25 for standard-sized patients, 40 for large patients) on a 64-slice scanner (Sensation 64, Siemens Healthcare). All images were reconstructed with 1-mm slice thickness, B50 kernel. 10 of the cases had at least one nodule reported on the NLST reader forms. Based on a previously-published technique, we added noise to the raw data to simulate reduced-dose versions of each case at 50% and 25% of the original NLST dose (i.e. approximately 1.0 and 0.5 mGy CTDIvol). For each case at each dose level, the CAD detection algorithm was run and nodules greater than 4 mm in diameter were reported. These CAD results were compared to “truth”, defined as the approximate nodule centroids from the NLST reports. Subject-level mean sensitivities and false-positive rates were calculated for each dose level. Results: The mean sensitivities of the CAD algorithm were 35% at the original dose, 20% at 50% dose, and 42.5% at 25% dose. The false-positive rates, in decreasing-dose order, were 3.7, 2.9, and 10 per case. In certain cases, particularly in larger patients, there were severe photon-starvation artifacts, especially in the apical region due to the high-attenuating shoulders. Conclusion: The detection task was challenging for the CAD algorithm at all dose levels, including the original NLST dose. However, the false-positive rate at 25% dose approximately tripled, suggesting a loss of CAD robustness somewhere between 0.5 and 1.0 mGy. NCI grant U01 CA181156 (Quantitative Imaging Network); Tobacco Related Disease Research Project grant 22RT-0131.

60 APPLIED LIFE SCIENCES↗

Method for simulating dose reduction in digital mammography using the Anscombe transformation

Purpose: This work proposes an accurate method for simulating dose reduction in digital mammography starting from a clinical image acquired with a standard dose. Methods: The method developed in this work consists of scaling a mammogram acquired at the standard radiation dose and adding signal-dependent noise. The algorithm accounts for specific issues relevant in digital mammography images, such as anisotropic noise, spatial variations in pixel gain, and the effect of dose reduction on the detective quantum efficiency. The scaling process takes into account the linearity of the system and the offset of the detector elements. The inserted noise is obtained by acquiring images of a flat-field phantom at the standard radiation dose and at the simulated dose. Using the Anscombe transformation, a relationship is created between the calculated noise mask and the scaled image, resulting in a clinical mammogram with the same noise and gray level characteristics as an image acquired at the lower-radiation dose. Results: The performance of the proposed algorithm was validated using real images acquired with an anthropomorphic breast phantom at four different doses, with five exposures for each dose and 256 nonoverlapping ROIs extracted from each image and with uniform images. The authors simulated lower-dose images and compared these with the real images. The authors evaluated the similarity between the normalized noise power spectrum (NNPS) and power spectrum (PS) of simulated images and real images acquired with the same dose. The maximum relative error was less than 2.5% for every ROI. The added noise was also evaluated by measuring the local variance in the real and simulated images. The relative average error for the local variance was smaller than 1%. Conclusions: A new method is proposed for simulating dose reduction in clinical mammograms. In this method, the dependency between image noise and image signal is addressed using a novel application of the Anscombe transformation. NNPS, PS, and local noise metrics confirm that this method is capable of precisely simulating various dose reductions.

60 APPLIED LIFE SCIENCES↗

Technical Note: Enhancing the surface dose using a weak longitudinal magnetic field

Purpose: The surface dose in radiotherapy is subject to the physical properties of the radiation beam and collimator. The purpose of this work is to investigate the manipulation of surface dose using magnetic fields produced with a resistive magnet. Better understanding of the feasibility and mechanisms of altered surface dose could have important clinical applications where the surface dose must be increased for therapeutic goals, or reduced to enhance the therapeutic benefit. Methods: A resistive magnet capable of generating a peak magnetic field up to 0.24 T was integrated with a cobalt treatment unit. The magnetic fringe field of the magnet was small due to the self-shielding built within the magnet. The magnetic field at the beam collimation jaws of the cobalt irradiator was less than 10 G. The surface dose and depth dose were measured for varying magnetic field strengths. Results: The resistive magnet was able to alter the dose in the buildup region of the {sup 60}Co depth dose significantly, and the magnitude of dose enhancement was directly related to the strength of the longitudinal magnetic field. Peak magnetic fields as low as 0.08 T were able to affect the surface dose. At a peak field of 0.24 T, the authors measured a surface dose enhancement of 2.8-fold. Conclusions: Surface dose enhancement using resistive magnets is feasible. Further experimental study is needed to understand the origin of the scattered electrons that contribute to the increase in surface dose.

