The impact of advancing the standard of care in radiotherapy on operational treatment resources.

PURPOSE: To demonstrate the impact of implementing hypofractionated prescription regimens and advanced treatment techniques on institutional operational hours and radiotherapy personnel resources in a multi-institutional setting. The study may be used to describe the impact of advancing the standard of care with modern radiotherapy techniques on patient and staff resources. METHODS: This study uses radiation therapy data extracted from the radiotherapy information system from two tertiary care, university-affiliated cancer centers from 2012 to 2021. Across all patients in the analysis, the average fraction number for curative and palliative patients was reported each year in the decade. Also, the institutional operational treatment hours are reported for both centers. A sub-analysis for curative intent breast and lung radiotherapy patients was performed to contextualize the impact of changes to imaging, motion management, and treatment technique. RESULTS: From 2012 to 2021, Center 1 had 42 214 patient plans and Center 2 had 43 252 patient plans included in the analysis. Averaged over both centers across the decade, the average fraction number per patient decreased from 6.9 to 5.2 (25%) and 21.8 to 17.2 (21%) for palliative and curative patients, respectively. The operational treatment hours for both institutions increased from 8 h 15 min to 9 h 45 min (18%), despite a patient population increase of 45%. CONCLUSION: The clinical implementation of hypofractionated treatment regimens has successfully reduced the radiotherapy workload and operational treatment hours required to treat patients. This analysis describes the impact of changes to the standard of care on institutional resources.

Impact of abdominal compression on heart and stomach motion for stereotactic arrhythmia radioablation.

PURPOSE: To evaluate the effectiveness of abdominal compression (AC) as a respiratory motion management method for the heart and stomach during stereotactic arrhythmia radioablation (STAR). METHODS: 4D computed tomography (4DCT) scans of patients imaged with AC or without AC (free-breathing: FB) were obtained from ventricular-tachycardia (VT) (n = 3), lung cancer (n = 18), and liver cancer (n = 18) patients. Patients treated for VT were imaged both FB and with AC. Lung and liver patients were imaged once with FB or with AC, respectively. The heart, left ventricle (LV), LV components (LVCs), and stomach were contoured on each phase of the 4DCTs. Centre of mass (COM) translations in the left/right (LR), ant/post (AP), and sup/inf (SI) directions were measured for each structure. Minimum distances between LVCs and the stomach over the respiratory cycle were also measured on each 4DCT phase. Mann-Whitney U-tests were performed between AC and FB datasets with a significance of α = 0.05. RESULTS: No statistical difference (all p values were >0.05) was found in COM translations between FB and AC patient datasets for all contoured cardiac structures. A reduction in COM translation with AC relative to FB was patient, direction, and structure specific for the three VT patients. A significant decrease in the AP range of motion of the stomach was observed under AC compared to FB. No statistical difference was found between minimum distances to the stomach and LVCs between FB and AC. CONCLUSIONS: AC was not a consistent motion management method for STAR, nor does not uniformly affect the separation distance between LVCs and the stomach. If AC is employed in future STAR protocols, the motion of the target volume and its relative distance to the stomach should be compared on two 4DCTs: one while the patient is FB and one under AC.

Generation and comparison of 3D dosimetric reference datasets for COMS eye plaque brachytherapy using model-based dose calculations.

