Symmetry, separation, and stability: Physical properties for effective dosimetric space with a stabilized hyaluronic acid spacer.

BACKGROUND: The proximity of the rectum to the prostate in radiation therapy (RT) for prostate cancer presents a significant dosimetric challenge, leading to high rectal doses and resulting in detrimental side effects. Perirectal tissue spacing reduces rectal dose and gastrointestinal toxicities by mechanically separating these organs. A variety of materials have been explored for use as rectal spacers, most recently, a stabilized hyaluronic acid (HA) gel, which can be formed into deliberate a shape, and retains the definition of that shape, while remaining flexible, unlike polyethylene glycol (PEG) hydrogels. PURPOSE: This study evaluates the dosimetric impact of the spacer, including shape symmetry, the degree of separation at different locations, and the temporal stability of the space. Our goal is to provide physics-informed guidance on the optimal use of this sculptable spacer. METHODS: A secondary analysis was performed on data from a 13-center prospective randomized trial (NCT04189913), involving 136 patients with centrally-reviewed treatment plans conducted on CT/MR simulation scans before and after receiving HA spacer implants. Patients were treated with 60 Gy in 20 fractions to the prostate. For this study, python software was utilized for automated processing of DICOM RTstruct and RTdose files, facilitating detailed analysis of the spacer's impact on anatomical displacement and dosimetric outcomes. Complete dose-volume histograms (DVHs) were reconstructed, and combined into composite population DVHs before and after implant, verified against trial-reported dose points. Patients were divided into similar groups of separation and symmetry, and differences in their composite DVHs were tested for significance. Stability of the spacer was studied by comparing serial MRI images and by computing the distance between contours at four axial planes, at simulation and 3-month follow-up, post RT. RESULTS: The introduction of the HA spacer significantly enhanced rectal sparing, as evidenced by a reduction in the mean rectal integral dose by over 6 Gy. High rates of implant symmetry (>95%) were observed, indicating nearly optimal lateral spacer placement. In superior-inferior coverage, this study like many others, saw the spacing largest at the superior extent but becoming more variable inferiorly at the level of the prostate apex. This allowed study of the apex as a specific area for dosimetric concern. Stability assessments confirmed that the spacer maintained its position and dimensions between the simulation and the 3-month post-RT, implying stable geometry during treatment, with only minimal separation changes observed. Statistical analysis using the Kruskal-Wallis test revealed significant correlations of larger separations at the inferior and apical planes with improved dosimetric outcomes, including rV30Gy. CONCLUSION: The use of a stabilized HA spacer in prostate RT effectively enhances prostate-rectum separation, leading to significant rectal sparing without undesirable dose compromises. This study underscores the role of strategic placement and shape, specifically including > 1 cm separation from the base down to the prostate apex. When combined with the treatment planning techniques used in the trial to create a steep dosimetric gradient across the spacer, these findings elucidate the dosimetric outcomes that can be expected in the clinical implementation of HA spacer. This is particularly relevant in the evolution of hypofractionated treatment regimens for prostate cancer therapy.

Evaluating the Quality-of-Life Effect of Apical Spacing with Hyaluronic Acid Prior to Hypofractionated Prostate Radiation Therapy: A Secondary Analysis.

PURPOSE: Recently, a randomized trial demonstrated that a hyaluronic acid (HA) spacer placed before prostate hypofractionated intensity modulated radiation therapy improved rectal dosimetry and reduced acute grade 2+ gastrointestinal toxicity. However, 26.5% of patients receiving the spacer experienced a minimal clinically important decline (MCID) in bowel quality-of-life (QOL). The purpose of this study is to evaluate whether certain characteristics of the rectal spacer, as determined on postimplant imaging, were associated with change in bowel QOL at 3-months. METHODS AND MATERIALS: This is a secondary analysis of the 136 patients who received the HA spacer on the randomized trial. Postimplant spacer characteristics (ie, prostate-rectum spacing at superior/midgland/inferior/apex planes, symmetry, prostate volume, spacer volume) were systematically analyzed from structure sets using custom software code. Characteristics demonstrating significant associations with rectal V30 on multivariate linear regression were identified. Linear regression models were used to analyze the associations of such characteristics with change (baseline to 3 months) in both bowel and urinary QOL. RESULTS: Apical spacing (mean 9.4 (standard deviation 4.0)) was significantly smaller than spacing measurements at more superior planes. 95.6% of patients had a symmetrical implant. Apical spacing (P < .001) and prostate volume (P = .01) were significantly associated with rectal V30 on multivariate analysis. However, only apical spacing (0.38/mm; P = .01) was associated with change in bowel QOL, even with adjustment of baseline bowel score (-0.33; P < .01). Percentages of patients with bowel MCID were 14.8% for >= 10 mm versus 36.6% for <10 mm apical spacing (P = .01). Apical spacing was not associated with change in urinary QOL (-0.09; P = .72), when adjusted for baseline urinary QOL (-0.52; P < .01). CONCLUSION: Greater apical spacing was associated with improved rectal dosimetry and smaller decline in bowel QOL at 3-months. Further prospective data are needed to fully understand the ramifications of increased apical spacing.

