J Hanlon

Kilovoltage stereotactic radiosurgery for age‐related macular degeneration: Assessment of optic nerve dose and patient effective dose

Age-related macular degeneration (AMD) is a leading cause for vision loss for people over the age of 65 in the United States and a major health problem worldwide. Research for new treatments of the wet form of the disease using kilovoltage stereotactic radiosurgery is currently underway at Oraya Therapeutics, Inc. In the present study, the authors extend their previous computational stylized model of a single treated eye [Med. Phys. 35, 5151-5160 (2008)] to include full NURBS-based reference head phantoms of the adult male and female using anatomical data from ICRP Publication 89. The treatment was subsequently modeled in MCNPX 2.5 using a 1 x 1 x 1 mm3 voxelized version of the NURBS models. These models incorporated several organs of interest including the brain, thyroid, salivary glands, cranium, mandible, and cervical vertebrae. A higher resolution eye section at 0.5 x 0.5 x 0.5 mm3 voxel resolution was extracted from the head phantoms to model smaller eye structures including the macula target, cornea, lens, vitreous humor, sclera/retina layer, and optic nerve. Due to lack of literature data on optic nerve pathways, a CT imaging study was undertaken to quantify the anatomical position of the optic nerve. The average absorbed doses to the organs of interest were below generally accepted thresholds for radiation safety. The estimated effective dose was 0.28 mSv which is comparable to diagnostic procedures such as a head radiograph and a factor of 10 lower than a head CT scan.

Stereotactic radiosurgery for AMD: a Monte Carlo-based assessment of patient-specific tissue doses.

PURPOSE To define the radiation doses to nontargeted ocular and adnexal tissues with Monte-Carlo simulation using a stereotactic low-voltage x-ray irradiation system for the treatment of wet age-related macular degeneration. METHODS Thirty-two right/left eye models were created from three-dimensional reconstructions of 1-mm computed tomography images of the head and orbital region. The resultant geometric models were voxelized and imported to the MCNPX 2.5.0 radiation transport code for Monte Carlo-based simulations of AMD treatment. Clinically, treatment is delivered noninvasively by three divergent 100-kVp photon beams entering through the sclera and overlapping on the macula cumulating in a therapeutic dose. Tissue-averaged doses, localized point doses, and color-coded dose contour maps are reported from Monte Carlo simulations of x-ray energy deposition for several tissues of interest, including the lens, optic nerve, macula, brain, and orbital bone. RESULTS For all eye models in this study (n = 32), tissues at risk did not receive tissue-averaged doses over the generally accepted thresholds for serious complication, specifically the formation of cataracts or radiation-induced optic neuropathy. Dose contour maps are included for three patients, each from separate groups defined by coherence to clinically realistic treatment setups. Doses to the brain and orbital bone were found to be insignificant. CONCLUSIONS The computational assessment performed indicates that a previously established therapeutic dose can be delivered effectively to the macula with the scheme described so that the potential for complications to nontargeted radiosensitive tissues might be reduced.

ITAR: A modified TAR method to determine depth dose distribution for an ophthalmic device that performs kilovoltage x‐ray pencil‐beam stereotaxy

PURPOSE New technology has been developed to treat age-related macular degeneration (AMD) using 100 kVp pencil-beams that enter the patient through the radio-resistant sclera with a depth of interest between 1.6 and 2.6 cm. Measurement of reference and relative dose in a kilovoltage x-ray beam with a 0.42 cm diameter field size and a 15 cm source to axis distance (SAD) is a challenge that is not fully addressed in current guidelines to medical physicists. AAPMs TG-61 gives dosimetry recommendations for low and medium energy x-rays, but not all of them are feasible to follow for this modality. METHODS An investigation was conducted to select appropriate equipment for the application. PTWs Type 34013 Soft X-Ray Chamber (Freiburg, Germany) and CIRSs Plastic Water LR (Norfolk, VA) were found to be the best available options. Attenuation curves were measured with minimal scatter contribution and thus called Low Scatter Tissue Air Ratio (LSTAR). A scatter conversion coefficient (C(scat)) was derived through Monte Carlo radiation transport simulation using MCNPX (LANL, Los Alamos, NM) to quantify the difference between a traditional TAR curve and the LSTAR curve. A material conversion coefficient (C(mat)) was determined through experimentation to evaluate the difference in attenuation properties between water and Plastic Water LR. Validity of performing direct dosimetry measurements with a source to detector distance other than the treatment distance, and therefore a different field size due to a fixed collimator, was explored. A method--Integrated Tissue Air Ratio (ITAR)--has been developed that isolates each of the three main radiological effects (distance from source, attenuation, and scatter) during measurement, and integrates them to determine the dose rate to the macula during treatment. RESULTS LSTAR curves were determined to be field size independent within the range explored, indicating that direct dosimetry measurements may be performed with a source to detector distance of 20 cm even though the SAD is 15 cm during treatment. C(scat) varied from 1.102 to 1.106 within the range of depths of interest. The experimental variance among repeated measurements of C(mat) was larger than depth dependence, so C(mat) was estimated as1.019 for all depths of interest. CONCLUSIONS Equipment selection, measurement techniques, and formalism for the determination of dose rate to the macula during stereotaxy for AMD have been determined and are strongly recommended by the authors of this paper to be used by clinical medical physicists.