07 ISOTOPE AND RADIATION SOURCES↗

SU-C-BRC-03: Development of a Novel Strategy for On-Demand Monte Carlo and Deterministic Dose Calculation Treatment Planning and Optimization for External Beam Photon and Particle Therapy

Purpose: Accurate and fast dose calculation is a prerequisite of precision radiation therapy in modern photon and particle therapy. While Monte Carlo (MC) dose calculation provides high dosimetric accuracy, the drastically increased computational time hinders its routine use. Deterministic dose calculation methods are fast, but problematic in the presence of tissue density inhomogeneity. We leverage the useful features of deterministic methods and MC to develop a hybrid dose calculation platform with autonomous utilization of MC and deterministic calculation depending on the local geometry, for optimal accuracy and speed. Methods: Our platform utilizes a Geant4 based “localized Monte Carlo” (LMC) method that isolates MC dose calculations only to volumes that have potential for dosimetric inaccuracy. In our approach, additional structures are created encompassing heterogeneous volumes. Deterministic methods calculate dose and energy fluence up to the volume surfaces, where the energy fluence distribution is sampled into discrete histories and transported using MC. Histories exiting the volume are converted back into energy fluence, and transported deterministically. By matching boundary conditions at both interfaces, deterministic dose calculation account for dose perturbations “downstream” of localized heterogeneities. Hybrid dose calculation was performed for water and anthropomorphic phantoms. Results: We achieved <1% agreement between deterministic and MC calculations in the water benchmark for photon and proton beams, and dose differences of 2%–15% could be observed in heterogeneous phantoms. The saving in computational time (a factor ∼4–7 compared to a full Monte Carlo dose calculation) was found to be approximately proportional to the volume of the heterogeneous region. Conclusion: Our hybrid dose calculation approach takes advantage of the computational efficiency of deterministic method and accuracy of MC, providing a practical tool for high performance dose calculation in modern RT. The approach is generalizable to all modalities where heterogeneities play a large role, notably particle therapy.

60 APPLIED LIFE SCIENCES↗

SU-F-I-73: Surface Dose from KV Diagnostic Beams From An On-Board Imager On a Linac Machine Using Different Imaging Techniques and Filters

Purpose: To quantitatively investigate the surface dose deposited in patients imaged with a kV on-board-imager mounted on a radiotherapy machine using different clinical imaging techniques and filters. Methods: A high sensitivity photon diode is used to measure the surface dose on central-axis and at an off-axis-point which is mounted on the top of a phantom setup. The dose is measured for different imaging techniques that include: AP-Pelvis, AP-Head, AP-Abdomen, AP-Thorax, and Extremity. The dose measurements from these imaging techniques are combined with various filtering techniques that include: no-filter (open-field), half-fan bowtie (HF), full-fan bowtie (FF) and Cu-plate filters. The relative surface dose for different imaging and filtering techniques is evaluated quantiatively by the ratio of the dose relative to the Cu-plate filter. Results: The lowest surface dose is deposited with the Cu-plate filter. The highest surface dose deposited results from open fields without filter and it is nearly a factor of 8–30 larger than the corresponding imaging technique with the Cu-plate filter. The AP-Abdomen technique delivers the largest surface dose that is nearly 2.7 times larger than the AP-Head technique. The smallest surface dose is obtained from the Extremity imaging technique. Imaging with bowtie filters decreases the surface dose by nearly 33% in comparison with the open field. The surface doses deposited with the HF or FF-bowtie filters are within few percentages. Image-quality of the radiographic images obtained from the different filtering techniques is similar because the Cu-plate eliminates low-energy photons. The HF- and FF-bowtie filters generate intensity-gradients in the radiographs which affects image-quality in the different imaging technique. Conclusion: Surface dose from kV-imaging decreases significantly with the Cu-plate and bowtie-filters compared to imaging without filters using open-field beams. The use of Cu-plate filter does not affect image-quality and may be used as the default in the different imaging techniques.