PURPOSE: A joint Working Group of the American Association of Physicists in Medicine (AAPM), the European Society for Radiotherapy and Oncology (ESTRO), and the Australasian Brachytherapy Group (ABG) was created to aid in the transition from the AAPM TG-43 dose calculation formalism, the current standard, to model-based dose calculations. This work establishes the first test cases for low-energy photon-emitting brachytherapy using model-based dose calculation algorithms (MBDCAs). ACQUISITION AND VALIDATION METHODS: Five test cases are developed: (1) a single model 6711 125 I brachytherapy seed in water, 13 seeds (2) individually and (3) in combination in water, (4) the full Collaborative Ocular Melanoma Study (COMS) 16 mm eye plaque in water, and (5) the full plaque in a realistic eye phantom. Calculations are done with four Monte Carlo (MC) codes and a research version of a commercial treatment planning system (TPS). For all test cases, local agreement of MC codes was within ∼2.5% and global agreement was ∼2% (4% for test case 5). MC agreement was within expected uncertainties. Local agreement of TPS with MC was within 5% for test case 1 and ∼20% for test cases 4 and 5, and global agreement was within 0.4% for test case 1 and 10% for test cases 4 and 5. DATA FORMAT AND USAGE NOTES: Dose distributions for each set of MC and TPS calculations are available online (https://doi.org/10.52519/00005) along with input files and all other information necessary to repeat the calculations. POTENTIAL APPLICATIONS: These data can be used to support commissioning of MBDCAs for low-energy brachytherapy as recommended by TGs 186 and 221 and AAPM Report 372. This work additionally lays out a sample framework for the development of test cases that can be extended to other applications beyond eye plaque brachytherapy.

Durvalumab-Associated Pneumonitis in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Real-World Population Study.

The PACIFIC trial led to a new standard of care for patients with locally advanced lung cancer, but real-world practice has demonstrated that immune checkpoint inhibitor (ICI) pneumonitis can lead to significant clinical complications. This study aimed to examine the clinical predictors, outcomes, and healthcare utilization data in patients who received consolidation durvalumab. Using the Alberta Immunotherapy Database, NSCLC patients who received durvalumab in Alberta, Canada, from January 2018 to December 2021 were retrospectively evaluated. We examined incidence and predictive values of severe pneumonitis, with overall survival (OS) and time-to-treatment failure (TTF) using exploratory multivariate analyses. Of 189 patients, 91% were ECOG 0-1 and 85% had a partial response from chemoradiation prior to durvalumab. Median TTF and OS were not reached; 1-year OS was 82%. An amount of 26% developed any grade of pneumonitis; 9% had ≥grade 3 pneumonitis. Male gender and a pre-existing autoimmune condition were associated with severe pneumonitis. V20 was associated with any grade of pneumonitis. Pneumonitis development was found to be an independent risk factor for worse OS (p = 0.038) and TTF (p = 0.007). Our results suggest clinical and dosimetric predictive factors of durvalumab-associated pneumonitis. These results affirm the importance of careful patient selection for safe completion of consolidation durvalumab in real-world LA-NSCLC population.

High replication stress and limited Rad51-mediated DNA repair capacity, but not oxidative stress, underlie oligodendrocyte precursor cell radiosensitivity.

Cranial irradiation is part of the standard of care for treating pediatric brain tumors. However, ionizing radiation can trigger serious long-term neurologic sequelae, including oligodendrocyte and brain white matter loss enabling neurocognitive decline in children surviving brain cancer. Oxidative stress-mediated oligodendrocyte precursor cell (OPC) radiosensitivity has been proposed as a possible explanation for this. Here, however, we demonstrate that antioxidants fail to improve OPC viability after irradiation, despite suppressing oxidative stress, suggesting an alternative etiology for OPC radiosensitivity. Using systematic approaches, we find that OPCs have higher irradiation-induced and endogenous γH2AX foci compared to neural stem cells, neurons, astrocytes and mature oligodendrocytes, and these correlate with replication-associated DNA double strand breakage. Furthermore, OPCs are reliant upon ATR kinase and Mre11 nuclease-dependent processes for viability, are more sensitive to drugs increasing replication fork collapse, and display synthetic lethality with PARP inhibitors after irradiation. This suggests an insufficiency for homology-mediated DNA repair in OPCs-a model that is supported by evidence of normal RPA but reduced RAD51 filament formation at resected lesions in irradiated OPCs. We therefore propose a DNA repair-centric mechanism of OPC radiosensitivity, involving chronically-elevated replication stress combined with 'bottlenecks' in RAD51-dependent DNA repair that together reduce radiation resilience.

Competency-Based Medical Education in Radiation Therapy Treatment Planning.

