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Purpose/Objective(s) Uveal melanoma (UM) is particularly rare and potentially devastating for patients ≤ 45 years old (yo). Limited long term data exist post-particle beam radiation (RT) for this age group and hence an in-depth analysis of clinical outcomes is presented. Materials/Methods Patients were identified in a single institution's prospectively maintained database (n = 2558) of eye treatment with proton beam radiation (PBRT, 1994-2020) and helium ion RT (1979-1992). All included patients were treated for UM. Post-local eyewall resection or salvage RT patients were excluded. Patients were aged ≤ 45 yo at radiation (PBRT, n = 247 and helium, n = 80). PBRT patients undergoing 56 GyE in 4 fractions (n = 240) were further analyzed for local control (LC), eye preservation, distant metastasis (DM), and overall survival (OS). Univariate analysis using the Kaplan-Meier method (log rank test) and multivariate regression analysis using Cox's proportional hazard model (likelihood ratio test) were performed. Results Median follow-up for PBRT pts was 85.7 months (3.0-317.5). Median age at RT was 38.3 years (13.3-45.9); tumor location was 87% choroidal, 11% ciliary body (CB), and 2% iris only; tumor height 4.4 mm (0.8-15.8), largest tumor diameter (LTD) 10.5 mm (2.1-25.1), distance to disc/fovea 3.1/1.9 mm. 5-year (y) LC was 95% and 10y 94%. Ciliary body (CB) tumors showed lower LC (P = 0.02). LTD was the one independent multivariate predictor of LC (P = 0.04). Three patients had very late local failures (LF), all showed spindle-cell features [time-to-LF 13.2, 16.1, 17.5 years]. 10y overall eye preservation was 83%. Enucleation risk decreased with greater tumor-disc distance (P = 0.0001). Improved eye preservation was noted with ≤ 50% dose to lens (P = 0.01), ≤ 20% CB (P = 0.02), disc (P = 0.004), macula (P = 0.03), and nerve (P = 0.009). Multivariate analysis identified nerve length receiving 50% dose (P = 0.0003) and tumor height (P = 0.0008) as significant independent predictors of enucleation. 10y DM-free rate was 81% and 10y OS was 83%. LTD was the most significant predictor of DM (P = 0.0001) followed by age > 30 vs ≤ 30 (P = 0.03). The age ≤ 30 subgroup (n = 44) had a 5y DM-free of 100%, and had only 2% CB tumors. Two of seven early (1994-1995) proton patients receiving 48 GyE in 4 fx, had LF. The helium cohort median follow-up was 160.9 months (23.9-292.8). Median age at RT was 37.2 (18.1-45.9), tumor height 6.2 mm (2.9-14), LTD 10.5 mm (5-25), distance to disc/fovea 3.8/3.0 mm, and 24% had tumors with ciliary body involvement. Median (range) for helium RT dose was 70 GyE (48-80). Helium cohort 10y LC was 99%, 10y eye preservation was 82%. Conclusion Excellent long-term local control (10y 94% PBRT and 99% Helium cohorts) and eye preservation is seen in UM patients aged ≤ 45 treated with proton and helium ion radiation. Specific clinical and dose-volume parameters may be utilized to assess patient prognosis.