60 APPLIED LIFE SCIENCES↗

SU-F-T-151: Measurement Evaluation of Skin Dose in Scanning Proton Beam Therapy for Breast Cancer

Purpose: To measure the skin dose and compare it with the calculated dose from a treatment planning system (TPS) for breast cancer treatment using scanning proton beam therapy (SPBT). Methods: A single en-face-beam SPBT plan was generated by a commercial TPS for two breast cancer patients. The treatment volumes were the entire breasts (218 cc and 1500 cc) prescribed to 50.4 Gy (RBE) in 28 fractions. A range shifter of 5 cm water equivalent thickness was used. The organ at risk (skin) was defined to be 5 mm thick from the surface. The skin doses were measured in water with an ADCL calibrated parallel plate (PP) chamber. The measured data were compared with the values calculated in the TPS. Skin dose calculations can be subject to uncertainties created by the definition of the external contour and the limitations of the correction based algorithms, such as proton convolution superposition. Hence, the external contours were expanded by 0, 3 mm and 1 cm to include additional pixels for dose calculation. In addition, to examine the effects of the cloth gown on the skin dose, the skin dose measurements were conducted with and without gown. Results: On average the measured skin dose was 4% higher than the calculated values. At deeper depths, the measured and calculated doses were in better agreement (< 2%). Large discrepancy occur for the dose calculated without external expansion due to volume averaging. The addition of the gown only increased the measured skin dose by 0.4%. Conclusion: The implemented TPS underestimated the skin dose for breast treatments. Superficial dose calculation without external expansion would result in large errors for SPBT for breast cancer.

60 APPLIED LIFE SCIENCES↗

SU-F-T-329: Characteristic Study of a Rado-Photoluminescenct Glass Dosimeter with Accumulated Dose

Purpose: This study investigated the effect of accumulated dose on radiophotoluminescent glass dosimeter in megavoltage photon. Methods: 45 commercially-available radio-photoluminescence glass dosimeters (RPLGD; GD-302M, Asahi Techno Glass Co., Shizuoka, JAPAN) were irradiated to 10 × 10 cm{sup 2} open-field with 6, 10 and 15 MV photon beams at 100 cm of source to surface distance and dose maximum depths. Each energy has consists of five groups which is consists of three detectors. A group #1 and #2 was irradiated about 1 Gy to 100 Gy, and estimated the integral dose response with and without annealing procedure. A group #3 was read the dose after irradiated 10 Gy of dose by 10 times repeatedly to estimate the fading effect of RPLGD. A group #4 and #5 was produced same ways with different irradiation dose such as 50 Gy for group #4 and 100 Gy for group #5. Results: From the results of group #1 and #2, an annealed detector shows linear response to integral dose but other detectors without the annealing process, has supra linearity for integral dose especially close to 100 Gy dose. For group #3, #4 and #5, the dose response of repeated irradiation, the dose response was decreased about 15%, 12% and 7% for 6 MV, 10 MV and 15MV. Conclusion: It was found that RPLGD response to accumulated dose was supra linear and this respond was altered with amount of accumulated dose to the RPLGD. In addition, the fading effect need to be concern with RPLGD.

36 MATERIALS SCIENCE↗

SU-F-T-381: Fast Calculation of Three-Dimensional Dose Considering MLC Leaf Positional Errors for VMAT Plans

Purpose: In this study, we developed a system to calculate three dimensional (3D) dose that reflects dosimetric error caused by leaf miscalibration for head and neck and prostate volumetric modulated arc therapy (VMAT) without additional treatment planning system calculation on real time. Methods: An original system called clarkson dose calculation based dosimetric error calculation to calculate dosimetric error caused by leaf miscalibration was developed by MATLAB (Math Works, Natick, MA). Our program, first, calculates point doses at isocenter for baseline and modified VMAT plan, which generated by inducing MLC errors that enlarged aperture size of 1.0 mm with clarkson dose calculation. Second, error incuced 3D dose was generated with transforming TPS baseline 3D dose using calculated point doses. Results: Mean computing time was less than 5 seconds. For seven head and neck and prostate plans, between our method and TPS calculated error incuced 3D dose, the 3D gamma passing rates (0.5%/2 mm, global) are 97.6±0.6% and 98.0±0.4%. The dose percentage change with dose volume histogram parameter of mean dose on target volume were 0.1±0.5% and 0.4±0.3%, and with generalized equivalent uniform dose on target volume were −0.2±0.5% and 0.2±0.3%. Conclusion: The erroneous 3D dose calculated by our method is useful to check dosimetric error caused by leaf miscalibration before pre treatment patient QA dosimetry checks.