PURPOSE: To develop a technology-enhanced education methodology with competency-based evaluation for radiation therapy treatment planning. The education program is designed for integration in the existing framework of Commission on Accreditation of Medical Physics Education Programs (CAMPEP) accredited medical physics residency programs. METHODS AND MATERIALS: This education program pairs an accessible, multi-institutional infrastructure with established medical education evaluation tools to modernize treatment planning education. This program includes 3 evaluation components: (1) competency-based evaluation, (2) inter- and intramodality comparison, and (3) learner feedback. For this study, synchronous bilateral breast cancer was selected to demonstrate a complex treatment site and nonstandardized technique. Additionally, an online study was made available to a public cohort of worldwide participants of certified Medical Dosimetrists and Medical Physicists to benchmark performance. Before evaluation, learners were given a disease site-specific education session on potential clinical treatment strategies. During the assessment, learners generated treatment plans in their institutional planning system under the direct observation of an expert evaluator. Qualitative proficiency was evaluated for all learners on a 5-point scale of graduated task independence. Quantitative dosimetry was compared between the learner cohort and public cohort. A feedback session provided learners context of multi-institutional experience through multimodality and technique comparison. After study completion, learners were provided a survey that was used to gauge their perception of the education program. RESULTS: In the public study, 34 participants submitted treatment plans. Across 3 CAMPEP-accredited residency programs, 6 learners participated in the education and evaluation program. All learners successfully completed treatment plans that met the dosimetric constraints described in the case study. All learners favorably reviewed the study either comprehensively or in specified domains. CONCLUSIONS: The competency-based education and evaluation program developed in this work has been incorporated in CAMPEP-accredited residency programs and is adaptable to other residency programs with minimal resource commitment.

Dosimetry of a sonolucent material for an ultrasound-compatible gynecologic high-dose-rate brachytherapy cylinder using Monte Carlo simulation and radiochromic film.

PURPOSE: he purpose of this study was to study the dosimetric characterization of sonolucent material "TPX" to be used toward gynecologic high-dose-rate brachytherapy treatments using ultrasound-compatible cylinders in non-model-based dose calculation workflows. METHODS: Monte Carlo simulations were performed using EGSnrc application egs_brachy in cylinders of polymethylpentene (TPX) plastic, water, and PMMA. Simulations were performed of five 192Ir sources placed longitudinally in ∼3.7 cm diameter, 5.0 cm length cylinders (matching physical cylinders used in film measurements). TPX and PMMA dose distributions and percentage depth dose curves were compared relative to water. Film measurements were performed to validate egs_brachy simulations. TPX and PMMA cylinders were placed in a water tank using 3D-printed supports to position film radially and touching the surface of the cylinders. The same five 192Ir dwell positions were delivered as simulated in egs_brachy. RESULTS: The egs_brachy and film percentage depth doses agreed within film uncertainties. The egs_brachy relative dose difference between TPX and water was (0.74 ± 0.09)% and between PMMA and water was (-0.79 ± 0.09)% over the dose scoring phantom. Dose differences for TPX and PMMA relative to water were less than ± 1% within 5 cm of the cylinder surface. CONCLUSIONS: In a solid sonolucent sheath of TPX, the dosimetric differences are comparable with PMMA and other applicator materials in clinical use. No additional uncertainty to dose calculation is introduced when treating through TPX cylinders compared with current applicator materials, and therefore, it is acceptable to perform gynecologic brachytherapy treatments with a sonolucent sheath inserted during radiation delivery.

A high-throughput alpha particle irradiation system for monitoring DNA damage repair, genome instability and screening in human cell and yeast model systems.