SU-E-T-207: Comparison of Integrated Tissue Air Ratio (ITAR) to Traditional TAR for Kilovoltage Pencil-Beams

Purpose: Clinically viable depth dose determination in kilovoltage pencil-beams is a great challenge that resulted in a published dosimetry method called ITAR, which involves measurement of air kerma and attenuation with a detector in a low scatter environment coupled with MCNP scatter calculations. The objective of this work is to compare ITAR to traditional TAR using inherently water-proof microchambers that have only recently become commercially available. Methods: An Exradin A26 microchamber was centered 150 mm from a 100 kVp x-ray source with 2 mm aluminum HVL. Depth dose in water from 16 to 24 mm in 2 mm increments was determined by: (1) placing blocks of Plastic Water LR near the source to minimize scatter and using previously published conversion coefficients [ITAR method] and (2) submerging the detector in a water tank with 2 mm thick Plastic Water LR walls and jogging the tank with motor controllers while keeping the detector position fixed [traditional TAR method]. Each method was repeated four to five times. For each repetition, dose was measured free in-air to normalize the data for exponential regression. Results: Traditional TAR indicated higher depth dose than ITAR; differences ranged from 2.1% at 24 mm depth to 2.5% at 16 mm depth. However, the results of traditional TAR did not include a correction for Pq,cham because it is unknown for this detector type in these conditions. It is estimated that the component of Pq,cham due to the effect of water displacement alone is ∼0.94, but Pq,cham is likely several percent larger than 0.94 due to the energy dependency of the microchamber in the presence of low energy scatter that is not present during in-air calibration. Conclusion: The ITAR method remains preferable for clinical depth dose determination in kilovoltage pencil-beams due to Pq,cham being unknown for suitable detectors in relevant conditions. All four of the authors are either current full time employees, which include stock option grants, or consultants of Oraya Therapeutics Inc.

SU‐E‐T‐477: Influence of Eye Size on Radiation Absorbed Dose Delivered to Non‐ Targeted Tissues during Stereotactic Radiosurgery for Age‐Related Macular Degeneration

PURPOSE This work determines how variations in eye size will influence the radiation absorbed dose delivered to non-targeted tissues within the eye during stereotactic radiosurgery of age-related macular degeneration (AMD) using the IRay™ treatment. METHODS Stylized models of the eye were created with axial lengths of 20, 22, 24, 26, and 28mm. Each model was based upon the reference eye model from NCRP Report 130 and then scaled appropriately for each axial length. Models were incorporated with MCNPX radiation transport code in order to simulate the three beam IRay™ delivery system. Simulation results were assessed for both the mean absorbed dose and dose-volume histograms (DVH) for both target (macula) and non- targeted eye tissues, including the lens, retina, central retinal artery, and optic nerve. RESULTS For each of the three beams, an average dose of 8Gy was delivered to the macula resulting in a total average dose of 24Gy for each eye model. The lens of the eye received a total average dose ranging from 146 to 189mGy, with the larger doses occurring in the smaller eye models since the beams traverse through the sciera closer to the limbus. The distal tip (1.5mm) of the central retinal artery received a total average dose ranging from 499 to 567mGy, with the larger doses occurring in the larger eye models due to increased scatter resulting from longer tissue path length to the nominal target. The optic nerve received a total average dose ranging from 207 to 225mGy, with the larger doses occurring in the smaller eye models. CONCLUSIONS The small variation in dose to the lens, central retinal artery, and optic nerve suggests that eye size does not significantly affect radiation dose to non-targeted eye tissues. This work was sponsored by Oraya Therapeutics.