60 APPLIED LIFE SCIENCES↗

SU-G-JeP2-09: Minimal Skin Dose Increase in Longitudinal Rotating Biplanar Linac-MR Systems: Examination of Radiation Energy and Flattening Filter Design

Purpose: To quantify increase in entrance skin-dose due to magnetic fields of the Alberta longitudinal linac-MR by examining the effect of radiation energy and flattening filter, using Monte Carlo calculations and accurate 3-D models of the magnetic field. Methods: The 3-D magnetic fields generated by the bi-planar Linac-MR are calculated with FEM using Opera-3D. BEAMnrc simulates the particle phase-space in the presence of the rapidly decaying fringe field of 0.5T MRI assembled with a Varian 600C linac with an isocentre distance of 130 cm for 6 MV and 10 MV beams. Skin doses are calculated at an average depth of 70 µm using DOSXYZnrc with varying SSDs and field sizes. Furthermore, flattening filters are reshaped to compensate for the significant drop in dose rate due to increased SAD of 130 cm and skin-doses are evaluated. Results: The confinement effect of the MRI fringe field on the contaminant electrons is minimal. For SSDs of 100 – 120 cm the increase in skin dose is ∼6% – 19% and ∼1% – 9% for the 6 and 10 MV beams, respectively. For 6MV, skin dose increases from ∼10.5% to 1.5%. for field-size increases of 5×5 cm2 to 20×20 cm2. For 10 MV, skin dose increases by ∼6% for a 5×5 cm2 field, and decreases by ∼1.5% for a 20×20 cm2 field. The reshaped flattening filter increases the dose rate from 355 MU/min to 529 MU/min (6 MV) or 604 MU/min (10 MV), while the skin-dose increases by only an additional ∼2.6% (all percent increases in skin dose are relative to Dmax). Conclusion: There is minimal increase in the entrance skin dose and minimal/no decrease in the dose rate of the Alberta longitudinal linac-MR system. There is even lower skin-dose increase at 10 MV. Funding: Alberta Innovates - Health Solutions (AIHS) Conflict of Interest: Fallone is a co-founder and CEO of MagnetTx Oncology Solutions (under discussions to license Alberta bi-planar linac MR for commercialization)

60 APPLIED LIFE SCIENCES↗

SU-G-IeP4-07: Feasibility of Low Dose 18FDG PET in Pediatric Oncology Patients

Purpose: To evaluate and demonstrate the feasibility of low dose FDG PET in pediatric oncology patients using virtual dose reduction as well as true patients PET/CT scans. Methods: Wholebody 18F-FDG PET/CT of 39 clinical pediatric patients (0.16±0.06MBq/kg) were scanned on a Gemini TF 64 system at 75±5 min post FDG injection using 3min/bed. Based on the 180s/bed listmode PET data, subsets of total counts in 120s, 90s, 60s, 30s and 15s per bed position were extracted for PET reconstruction to simulate lower dose PET at 2/3th, 1/2th, 1/3th, 1/6th and 1/12th dose levels. PET/CT scans of Jaszczak PET phantom with 6 hot hollow spheres varying with sizes and contrast ratios were performed (real PET versus simulated PET) to validate the methodology of virtual dose PET simulation. Region of interests (ROIs) were placed on lesions and normal anatomical tissues with quantitative and qualitative assessment performed. Significant lower FDG dose PET/CT of 5 research adolescents were scanned to validate the proposal and low dose PET feasibility. Results: Although all lesions are visible on the 1/12th dose PET, overall PET image quality appears to be influenced in a multi-factorial way. 30%–60% dose reduction from current standard of care FDG PET is recommended to maintain equivalent quality and PET quantification. An optimized BMI-based FDG administration is recommended (from 1.1±0.5 mCi for BMI < 18.5 to 4.8±1.5 mCi for BMI > 30). A linear lowest “Dose-BMI” relationship is given. SUVs from 1/12th to full dose PETs were identified as consistent (R2 = 1.08, 0.99, 1.01, 1.00 and 0.98). No significant variances of count density, SUV and SNR were found across certain dose ranges (p<0.01). Conclusion: Pediatric PET/CT can be performed using current time-of-flight systems at substantially lower PET doses (30–60%) than the standard of care PET/CT without compromising qualitative and quantitative image quality in clinical.