Ionizing radiation (IR) is environmentally prevalent and, depending on dose and linear energy transfer (LET), can elicit serious health effects by damaging DNA. Relative to low LET photon radiation (X-rays, gamma rays), higher LET particle radiation produces more disease causing, complex DNA damage that is substantially more challenging to resolve quickly or accurately. Despite the majority of human lifetime IR exposure involving long-term, repetitive, low doses of high LET alpha particles (e.g. radon gas inhalation), technological limitations to deliver alpha particles in the laboratory conveniently, repeatedly, over a prolonged period, in low doses and in an affordable, high-throughput manner have constrained DNA damage and repair research on this topic. To resolve this, we developed an inexpensive, high capacity, 96-well plate-compatible alpha particle irradiator capable of delivering adjustable, low mGy/s particle radiation doses in multiple model systems and on the benchtop of a standard laboratory. The system enables monitoring alpha particle effects on DNA damage repair and signalling, genome stability pathways, oxidative stress, cell cycle phase distribution, cell viability and clonogenic survival using numerous microscopy-based and physical techniques. Most importantly, this method is foundational for high-throughput genetic screening and small molecule testing in mammalian and yeast cells.

Delivered dose changes in COMS plaque-based ocular brachytherapy arising from vitrectomy with silicone oil replacement.

PURPOSE: The purpose of the study was to determine dosimetric effects of performing concurrent I-125 Collaborative Ocular Melanoma Study plaque brachytherapy and vitrectomy with replacement using silicone oil, previously shown to be a means of shielding uninvolved parts of the eye. METHODS AND MATERIALS: Monte Carlo simulations using MCNP6 were performed to compare the dosimetry with all eye materials assigned as water, and for the vitreous (excluding the tumor), composed of polydimethylsiloxane oil for three generic, one large tumor, and two patient geometry scenarios. Dose was scored at the tumor apex, along the sclera, and within a 3D grid encompassing the eye. The assessed patient cases included vitrectomies to treat intraocular pathologies; not to enhance attenuation/shielding. RESULTS: The doses along the sclera and for the entire eye were decreased when the silicone oil replaced the vitreal fluid, with a maximum decrease at the opposite sclera of 63%. Yet, absolute changes in dose to critical structures were often small and likely not clinically significant. The dose at the tumor apex was decreased by 3.1-9.4%. Dose was also decreased at the edges of the tumor because of decreased backscatter at the tumor-oil interface. CONCLUSIONS: Concurrent silicone vitrectomy was found to reduce total radiation dose to the eye. Based on current radiation retinopathy predictive models, the evaluation of the absolute doses revealed only a subset of patients in which a clinically significant difference in outcomes is expected. Furthermore, the presence of the silicone oil decreased dose to the tumor edges, indicating that the tumor could be underdosed if the oil is unaccounted for.

Advanced Collapsed cone Engine dose calculations in tissue media for COMS eye plaques loaded with I-125 seeds.

PURPOSE: To investigate the dose calculation accuracy of the Advanced Collapsed cone Engine (ACE) algorithm for ocular brachytherapy using a COMS plaque loaded with I-125 seeds for two heterogeneous patient tissue scenarios. METHODS: The Oncura model 6711 I-125 seed and 16 mm COMS plaque were added to a research version (v4.6) of the Oncentra® Brachy (OcB) treatment planning system (TPS) for dose calculations using ACE. Treatment plans were created for two heterogeneous cases: (a) a voxelized eye phantom comprising realistic eye materials and densities and (b) a patient CT dataset with variable densities throughout the dataset. ACE dose calculations were performed using a high accuracy mode, high-resolution calculation grid matching the imported CT datasets (0.5 × 0.5 × 0.5 mm3 ), and a user-defined CT calibration curve. The accuracy of ACE was evaluated by replicating the plan geometries and comparing to Monte Carlo (MC) calculated doses obtained using MCNP6. The effects of the heterogeneous patient tissues on the dose distributions were also evaluated by performing the ACE and MCNP6 calculations for the same scenarios but setting all tissues and air to water. RESULTS: Average local percent dose differences between ACE and MC within contoured structures and at points of interest for both scenarios ranged from 1.2% to 20.9%, and along the plaque central axis (CAX) from 0.7% to 7.8%. The largest differences occurred in the plaque penumbra (up to 17%), and at contoured structure interfaces (up to 20%). Other regions in the eye agreed more closely, within the uncertainties of ACE dose calculations (~5%). Compared to that, dose differences between water-based and fully heterogeneous tissue simulations were up to 27%. CONCLUSIONS: Overall, ACE dosimetry agreed well with MC in the tumor volume and along the plaque CAX for the two heterogeneous tissue scenarios, indicating that ACE could potentially be used for clinical ocular brachytherapy dosimetry. In general, ACE data matched the fully heterogeneous MC data more closely than water-based data, even in regions where the ACE accuracy was relatively low. However, depending on the plaque position, doses to critical structures near the plaque penumbra or at tissue interfaces were less accurate, indicating that improvements may be necessary. More extensive knowledge of eye tissue compositions is still required.