SU‐E‐T‐713: Kilovoltage Stereotactic Radiosurgery for AMD: A More Complete Evaluation of Effective Dose

Purpose: Age‐related Macular Degeneration is a leading cause of blindness for the elderly population in industrialized nations. Monthly injections of ranibizumab stabilize the progression of the disease, and a novel non‐invasive stereotactic radiosurgery is being explored as an adjunct to injections. An estimation of effective dose for a 3 beam × 8 Gy therapeuticdose to the macula had been reported previously by the authors of this paper using head and neck phantoms. Several improvements have been made: expansion of the geometric models to include tissues in the torso, an estimation of leakage contribution, and effect of lead vest usage.Methods: Male and female hybrid voxel torso phantoms were derived from CT slice segmentation and scaled to ICRP Publication 89 reference values. A MATLAB code was developed to “wrap” a single layer of voxels around the torsos, representative of a 0.5 mm lead vest equivalent. A three‐beam photontreatment (100 kVp) was modeled using the MCNPXradiation transport code to evaluate effective dose as per the ICRP Publication 103 schema. A similar calculation was made for leakage, but using a “hard” mono‐energetic (100 keV) point source as an approximation. Results: The calculations yielded an effective dose of 0.389 mSv for the control group, and 0.369 and 0.376 mSv for the use of a lead vest with and without a neck cover, respectively. Comparatively, 0.281 mSv was reported previously for the head and neck phantoms (19% versus 99% wTs). Leakage contribution was estimated to be approximately 0.009 mSv Conclusions: The expanded geometric models and inclusion of leakage contribution provide a more complete estimation of the effective dose than previously reported. The use of lead vests with and without a neck cover result in a 5% and 3% reduction of effective dose, respectively. This work was sponsored by Oraya Therapeutics.

SU‐GG‐T‐548: Energy and Spatial Distribution of Photon Fluence Emanating from the Head during Stereotactic Radiosurgery for Age‐Related Macular Degeneration

Purpose: Kilovoltage stereotactic radiosurgery(SRS) is currently being explored as a treatment option for wet age‐related macular degeneration (AMD), a leading cause of vision loss in the United States. An evaluation of the distribution of photons exiting the head during treatment will be useful in determining safety parameters regarding clinical staff present. Method and Materials: A male reference head phantom was computationally modeled with Rhinoceros 4.0 using CT slice segmentation scaled to ICRP Publication 89 reference values. The head phantom was voxelized and a three‐beam photontreatment (100 kVp) was modeled using the MCNPX radiation transport code. The beams enter through the sciera at a 30° polar angle relative to the geometric axis of the eye, and deliver a cumulative therapeuticdose of 24 Gy to the macula (8 Gy per beam). An F1 tally sphere, with its origin at the macula target and normal vector aligned with the geometric axis, was used to evaluate the energy and angular distributions of photon fluence at a radius of 0.5 meters. Two‐dimensional matrices were implemented using type 1 mesh tallies, flush with the head tissue, which were used to characterize the spatial distribution of photons emanating from each side of the model. Results:Photon fluence was mostly forward directed with respect to the patients gaze (backscattered in reference to beam entry) with maxima in the 50–60° and 44.4–50 keV bins. A portion of the beam traverses through the head unattenuated, resulting in a smaller peak around 150°. Color coded contour fluence maps will be created from the mesh tallies to supply a visual representation of fluence. Conclusion: The results of this study will contribute towards the design development of safety parameters related to the treatment device. This work was sponsored by Oraya Therapeutics.