60 APPLIED LIFE SCIENCES↗

SU-G-TeP4-02: A Method for Evaluating the Direct Impact of Failed IMRT QAs On Patient Dose

Purpose: We developed a method to calculate patient doses corresponding to IMRT QA measurements in order to determine and assess the actual dose delivered for plans with failed (or borderline) IMRT QA. This work demonstrates the feasibility of automatically computing delivered patient dose from portal dosimetry measurements in the Varian TPS system, which would provide a valuable and clinically viable IMRT QA tool for physicists and physicians. Methods: IMRT QA fluences were measured using portal dosimetry, processed using in-house matlab software, and imported back into Eclipse to calculate dose on the planning CT. To validate the proposed workflow, the Eclipse calculated portal dose for a 5-field sliding window prostate boost plan was processed as described above. The resulting dose was compared to the planned dose and found to be within 0.5 Gy. Two IMRT QA results for the prostate boost plan (one that failed and one that passed) were processed and the resulting patient doses were evaluated. Results: The max dose difference between IMRT QA #1 and the original planned and approved dose is 4.5 Gy, while the difference between the planned and IMRT QA #2 dose is 4.0 Gy. The inferior portion of the PTV is slightly underdosed in both plans, and the superior portion is slightly overdosed. The patient dose resulting from IMRT QA #1 and #2 differs by only 0.5 Gy. With this new information, it may be argued that the evaluated plan alteration to obtain passing gamma analysis produced clinically irrelevant differences. Conclusion: Evaluation of the delivered QA dose on the planning CT provides valuable information about the clinical relevance of failed or borderline IMRT QAs. This particular workflow demonstrates the feasibility of pushing the measured IMRT QA portal dosimetry results directly back onto the patient planning CT within the Varian system.

60 APPLIED LIFE SCIENCES↗

Dose-finding studies in drug development for rare genetic diseases

The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure–response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure–response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.

60 APPLIED LIFE SCIENCES↗

Broadly Applicable Dose Model for Radiotherapy Beams from 6-25 MV

The goal of modern external beam radiotherapy is to deliver a highly targeted radiation dose to a specified treatment volume while sparing the healthy surrounding tissue as much as possible. However, some healthy tissue radiation exposure is unavoidable. Healthy tissue in the margin of the treatment field will receive absorbed doses on the order of the prescribed dose, and tissue far out of field will receive stray dose from scattered and leakage radiation. These doses can lead to late effects such as secondary cancers both near the treatment field and far out of field in tissues only receiving stray radiation dose. Many researchers have investigated algorithms to model absorbed dose from external beam photon radiation therapy; however, none of these works have fully addressed the stray dose far from the treatment field. The AAPM Task Group Report No. 36 described three main sources of stray radiation from external beam radiation therapy delivered with electron linear accelerators. Radiation scattered from the treatment head, known as head scatter, is primarily important within about 10 cm from the field edge. Patient scatter is an important source up to around 30 cm from the field edge. Finally, leakage radiation emanates from the treatment enclosure and predominates the stray radiation dose beyond about 30 cm. Monte Carlo simulations have been a useful research tool for modeling stray dose, but these methods have not found use in clinical settings due to their complexity and long computational times. The feasibility of analytical models to predict stray dose from radiation therapy has been supported by several works, but few attempts have been made at developing models accurate for both in-field and out-of-field doses. Jagetic and Newhauser reported on one such model that predicts absorbed dose from therapeutic, scatter, and leakage radiation with promising results. This model was validated at 6 MV for Conformal Radiation Therapy (CRT) beams from an Elekta linac. Intensity Modulated Radiation Therapy (IMRT) was not considered, and the model has not been tested at beam energies greater than 6 MV. Additionally, this model relies on proprietary, machine specific parameters, and so adapting the model for use on treatment units from other manufacturers is not straightforward. In this study we aim to test whether a physics-based analytical modeling approach is broadly applicable and if sufficient accuracy can be achieved without the need for proprietary, machine specific parameters. In order to accomplish this, a new analytical model was developed that does not rely on machine specific parameters, so that it can easily be trained on measurements from whatever treatment machine is available at a given clinic. This model was tested using measured data from a variety of treatment machines and techniques in the 6 MV to 25 MV energy interval. (authors)