Initial evaluation of Advanced Collapsed cone Engine dose calculations in water medium for I-125 seeds and COMS eye plaques.

PURPOSE: To investigate the dose calculation accuracy in water medium of the Advanced Collapsed cone Engine (ACE) for three sizes of COMS eye plaques loaded with low-energy I-125 seeds. METHODS: A model of the Oncura 6711 I-125 seed was created for use with ACE in Oncentra® Brachy (OcB) using primary-scatter separated (PSS) point dose kernel and Task Group (TG) 43 datasets. COMS eye plaque models of diameters 12, 16, and 20 mm were introduced into the OcB applicator library based on 3D CAD drawings of the plaques and Silastic inserts. To perform TG-186 level 1 commissioning, treatment plans were created in OcB for a single source in water and for each COMS plaque in water for two scenarios: with only one centrally loaded seed, or with all seed positions loaded. ACE dose calculations were performed in high accuracy mode with a 0.5 × 0.5 × 0.5 mm3 calculation grid. The resulting dose data were evaluated against Monte Carlo (MC) calculated doses obtained with MCNP6, using both local and global percent differences. RESULTS: ACE doses around the source for the single seed in water agreed with MC doses on average within < 5% inside a 6 × 6 × 6 cm3 region, and within < 1.5% inside a 2 × 2 × 2 cm3 region. The PSS data were generated at a higher resolution within 2 cm from the source, resulting in this improved agreement closer to the source due to fewer approximations in the ACE dose calculation. Average differences in both investigated plaque loading patterns in front of the plaques and on the plaque central axes were ≤ 2.5%, though larger differences (up to 12%) were found near the plaque lip. CONCLUSIONS: Overall, good agreement was found between ACE and MC dose calculations for a single I-125 seed and in front of the COMS plaques in water. More complex scenarios need to be investigated to determine how well ACE handles heterogeneous patient materials.

Experimental assessment of the Advanced Collapsed-cone Engine for scalp brachytherapy treatments.

PURPOSE: To experimentally assess the performance of the Advanced Collapsed-cone Engine (ACE) for 192Ir high-dose-rate brachytherapy treatment planning of nonmelanoma skin cancers of the scalp. METHODS AND MATERIALS: A layered slab phantom was designed to model the head (skin, skull, and brain) and surface treatment mold using tissue equivalent materials. Six variations of the phantom were created by varying skin thickness, skull thickness, and size of air gap between the mold and skin. Treatment planning was initially performed using the Task Group 43 (TG-43) formalism with CT images of each phantom variation. Doses were recalculated using standard and high accuracy modes of ACE. The plans were delivered to Gafchromic EBT3 film placed between different layers of the phantom. RESULTS: Doses calculated by TG-43 and ACE and those measured by film agreed with each other at most locations within the phantoms. For a given phantom variation, average TG-43- and ACE-calculated doses were similar, with a maximum difference of (3 ± 12)% (k = 2). Compared to the film measurements, TG-43 and ACE overestimated the film-measured dose by (13 ± 12)% (k = 2) for one phantom variation below the skull layer. CONCLUSIONS: TG-43- and ACE-calculated and film-measured doses were found to agree above the skull layer of the phantom, which is where the tumor would be located in a clinical case. ACE appears to underestimate the attenuation through bone relative to that measured by film; however, the dose to bone is below tolerance levels for this treatment.