TH-C-BRD-03: Kilovoltage Stereotactic Radiosurgery for Age Related Macula Degeneration: Assessment of Patient Effective Dose and Patient Specific Tissue Doses

Purpose: Age‐related macula degeneration (AMD) is a leading cause of vision loss in the United States. Radiation therapy was initially explored as a treatment option in the 1990s, but has since been abandoned in favor of intraocular drug injections. Interest continues for stereotactic radiosurgery(SRS), an option that provides a noninvasive treatment for the wet form of AMD. Method and Materials: Two adult heads, male and female, were computationally modeled with Rhinoceros 4.0 using CT slice segmentation scaled to ICRP Publication 89 reference values. The head phantoms were voxelized and a three‐beam photontreatment (100 kVp) was modeled using the MCNPXradiation transport code to evaluate tissuedose and effective dose.Treatment was also simulated using the reference heads with changeable optic nerve positions based on individual patient variability seen in a head CT scan review. Results: A cumulative dose of 24 Gy to the macula (8 Gy per beam) yielded an effective dose of 0.28 mSv. The maximum doses to the most extreme patient specific optic nerve positions were evaluated using Dose Volume Histograms and found to be below the thresholds for serious complications, as were other reference tissues.Conclusion: The results of this study show that SRS is a safe option considering effective dose and tissue toxicity for a reference individual. Patient specific models will be created from the CT review and treatment will be modeled using MCNPX to establish certainty that this is a safe treatment option for all individuals considering other patient specific variations in anatomy. This work was sponsored by Oraya Therapeutics.

MO‐FF‐A2‐05: A Novel Stereotactic Radiosurgical Device for the Treatment of Age‐Related Macular Degeneration (AMD)

Purpose: Age‐related Macular Degeneration (AMD) is the leading cause of blindness in people over 65 in the U.S. It is caused by a proliferation of capillaries in the retina and can result in profound and rapid loss of central vision. As a neovascular disease, it has been shown to be susceptible to radiotherapy. Recently, a 100kVp tabletop stereotactic radiosurgical (SRS) device has been developed to deliver highly‐collimated beams of X‐rays to the fovea to treat AMD. This study is an evaluation of that system. Method and Materials: The device delivers a three‐port, 16Gy single fraction dose to the macula. Using a suction‐enabled contact lens assembly (“the I‐Guide”) to stabilize the eye, three 4mm diameter beams of 100kVp x‐rays are delivered to the fovea, directed by a positioning robot. The beams enter the eye through the sclera and avoid the radio‐sensitive lens. The I‐Guide includes reflective fiducials that are monitored by cameras, and the real‐time position of the beam on the retina is calculated from the fiducial positions. Because of uniformity across adult eye populations, a class‐solution treatment plan was implemented using a single parameter (eye length). Software manages treatment time and automatic gating of beam in case of excessive eye motion. A clinical trial is underway. Results: 100kVp proves an optimal energy for ophthalmic radiotherapy. A therapeuticdose to the retina can be delivered with negligible impact to the brain and the scleral entry dose is well‐tolerated. The scatter from the narrow beam is minimal to sensitive structures in the eye. Submillimeter targeting precision was demonstrated in the lab and in the clinic. Submillimeter motion‐management was also demonstrated. Conclusion: The eye‐specific SRS device shows great promise for providing a precise and non‐invasive method of treating AMD. Research sponsored by Oraya Therapeutics.

WE‐D‐351‐03: NURBS‐Based Head and Eye Dosimetry Models for Ocular Radiosurgery

Purpose: Age‐related macular degeneration (AMD) is a leading cause for vision loss for people over the age of 65 in the United States. There are a number of treatments used to help slow and in some cases stabilize the process of AMD, but these require frequent invasive injections into the eye. This paper presents a potential radiotherapytreatment used to destroy the leaky vasculature while minimizing dose to surrounding tissues, allowing for combination therapy to treat AMD. Method and Materials: An adult male head phantom was modeled with Rhinoceros 4.0 using ICRP Publication 89 reference values. The head phantom was voxelized and modeled using the MCNPX radiation transport code with a photon beam treatment operated at 100 kVp. Doses to the macula target, lens, optic nerve, brain, thyroid, and salivary glands were tabulated using MCNPX at 8 beam angles. These angles can be characterized using a spherical 3D polar coordinate system with the macula at the origin, the z‐axis as the axis of vision, a radius of 13 cm, a polar angle of 30 degrees, and azimuth angles in 8 increments of 45 degrees. Results: For each beam angle, the doses to the organs of interest were several orders of magnitude less than the 8 Gy dose to the macula target and significantly lower than the thresholds for serious implications. Conclusion: The preliminary results bode well for the proposed radiotherapytreatment.Dose Volume Histograms (DVH) will be tabulated using MCNPX so that the maximum dose to localized portions of each organ of interest can be determined. The safest beam angle for treatment will be determined from the results of this study.