61 RADIATION PROTECTION AND DOSIMETRY↗

Improving perfusion defect detection with respiratory motion correction in cardiac SPECT at standard and reduced doses

Background: In cardiac SPECT perfusion imaging, respiratory motion can cause non-uniform blurring in the reconstructed myocardium. We investigate the potential benefit of respiratory correction with respiratory-binned acquisitions, both at standard dose and at reduced dose, for defect detection and for left ventricular (LV) wall resolution. Methods: We applied two reconstruction methods for respiratory motion correction: post-reconstruction motion correction (PMC) and motion-compensated reconstruction (MCR), and compared with reconstruction without motion correction (Non-MC). We quantified the presence of perfusion defects in reconstructed images by using the total perfusion deficit (TPD) scores and conducted receiver-operating-characteristic (ROC) studies using TPD. We quantified the LV spatial resolution by using the FWHM of its cross-sectional intensity profile. Results: The values in the area-under-the-ROC-curve (AUC) achieved by MCR, PMC, and Non-MC at standard dose were 0.835, 0.830, and 0.798, respectively. Similar AUC improvements were also obtained by MCR and PMC over Non-MC at 50%, 25%, and 12.5% of full dose. Improvements in LV resolution were also observed with motion correction. Conclusions: Respiratory-binned acquisitions can improve perfusion-defect detection accuracy over traditional reconstruction both at standard dose and at reduced dose. Motion correction may contribute to achieving further dose reduction while maintaining the diagnostic accuracy of traditional acquisitions. [French] French Abstract: Contexte: Les mouvements respiratoires peuvent entrainer des artefacts de uniformité lors de la reconstruction des images de perfusion myocardique en SPECT. Dans cet article, nous rapportons nos résultats sur le bénéfice potentiel du « gating » respiratoire avec des doses standards et réduites de radio-pharmaceutiques pour la détection des anomalies de perfusion et les mesures de la paroi ventriculaire gauche. Méthodes: Nous avons appliqué deux méthodes de reconstruction pour la correction du mouvement respiratoire: la première fait appel a une correction après reconstruction des images (PMC) ; la seconde fait appel à la correction des images avant reconstruction (MRC). Les deux approches ont été comparées à la reconstruction sans correction de mouvement (Non-MC). Nous avons quantifié les déficits de perfusion myocardiques sur les images reconstruites avec le système des scores de déficit de perfusion et analysé les résultats en utilisant les courbes ROC. Nous avons quantifié la résolution spatiale du VG en utilisant le FWHM du profil d’intensité de sa section transversale. Résultats: Les valeurs des surfaces en dessous des courbes ROC (AUC) obtenues par MCR, PMC et Non-MC avec doses standard de radio-pharmaceutiques étaient de 0,835, 0,830 et 0,798, respectivement. Des améliorations similaires de l’AUC ont également été obtenues par MCR et PMC sur Non-MC avec 50%, 25% et 12,5% des doses entières. Les mesures de résolution spatiale de la paroi du VG ont également été améliorées avec la correction des mouvements respiratoires. Conclusions: La correction des images de perfusion myocardiques en SPECT par « gating » respiratoire paraît améliorer la quantification des déficits perfusionels à la fois à dose standard et à dose réduite de radio-pharmaceutiques. L’application de cette correction devrait permettre de réduire les doses de radio-pharmaceutiques utilisées tout en maintenant la précision diagnostique des acquisitions traditionnelles. [Spanish] Spanish Abstract: Antecedentes: En los estudios de perfusión cardiaca por SPECT, los movimientos respiratorios pueden causar distorsión no uniforme en el miocardio reconstruido. Investigamos el beneficio potencial de la corrección respiratoria con adquisición de imágenes sincronizadas con la respiración, tanto a dosis estándar como a dosis reducida, para detección de defectos y para resolución de pared de ventrículo izquierdo (VI). Métodos: Aplicamos dos métodos de reconstrucción para corrección de movimientos respiratorios: Corrección de movimiento post reconstrucción (PMC) y reconstrucción compensada a movimiento (MCR), y los comparamos con la reconstrucción sin corrección de movimiento (Non-MC). Cuantificamos la presencia de defectos de perfusión en las imágenes reconstruidas usando los scores de déficit total de perfusión (TPD) y análisis ROC usando el TPD. Cuantificamos la resolución espacial del VI usando la anchura a media altura de su perfil de intensidad transversal. Resultados: Los valores en el área bajo la curva ROC (ABC) obtenidos por MCR, PMC y Non-MC a dosis estándar fueron 0.835, 0.830 y 0.798, respectivamente. Mejorías similares del ABC también se obtuvieron por MCR y PMC, sobre Non-MC a 50%, 25% y 12.5% de la dosis completa. Las mejorías en la resolución del VI fueron observadas también con corrección del movimiento. Conclusiones: Las adquisiciones sincronizadas con la respiración pueden mejorar la precisión de la detección de defectos de perfusión sobre las reconstrucciones tradicionales tanto a dosis estándar como a dosis reducida. La corrección de movimiento puede contribuir a lograr mayor reducción de la dosis manteniendo la precisión diagnóstica de las adquisiciones tradicionales. [Chinese] Chinese Abstract: 背景: 在心脏 SPECT 灌注成像中, 呼吸运动会导致心肌重建的不均匀模糊。我们研究了无论是标准剂量还是减少剂量的情况下, 呼吸跟踪采集的呼吸校正用于图像缺损检测和左心室 (LV) 室壁分辨率的潜在益处。 方法: 我们使用了两种呼吸运动校正的重建方法:重建后运动校正 (PMC) 和运动补偿重建 (MCR), 并与没有运动校正的重建 (Non-MC) 进行比较。 通过总灌注缺损 (TPD) 评分和其接受者操作特性曲线 (ROC) 来量化重建图像中的灌注缺陷。通过LV横截面强度分布的 FWHM来量化 LV 空间分辨率。 结果: MCR, PMC 和 Non-MC 在标准剂量下所获得的 ROC 曲线下面积 (AUC) 的值分别为0.835, 0.830 和 0.798。 在全剂量下, MCR, PMC和 Non-MC也获得类似的 AUC 提高, 分别为 50%, 25% 和 12.5%。 在运动校正下, LV的分辨率也得到了改善。 结论: 在标准剂量和减少剂量的情况下, 呼吸跟踪采集可以改善灌注缺损检测的准确性。 运动校正可能有助于进一步实现减少剂量的目标, 同时保证通过传统检测方法的诊断准确性。.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