BACKGROUND/OBJECTIVE: To determine if treatment of exudative age-related macular degeneration (eAMD) using proton beam therapy (PBT) combined with intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is safe and effective long term. SUBJECT/METHODS: Thirty eyes with newly diagnosed eAMD were enrolled in a phase I/II prospective, sham-controlled double-masked university study. Eyes were randomized 1:1:1–24 GyE, 16 GyE or sham radiation, and treated with three initial monthly intravitreal ranibizumab or bevacizumab. Subsequent anti-VEGF reinjection was based on monthly optical coherence tomography and examination for 2 years and standard of care thereafter. RESULTS: A total of 23 eyes completed 2-year study follow-up, of which 16 maintained monthly follow-up. Mean best-correct visual acuity (BCVA) at 2 years was similar among treatment groups (p > 0.05). The 24 GyE group required fewer anti-VEGF injections when compared with the sham group at 2 years (4.67 ± 1.9 vs 9.67 ± 3.5; p = 0.017). Extended follow-up (mean 4 years) available in 22 eyes showed persistent reduced need for anti-VEGF therapy among eyes treated with 24 GyE compared with sham radiation (2.0 ± 1.6 vs 4.84 ± 2.4 per year, p = 0.008). New and increasing geographic atrophy (GA), noted in some eyes in all treatment groups, resulted in decreased mean BCVA from baseline for the 24 GyE group on extended follow-up (p = 0.009). Possible mild radiation retinopathy noted in 15% of eyes was not visually significant. CONCLUSIONS: Initial treatment combining PBT (24 GyE) with intravitreal anti-VEGF therapy appears to decrease the need for anti-VEGF reinjection in eyes with newly diagnosed eAMD. Radiation retinopathy risk was low and does not appear visually significant. Long-term vision was limited by GA development especially in the 24 GyE group.

60% of all cancer treatment requires radiation therapy and the fundamental goal is to deposit sufficient energy in a tumor to irreparably damage its DNA. Unlike high energy photons which pass through the body, charged particles such as protons deposit the majority of their energy at a specific depth, the location of the Bragg peak. In theory, this allows high radiation doses to be delivered in submm proximity to critical organs such as the spinal cord (see Fig. 34.1.1). Unfortunately, mm-scale prediction of the in vivo Bragg peak location is challenging because particle energy loss and scattering are highly path-dependent and patient-specific, largely due to anatomical heterogeneity which drifts from day to day. Given this, clinicians usually reduce therapeutic doses or adjust treatment margins to avoid harming healthy, vital tissue in proximity to the tumor site. To alleviate this constraint, in vivo dosimeters (IVD) have been developed to report in situ radiation doses to clinicians, enabling more effective and safer closed-loop treatment. However, conventional IVDs can only measure the total accumulated energy deposited, i.e. the total dose [1]–[5]. Given this, conventional IVDs cannot distinguish between single high energy particle depositions and those due to the combined contributions from several lower energy depositions, which have significantly different biological effect on tissue [6]. Furthermore, these conventional lVDs employ a single large detector and thus suffers from low spatial resolution. Here, we present a mm-scale real-time single-particle dosimeter array for charged particle cancer therapy that solves these problems.