Experimental verification of Advanced Collapsed-cone Engine for use with a multichannel vaginal cylinder applicator.

Model-based dose calculation algorithms have recently been incorporated into brachytherapy treatment planning systems, and their introduction requires critical evaluation before clinical implementation. Here, we present an experimental evaluation of Oncentra® Brachy Advanced Collapsed-cone Engine (ACE) for a multichannel vaginal cylinder (MCVC) applicator using radiochromic film. A uniform dose of 500 cGy was specified to the surface of the MCVC using the TG-43 dose formalism under two conditions: (a) with only the central channel loaded or (b) only the peripheral channels loaded. Film measurements were made at the applicator surface and compared to the doses calculated using TG-43, standard accuracy ACE (sACE), and high accuracy ACE (hACE). When the central channel of the applicator was used, the film measurements showed a dose increase of (11 ± 8)% (k = 2) above the two outer grooves on the applicator surface. This increase in dose was confirmed with the hACE calculations, but was not confirmed with the sACE calculations at the applicator surface. When the peripheral channels were used, a periodic azimuthal variation in measured dose was observed around the applicator. The sACE and hACE calculations confirmed this variation and agreed within 1% of each other at the applicator surface. Additionally for the film measurements with the central channel used, a baseline dose variation of (10 ± 4)% (k = 2) of the mean dose was observed azimuthally around the applicator surface, which can be explained by offset source positioning in the central channel.

A brief look at model-based dose calculation principles, practicalities, and promise.

Model-based dose calculation algorithms (MBDCAs) have recently emerged as potential successors to the highly practical, but sometimes inaccurate TG-43 formalism for brachytherapy treatment planning. So named for their capacity to more accurately calculate dose deposition in a patient using information from medical images, these approaches to solve the linear Boltzmann radiation transport equation include point kernel superposition, the discrete ordinates method, and Monte Carlo simulation. In this overview, we describe three MBDCAs that are commercially available at the present time, and identify guidance from professional societies and the broader peer-reviewed literature intended to facilitate their safe and appropriate use. We also highlight several important considerations to keep in mind when introducing an MBDCA into clinical practice, and look briefly at early applications reported in the literature and selected from our own ongoing work. The enhanced dose calculation accuracy offered by a MBDCA comes at the additional cost of modelling the geometry and material composition of the patient in treatment position (as determined from imaging), and the treatment applicator (as characterized by the vendor). The adequacy of these inputs and of the radiation source model, which needs to be assessed for each treatment site, treatment technique, and radiation source type, determines the accuracy of the resultant dose calculations. Although new challenges associated with their familiarization, commissioning, clinical implementation, and quality assurance exist, MBDCAs clearly afford an opportunity to improve brachytherapy practice, particularly for low-energy sources.

Delivered dose uncertainty analysis at the tumor apex for ocular brachytherapy.