SU-F-T-258: Efficacy of Exit Fluence-Based Dose Calculation for Prostate Radiation Therapy

Purpose: To investigate the efficacy of exit-fluence-based dose computation for prostate radiotherapy by determining if it estimates true dose more accurately than the original planning dose. Methods: Virtual exit-fluencebased dose computation was performed for 19 patients, each with 9–12 repeat CT images. For each patient, a 78 Gy treatment plan was created utilizing 5 mm CTV-to-PTV and OAR-to-PRV margins. A Monte Carlo framework was used to compute dose and exit-fluence images for the planning image and for each repeat CT image based on boney-anatomyaligned and prostate-centroid-aligned CTs. Identical source particles were used for the MC dose-computations on the planning and repeat CTs to maximize correlation. The exit-fluence-based dose and image were computed by multiplying source particle weights by FC(x,y)=FP(x,y)/FT(x,y), where (x,y) are the source particle coordinates projected to the exit-fluence plane and we denote the dose/fluence from the plan by (DP,FP), from the repeat-CT as (DT,FT), and the exit-fluence computation by (DFC,FFC). DFC mimics exit-fluence backprojection through the planning image as FT=FFC. Dose estimates were intercompared to judge the efficacy of exit-fluence-based dose computation. Results: Boney- and prostate-centroid aligned results are combined as there is no statistical difference between them, yielding 420 dose comparisons per dose-volume metric. DFC is more accurate than DP for 46%, 33%, and 44% of cases in estimating CTV D98, D50, and D2 respectively. DFC improved rectum D50 and D2 estimates 54% and 49% respectively and bladder D50 and D2 47 and 49% respectively. While averaged over all patients and images DFC and DP were within 3.1% of DT, they differed from DT by as much as 22% for GTV D98, 71% for the Bladder D50, 17% for Bladder D2, 19% for Rectum D2. Conclusion: Exit-fluence based dose computations infrequently improve CTV or OAR dose estimates and should be used with caution. Research supported in part by Varian Medical Systems.

60 APPLIED LIFE SCIENCES↗