Proton beam therapy (PBRT) is an essential tool in the treatment of certain ocular tumors due to its characteristic fall-off and sharp beam parameters at critical structures. Review of clinical cases in our ocular PBRT program identified patients with silicone oil used as an intraocular tamponade following pars plana vitrectomy for repair of retinal detachment. Patient’s eye may be filled with silicone oil prior to PBRT for an ocular tumor. The objective of this study was to extend our knowledge of the physical characteristics of proton beams in silicone oil by measuring dose within a silicone tank itself, hence better representing the surgical eye, as well as applying the range changes to EYEPLAN software to estimate clinical impact. The relevant proton beam physical parameters in silicone oil were studied using a 67.5 MeV un-modulated proton beam. The beam parameters being defined included: 1) residual range; 2) peak/plateau ratio; 3) full width at half maximum (FWHM) of the Bragg peak; and 4) distal penumbra. Initially, the dose uniformity of the proton beam was confirmed at 10 mm and 28 mm depth, corresponding to plateau and peak region of the Bragg peak using Gefchromic film. Once the beam was established as expected, three sets of measurements of the beam parameters were taken in: a) water (control); b) silicone-1000 oil and water; and c) silicone-1000 oil only. Central-axis depth-ionization measurements were performed in a tank (“main tank”) with a 0.1cc ionization chamber (Model IC-18, Far west) having walls made of Shonka A150 plastic. The tank was 92 mm (length) × 40 mm (height) × 40 mm (depth). The tank had a 0.13 mm thick kapton entrance window through which the proton beam was incident. The ionization chamber was always positioned in the center of the circular field of diameter 30 mm with the phantom surface at isocenter. The ionization chamber measurements were taken at defined depths in increments of 2 mm, from 0 to 35 mm. To define the effect of silicone oil on the physical characteristics of proton beam, the above-defined three sets of measurements were made. In the first run (a), the Bragg-peak measurements were made in the main tank filled with water. In the second run (b), a second smaller tank filled with 10 mm depth silicone oil was placed in front of the water tank and the measurements were repeated in water. In the third run (c), the water in the main tank was replaced with silicone oil and the measurements were repeated in silicone directly (no second tank in runs “a” and “c”). Finally, the effects of change in range on dose distribution based on the EYEPLAN® treatment planning software of patients with lesions in close proximity to the disc/macula as well as ciliary body tumors were studied. The uniformity of the radiation across the treatment volume shows that the radiation field was uniform within ± 3% at 10 mm depth and within ±4% at 28 mm depth. Parameters evaluated for the three runs (a, b, c) included: 1) residual range; 2) peak/plateau ratio; 3) FWHM of the Bragg curve; and 4) distal penumbra. The measured data revealed that the un-modulated Bragg peak had a penetration at the isocenter of: a) 30 mm in water; b) 31.5 mm in silicone and water; and c) 32 mm range in silicone oil. The peak/plateau ratio of the depth dose curve is 3.1:1 in all three set-ups. The FWHM is: a) 9 mm in water; b) 10 mm in silicone and water; and c) 11 mm in silicone oil. The distal penumbra (from 90% to 20%) was: a) 1.1 mm; b) 1.4 mm; and c) 2 mm. Clinical relevance of the extended distal range in silicone was studied for impact in EYEPLAN treatment software, including cases in which tumors were in close proximity to the optic disc/nerve and macula as well as cases in which anterior ciliary body tumors were treated. The potential change of range by 2 mm in silicone would impact the dose-volume histograms (DVH) importantly for the posterior structures. In ciliary body/anterior tumors, an increase in distal range in silicone could result in optic disc/macula dose and length of optic nerve treated, compared with original EYEPLAN model DVHs. The use of silicone oil as a surgical tamponade in the treatment of retinal detachments has important implications for PBRT treatment planning. In patients with intraocular silicone oil, the physical parameters of the beam should be closely examined and DVHs for posterior structures should be analyzed for potential increased doses to the macula, disc, and length of optic nerve in the field. The change in beam parameters due to silicone oil is essential to consider in treatment planning and DVH interpretation for ocular patients with posterior as well as anterior ocular tumors.

Objective To assess the safety and efficacy of proton beam therapy (PBT) as an adjunct to intravitreal anti–vascular endothelial growth factor (VEGF) for the treatment of exudative age-related macular degeneration. Design Phase I/II, interventional, prospective, randomized, sham-controlled double-blinded study. Participants Eyes with newly diagnosed exudative age-related macular degeneration with vision between 20/40 and 20/400 were included. Exclusion criteria included diabetes or other ocular comorbidities affecting vision. Methods Eyes were randomized to receive either 16 GyE, 24 GyE, or sham PBT. All eyes had 3 monthly intravitreal anti-VEGF treatments, followed by monthly visits with treatments as needed. Main Outcome Measures Mean change in best-corrected visual acuity (BCVA), mean number of anti-VEGF injections, proportion of eyes with >15 letters BCVA decrease, proportion of eyes developing radiation retinopathy or papillopathy, proportion of eyes with cataract progression, and mean changes central retinal thickness on OCT and lesion size on angiography at 1 year. Results Of 30 enrolled eyes, 22 completed follow-up monthly for 12 months for analysis. The BCVA improved by a mean of 8 letters (0.48±0.36 logarithm of the minimum angle of resolution) overall from baseline. Overall, central retinal thickness decreased from 340±155 to 246±48 ( P = 0.008) at 12 months. The mean change in BCVA and central retinal thickness was not different among the 3 study groups. The mean number of anti-VEGF injections at 12 months was 6.13 for sham irradiation arm, 5.52 in the 16 GyE arm, and 3.83 for the 24 GyE arm ( P = 0.004 between sham and 24 GyE). No eye had severe visual loss, radiation retinopathy, or papillopathy. Conclusions No safety issue was noted associated with combining 16 GyE or 24 GyE PBT with intravitreal anti-VEGF therapy in eyes with exudative age-related macular degeneration. Overall improvements in BCVA and imaging parameters were not affected by the addition of PBT, but the number of anti-VEGF treatments needed was significantly lower with the addition of 24 GyE PBT.