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 mm. 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-µm greater reduction in mean central subfield thickness (-122.6 vs. -51.5 µm; 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. AAPM's 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. PTW's Type 34013 Soft X-Ray Chamber (Freiburg, Germany) and CIRS's 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.

Influence of eye size and beam entry angle on dose to non-targeted tissues of the eye during stereotactic x-ray radiosurgery of AMD.

Age-related macular degeneration is a leading cause of vision loss for the elderly population of industrialized nations. The IRay® Radiotherapy System, developed by Oraya® Therapeutics, Inc., is a stereotactic low-voltage irradiation system designed to treat the wet form of the disease. The IRay System uses three robotically positioned 100 kVp collimated photon beams to deliver an absorbed dose of up to 24 Gy to the macula. The present study uses the Monte Carlo radiation transport code MCNPX to assess absorbed dose to six non-targeted tissues within the eye-total lens, radiosensitive tissues of the lens, optic nerve, distal tip of the central retinal artery, non-targeted portion of the retina, and the ciliary body--all as a function of eye size and beam entry angle. The ocular axial length was ranged from 20 to 28 mm in 2 mm increments, with the polar entry angle of the delivery system varied from 18° to 34° in 2° increments. The resulting data showed insignificant variations in dose for all eye sizes. Slight variations in the dose to the optic nerve and the distal tip of the central retinal artery were noted as the polar beam angle changed. An increase in non-targeted retinal dose was noted as the entry angle increased, while the dose to the lens, sensitive volume of the lens, and ciliary body decreased as the treatment polar angle increased. Polar angles of 26° or greater resulted in no portion of the sensitive volume of the lens receiving an absorbed dose of 0.5 Gy or greater. All doses to non-targeted structures reported in this study were less than accepted thresholds for post-procedure complications.

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 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 film's 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.

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.

Dosimetry characterization of a multibeam radiotherapy treatment for age-related macular degeneration.

Age-related macular degeneration (ARMD) is a major health problem worldwide. Advanced ARMD, which ultimately leads to profound vision loss, has dry and wet forms, which account for 20% and 80% of cases involving severe vision loss, respectively. A new device and approach for radiation treatment of ARMD has been recently developed by Oraya Therapeutics, Inc. (Newark, CA). The goal of the present study is to provide a initial dosimetry characterization of the proposed radiotherapy treatment via Monte Carlo radiation transport simulation. A 3D eye model including cornea, anterior chamber, lens, orbit, fat, sclera, choroid, retina, vitreous, macula, and optic nerve was carefully designed. The eye model was imported into the MCNPX2.5 Monte Carlo code and radiation transport simulations were undertaken to obtain absorbed doses and dose volume histograms (DVH) to targeted and nontargeted structures within the eye. Three different studies were undertaken to investigate (1) available beam angles that maximized the dose to the macula target tissue, simultaneously minimizing dose to normal tissues, (2) the energy dependency of the DVH for different x-ray energies (80, 100, and 120 kVp), and (3) the optimal focal spot size among options of 0.0, 0.4, 1.0, and 5.5 mm. All results were scaled to give 8 Gy to the macula volume, which is the current treatment requirement. Eight beam treatment angles are currently under investigation. In all eight beam angles, the source-to-target distance is 13 cm, and the polar angle of entry is 300 from the geometric axis of the eye. The azimuthal angle changes in eight increments of 45 degrees in a clockwise fashion, such that an azimuthal angle of 0 degreee corresponds to the 12 o'clock position when viewing the treated eye. Based on considerations of nontarget tissue avoidance, as well as facial-anatomical restrictions on beam delivery, treatment azimuthal angles between 135 degrees and 225 degrees would be available for this treatment system (i.e., directly upward and entering the eye from below). At beam directions approaching 225 degrees and higher, some dose contribution to the optic nerve would result under the assumption that the optic nerve is tilted cranially above the geometric axis in a given patient, a feature not typically seen in past studies. A total treatment dose of 24 Gy would be delivered in three 8 Gy treatments at these selected azimuthal angles. Dose coefficients, defined as the macula radiation absorbed dose per unit air kerma in units of Gy/Gy, were 16% higher for 120 kVp x-ray beams in comparison to those at 80 kVp, thus requiring only 86% of the integrated tube current (mAs) for equivalent dose delivery. When 0.0, 0.4, and 1.0 mm focal spot sizes were used, the dose profiles in the macula are very similar and relatively uniform, whereas a 5.5 mm focal spot size produced a more nonuniform dose profile. The results of this study dem onstrate the therapeutic promise of this device and provide important information for further design and clinical implementation for radiotherapy treatments for ARMD.