PURPOSE: To estimate the total dosimetric uncertainty at the tumor apex for ocular brachytherapy treatments delivered using 16 mm Collaborative Ocular Melanoma Study (COMS) and Super9 plaques loaded with (125)I seeds in order to determine the size of the apex margin that would be required to ensure adequate dosimetric coverage of the tumor. METHODS: The total dosimetric uncertainty was assessed for three reference tumor heights: 3, 5, and 10 mm, using the Guide to the expression of Uncertainty in Measurement/National Institute of Standards and Technology approach. Uncertainties pertaining to seed construction, source strength, plaque assembly, treatment planning calculations, tumor height measurement, plaque placement, and plaque tilt for a simple dome-shaped tumor were investigated and quantified to estimate the total dosimetric uncertainty at the tumor apex. Uncertainties in seed construction were determined using EBT3 Gafchromic film measurements around single seeds, plaque assembly uncertainties were determined using high resolution microCT scanning of loaded plaques to measure seed positions in the plaques, and all other uncertainties were determined from the previously published studies and recommended values. All dose calculations were performed using plaque simulator v5.7.6 ophthalmic treatment planning system with the inclusion of plaque heterogeneity corrections. RESULTS: The total dosimetric uncertainties at 3, 5, and 10 mm tumor heights for the 16 mm COMS plaque were 17.3%, 16.1%, and 14.2%, respectively, and for the Super9 plaque were 18.2%, 14.4%, and 13.1%, respectively (all values with coverage factor k = 2). The apex margins at 3, 5, and 10 mm tumor heights required to adequately account for these uncertainties were 1.3, 1.3, and 1.4 mm, respectively, for the 16 mm COMS plaque, and 1.8, 1.4, and 1.2 mm, respectively, for the Super9 plaque. These uncertainties and associated margins are dependent on the dose gradient at the given prescription depth, thus resulting in the changing uncertainties and margins with depth. CONCLUSIONS: The margins determined in this work can be used as a guide for determining an appropriate apex margin for a given treatment, which can be chosen based on the tumor height. The required margin may need to be increased for more complex scenarios (mushroom shaped tumors, tumors close to the optic nerve, oblique muscle related tilt, etc.) than the simple dome-shaped tumor examined and should be chosen on a case-by-case basis. The sources of uncertainty contributing most significantly to the total dosimetric uncertainty are seed placement within the plaques, treatment planning calculations, tumor height measurement, and plaque tilt. This work presents an uncertainty-based, rational approach to estimating an appropriate apex margin.

Radiochromic film calibration for low-energy seed brachytherapy dose measurement.

PURPOSE: Radiochromic film dosimetry is typically performed for high energy photons and moderate doses characterizing external beam radiotherapy (XRT). The purpose of this study was to investigate the accuracy of previously established film calibration procedures used in XRT when applied to low-energy, seed-based brachytherapy at higher doses, and to determine necessary modifications to achieve similar accuracy in absolute dose measurements. METHODS: Gafchromic EBT3 film was used to measure radiation doses upwards of 35 Gy from 75 kVp, 200 kVp, 6 MV, and (∼28 keV) I-125 photon sources. For the latter irradiations a custom phantom was built to hold a single I-125 seed. Film pieces were scanned with an Epson 10000XL flatbed scanner and the resulting 48-bit RGB TIFF images were analyzed using both FilmQA Pro software andMATLAB. Calibration curves relating dose and optical density via a rational functional form for all three color channels at each irradiation energy were determined with and without the inclusion of uncertainties in the measured optical densities and dose values. The accuracy of calibration curve variations obtained using piecewise fitting, a reduced film measurement area for I-125 irradiation, and a reduced number of dose levels was also investigated. The energy dependence of the film lot used was also analyzed by calculating normalized optical density values. RESULTS: Slight differences were found in the resulting calibration curves for the various fitting methods used. The accuracy of the calibration curves was found to improve at low doses and worsen at high doses when including uncertainties in optical densities and doses, which may better represent the variability that could be seen in film optical density measurements. When exposing the films to doses > 8 Gy, two-segment piecewise fitting was found to be necessary to achieve similar accuracies in absolute dose measurements as when using smaller dose ranges. When reducing the film measurement area for the I-125 irradiations, the accuracy of the calibration curve was degraded due to the presence of localized film heterogeneities. No degradation in the calibration curves was found when reducing the number of calibration points down to only 4, but with piecewise fitting, 6 calibration points as well as a blank film are required. Variations due to photon energy in film optical density of up to 3% were found above doses of 2 Gy. CONCLUSIONS: A modified procedure for performing EBT3 film calibration was established for use with low-energy brachytherapy seeds and high dose exposures. The energy dependence between 6 MV and I-125 photons is significant such that film calibrations should be done with an appropriately low-energy source when performing low-energy brachytherapy dose measurements. Two-segment piecewise fitting with the inclusion of errors in measured optical density as well as dose was found to result in the most accurate calibration curves. Above doses of 1 Gy, absolute dose measurements can be made with an accuracy of 1.6% for 6 MV beams and 5.7% for I-125 seed exposures if using the I-125 source for calibration, or 2.3% if using the 75 kVp photon beam for calibration.