Purpose To assess the planning, treatment, and follow-up strategies worldwide in dedicated proton therapy ocular programs. Methods and Materials Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow. Results Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers ( P =.0161). Generally, ophthalmologists followed up the post–radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers. Conclusions The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients.

Since 1978, the University of California San Francisco (UCSF) Ocular Tumor Program has been using particle therapy for treating ocular patients with malignant as well as benign eye disease. Helium ion beams were used initially and were produced by two synchrotron-based systems: first by the 184-inch synchro-cyclotron and later by the Bevalac, at the Lawrence Berkeley National Laboratory (LBNL). Since 1994, protons, produced by a cyclotron-based system at the Crocker Nuclear Laboratory (CNL) Eye Treatment Facility (ETF), have been used for this purpose. The CNL cyclotron produces a 67.5 MeV beam, allowing for a uniquely homogeneous beam for eye treatment, without degradation of the beam or manipulation of the beam line. This paper describes, in detail, the control system for beam delivery, as implemented for measuring and delivering the radiation to ocular tumors at CNL. The control system allows for optimal delivery and rapid termination of the irradiation after the desired dose is achieved. In addition, several safeguard systems are discussed, as these are essential for such a system in the event of failure of software, electronics, or other hardware. The QA analysis shows that the total range of the proton beam is 30.7 ± 1.0 mm in water at iso-center. The beam distal penumbra (80% - 20%) is 1.1 mm for a range-modulated beam at a collimator to iso-center distance of 50 mm. Daily QA checks confirm that the range and modulation is within 0.1 mm. The beam flatness and symmetry in a 25 mm diameter beam are ±1% - 2%. Variation in the daily dosimetry system, as compared to standard dosimetry, is within ±3.5%, with a mean variation of 0.72(±1.9)% and 0.85(±2.3)% for segmented transmission ionization chambers IC1 (upstream) and IC2 (downstream), respectively. From May 1994 to the end of 2015, UCSF has treated 1838 proton ocular patients at the Davis ETF. During this period, no treatments were missed due to any cyclotron or control system failures. The overall performance, maintenance, and quality assurance of the cyclotron and the ocular control system have been excellent.

Proton beam radiotherapy for uveal melanoma can be administered as primary treatment, as salvage therapy for a recurrent tumor, as neoadjuvant therapy prior to surgical resection, or as adjuvant therapy after surgical resection. Of all eye-conserving forms of uveal melanoma treatment, proton beam is associated with the lowest overall risk of local tumor recurrence. The physical properties of proton beams make it possible to deliver high-radiation doses to tumors with relative sparing of adjacent tissues from collateral damage. The chances of survival, ocular conservation, visual preservation, and avoidance of iatrogenic morbidity depend greatly on the tumor size, location, and extent. When treating side effects and/or complications, it is helpful to consider whether the etiology is collateral damage to healthy ocular tissues, such as the optic disc, or exudation and release of angiogenic factors from the irradiated tumor, possibly resulting in neovascular glaucoma (‘toxic tumor syndrome’). As with any the...

