Erik Chell

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 targeting and dose verification for age-related macular degeneration

PURPOSE Validation of the targeting and dose delivery of the IRay low voltage age-related macular degeneration treatment system. METHODS Ten human cadaver eyes were obtained for this study and mounted in the IRay system. Using gel and vacuum, an I-Guide immobilization device was coupled to the eyes and radiochromic film was affixed to the posterior aspect of the globes. Three narrow x-ray beams were delivered through the pars plana to overlap on the predicted nominal fovea. A needle was placed through the center of the films beam spot and into the eye to register the film and the inner retina. The process was performed three times for each of the ten eyes (30 simulated treatments; 90 individual beams). The globes were dissected to assess the targeting accuracy by measuring the distances from the needles to the fovea. The dose to the fovea was calculated from the radiochromic film. RESULTS X-ray targeting on the retina averaged 0.6 +/- 0.4 mm from the fovea. Repeated treatments on the same eye showed a reproducibility of 0.4 +/- 0.4 mm. The optic nerve was safely avoided, with the 90% isodose edge of the beam spot between 0.4 and 2.6 mm from the edge of the optic disk. Measured dose matched that prescribed. CONCLUSIONS This study provides confidence that the IRay, with an average accuracy of 0.6 mm and a precision of 0.4 mm, can reliably treat most AMD lesions centered on the fovea. With the exception of motion, all sources of error are included.

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.

Assessment of targeting accuracy of a low-energy stereotactic radiosurgery treatment for age-related macular degeneration

Age-related macular degeneration (AMD), a leading cause of blindness in the United States, is a neovascular disease that may be controlled with radiation therapy. Early patient outcomes of external beam radiotherapy, however, have been mixed. Recently, a novel multimodality treatment was developed, comprising external beam radiotherapy and concomitant treatment with a vascular endothelial growth factor inhibitor. The radiotherapy arm is performed by stereotactic radiosurgery, delivering a 16 Gy dose in the macula (clinical target volume, CTV) using three external low-energy x-ray fields while adequately sparing normal tissues. The purpose of our study was to test the sensitivity of the delivery of the prescribed dose in the CTV using this technique and of the adequate sparing of normal tissues to all plausible variations in the position and gaze angle of the eye. Using Monte Carlo simulations of a 16 Gy treatment, we varied the gaze angle by ±5° in the polar and azimuthal directions, the linear displacement of the eye ±1 mm in all orthogonal directions, and observed the union of the three fields on the posterior wall of spheres concentric with the eye that had diameters between 20 and 28 mm. In all cases, the dose in the CTV fluctuated <6%, the maximum dose in the sclera was <20 Gy, the dose in the optic disc, optic nerve, lens and cornea were <0.7 Gy and the three-field junction was adequately preserved. The results of this study provide strong evidence that for plausible variations in the position of the eye during treatment, either by the setup error or intrafraction motion, the prescribed dose will be delivered to the CTV and the dose in structures at risk will be kept far below tolerance doses.

STEREOTACTIC RADIOTHERAPY FOR WET AGE-RELATED MACULAR DEGENERATION (INTREPID): Influence of Baseline Characteristics on Clinical Response

Purpose: To determine which patients respond best to stereotactic radiotherapy (SRT) for neovascular age-related macular degeneration. Methods: Participants (n = 230) receiving intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration enrolled in a randomized, double-masked sham-controlled trial comparing 16 Gray, 24 Gray, or Sham SRT. In a post hoc analysis, participants were grouped according to their baseline characteristics, to determine if these influenced SRT efficacy. Results: At 52 weeks, SRT was most effective for lesions ⩽4 mm in greatest linear dimension and with a macular volume greater than the median value of 7.4 mm3. For 26% of the participants with both these characteristics, SRT resulted in 55% fewer ranibizumab injections (2.08 vs. 4.60; P = 0.0002), a mean visual acuity change that was 5.33 letters superior to sham (+2.18 vs. −3.15 letters; P = 0.0284), and a 71.1-&mgr;m greater reduction in mean central subfield thickness (−122.6 vs. −51.5 &mgr;m; P = 0.027). Other features associated with a positive response to SRT included pigment epithelial detachment and the absence of fibrosis. Conclusion: Stereotactic radiotherapy is most effective for neovascular age-related macular degeneration lesions that are actively leaking at the time of treatment, and no larger than the 4-mm treatment zone.

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‐204: Real‐Time Monitoring of Age‐Related Macular Degeneration Radiosurgery Using Plastic Scintillation Dosimetry

Purpose: Age‐related macular degeneration (AMD) is the leading cause of vision loss and blindness among those over age 65. In its wet form, blood vessels grow from the choroid, causing macular tension and sometimes retinal displacement. As an alternative to monthly direct‐injection methods, Oraya Therapeutics has developed the IRayTM stereotactic radiosurgery device. This table‐top system has been validated in Monte Carlo simulations, human cadaver eye studies, pre‐clinical animal studies, and a phase 1 clinical trial. A plastic scintillation dosimetry (PSD) system was developed to monitor dose delivery in real‐time and provide measurement of total dose delivered. Methods: The IRayTM uses 100 keV x‐rays to deliver 24 Gy of macular dose, divided into three positions along the inferior pars plana. The PSDs small volume (0.5 mm diameter and 2 mm height), allows placement within the machine head. The PSD is fiber‐optically coupled to a photomultiplier tube via a plastic waveguide. Before direct characterization of the IRayTM, the preliminary PSD performance was tested using a portable x‐ray unit, mobile c‐arm fluoroscopy unit, and an ion chamber. Results: In order to avoid buffering issues, real‐time measurements used 250 ms bins, but can be adjustable to 10 ms. A calibration factor (CF) from PSD percent‐depth‐dose to ion chamber percent‐depth‐dose was 1.06 at a depth of 1.5 cm in solid water, the typical macular target depth. Counts‐to‐exposure CF varied less than 1% from 0.862 to 15.26R. Counts‐to‐exposure CF remained linear with R2 of 0.999 up to 16R even with varying dose rate (.002 R/s to 1.0 R/s). Conclusions: The PSD demonstrated linear dose measurements even at high dose and high dose rates. This study demonstrates the feasibility, accuracy, and precision of a PSD for clinical implantation in the IRayTM, a device for treatment of AMD. This research was supported by a grant from Oraya Therapeutics, Inc.

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.