Purpose: To measure depth dose curves for a 67.5 ± 0.1 MeV proton beam for benchmarking and validation of Monte Carlo simulation. Methods: Depth dose curves were measured in 2 beam lines. Protons in the raw beam line traversed a Ta scattering foil, 0.1016 or 0.381 mm thick, a secondary emission monitor comprised of thin Al foils, and a thin Kapton exit window. The beam energy and peak width and the composition and density of material traversed by the beam were known with sufficient accuracy to permit benchmark quality measurements. Diodes for charged particle dosimetry from two different manufacturers were used to scan the depth dose curves with 0.003 mm depth reproducibility in a water tank placed 300 mm from the exit window. Depth in water was determined with an uncertainty of 0.15 mm, including the uncertainty in the water equivalent depth of the sensitive volume of the detector. Parallel-plate chambers were used to verify the accuracy of the shape of the Bragg peak and the peak-to-plateau ratio measured with the diodes. The uncertainty in the measured peak-to-plateau ratio was 4%. Depth dose curves were also measured with a diode for a Bragg curve and treatment beam spread out Bragg peak (SOBP) on the beam line used for eye treatment. The measurements were compared to Monte Carlo simulation done with geant4 using topas. Results: The 80% dose at the distal side of the Bragg peak for the thinner foil was at 37.47 ± 0.11 mm (average of measurement with diodes from two different manufacturers), compared to the simulated value of 37.20 mm. The 80% dose for the thicker foil was at 35.08 ± 0.15 mm, compared to the simulated value of 34.90 mm. The measured peak-to-plateau ratio was within one standard deviation experimental uncertainty of the simulated result for the thinnest foil and two standard deviations for the thickest foil. It was necessary to include the collimation in the simulation, which had a more pronounced effect on the peak-to-plateau ratio for the thicker foil. The treatment beam, being unfocussed, had a broader Bragg peak than the raw beam. A 1.3 ± 0.1 MeV FWHM peak width in the energy distribution was used in the simulation to match the Bragg peak width. An additional 1.3–2.24 mm of water in the water column was required over the nominal values to match the measured depth penetration. Conclusions: The proton Bragg curve measured for the 0.1016 mm thick Ta foil provided the most accurate benchmark, having a low contribution of proton scatter from upstream of the water tank. The accuracy was 0.15% in measured beam energy and 0.3% in measured depth penetration at the Bragg peak. The depth of the distal edge of the Bragg peak in the simulation fell short of measurement, suggesting that the mean ionization potential of water is 2–5 eV higher than the 78 eV used in the stopping power calculation for the simulation. The eye treatment beam line depth dose curves provide validation of Monte Carlo simulation of a Bragg curve and SOBP with 4%/2 mm accuracy.

Purpose The purpose of this study is to explore the feasibility of the use of titanium fiducial markers to minimize the metallic artifact seen with tantalum markers which causes significant distortion on postoperative orbital CT scans. Method We designed and constructed the titanium markers in the shop of Crocker Nuclear Laboratory, UC Davis, CA. The markers were placed on an eyeball phantom. The eyeball was inserted into the Rando phantom in the orbital space. The Rando phantom was imaged with coplanar x rays on Nucletron simulator at UCSF, on digital panel on the eye beam line at CNL eye treatment facility and on CT scanner at UCSF. Results The titanium markers can be clearly seen on the hard copy of x rays and on digital panel. The CT scan of an orbit using tantalum markers on the right eye and titanium markers on the left eye shows the metal artifact from tantalum markers. Titanium markers show very little distortion on CT images. Conclusion The present study describes these markers and their relative benefit in comparison with tantalum marker, which has been used for localizing ocular tumor for decades.

Purpose To perform an in-depth temporal analysis of visual acuity (VA) outcomes after proton beam radiation therapy (PBRT) in a large, uniformly treated cohort of uveal melanoma (UM) patients, to determine trends in VA evolution depending on pretreatment and temporally defined posttreatment VA measurements; and to investigate the relevance of specific patient, tumor and dose-volume parameters to posttreatment vision loss. Methods and Materials Uveal melanoma patients receiving PBRT were identified from a prospectively maintained database. Included patients (n=645) received 56 GyE in 4 fractions, had pretreatment best corrected VA (BCVA) in the affected eye of count fingers (CF) or better, with posttreatment VA assessment at specified post-PBRT time point(s). Patients were grouped according to the pretreatment BCVA into favorable (≥20/40) or unfavorable (20/50-20/400) and poor (CF) strata. Temporal analysis of BCVA changes was described, and univariate and forward stepwise multivariate logistic regression analyses were performed to identify predictors for VA loss. Results Median VA follow-up was 53 months (range, 3-213 months). At 60-month follow up, among evaluable treated eyes with favorable pretreatment BCVA, 45% retained BCVA ≥20/40, whereas among evaluable treated eyes with initially unfavorable/poor BCVA, 21% had vision ≥20/100. Among those with a favorable initial BCVA, attaining BCVA of ≥20/40 at any posttreatment time point was associated with subsequent maintenance of excellent BCVA. Multivariate analysis identified volume of the macula receiving 28GyE ( P P =.0004) as independent dose-volume histogram predictors of 48-month post-PBRT vision loss among initially favorable treated eyes. Conclusions Approximately half of PBRT-treated UM eyes with excellent pretreatment BCVA assessed at 5 years after treatment will retain excellent long-term vision. 28GyE macula and optic nerve dose-volume histogram parameters allow for rational treatment planning optimization that may lead to improved visual outcomes. The detailed temporal analysis with intermediate as well as long-term functional prognosis, and the relationship of outcomes with clinical and treatment planning parameters, is critical for informed care of UM patients before and after PBRT.

The purpose of this study is to investigate the luminescence light output response in a plastic scintillator irradiated by a 67.5 MeV proton beam using various dosimetry parameters. The relationship of the visible scintillator light with the beam current or dose rate, aperture size and the thickness of water in the water-column was studied. The images captured on a CCD camera system were used to determine optimal dosimetry parameters for measuring the range of a clinical proton beam. The method was developed as a simple quality assurance tool to measure the range of the proton beam and compare it to (a) measurements using two segmented ionization chambers and water column between them, and (b) with an ionization chamber (IC-18) measurements in water. We used a block of plastic scintillator that measured 5×5×5 cm3 to record visible light generated by a 67.5 MeV proton beam. A high-definition digital video camera Moticam 2300 connected to a PC via USB 2.0 communication channel was used to record images of scintillation luminescence. The brightness of the visible light was measured while changing beam current and aperture size. The results were analyzed to obtain the range and were compared with the Bragg peak measurements with an ionization chamber. The luminescence light from the scintillator increased linearly with the increase of proton beam current. The light output also increased linearly with aperture size. The relationship between the proton range in the scintillator and the thickness of the water column showed good linearity with a precision of 0.33 mm (SD) in proton range measurement. For the 67.5 MeV proton beam utilized, the optimal parameters for scintillator light output response were found to be 15 nA (16 Gy/min) and an aperture size of 15 mm with image integration time of 100 ms. The Bragg peak depth brightness distribution was compared with the depth dose distribution from ionization chamber measurements and good agreement was observed. The peak/plateau ratio observed for the scintillator was found to be 2.21 as compared to the ionization chamber measurements of 3.01. The response of a scintillator block–CCD camera in 67.5 MeV proton beam was investigated. A linear response was seen between light output and beam current as well as aperture size. The relation between the thickness of water in the water column and the measured range also showed linearity. The results from the scintillator response was used to develop a simple approach to measuring the range and the Bragg peak of a proton beam by recording the visible light from a scintillator block with an accuracy of less than 0.33 mm. Optimal dosimetry parameters for our proton beam were evaluated. It is observed that this method can be used to confirm the range of a proton beam during daily treatment and will be useful as daily QA measurement for proton beam therapy.

PURPOSE: The purpose of this study is to evaluate a novel approach for treatment planning using digital fundus image fusion in EYEPLAN for proton beam radiation therapy (PBRT) planning for ocular melanoma. The authors used a prototype version of EYEPLAN software, which allows for digital registration of high-resolution fundus photographs. The authors examined the improvement in tumor localization by replanning with the addition of fundus photo superimposition in patients with macular area tumors. METHODS: The new version of EYEPLAN (v3.05) software allows for the registration of fundus photographs as a background image. This is then used in conjunction with clinical examination, tantalum marker clips, surgeon's mapping, and ultrasound to draw the tumor contour accurately. In order to determine if the fundus image superimposition helps in tumor delineation and treatment planning, the authors identified 79 patients with choroidal melanoma in the macular location that were treated with PBRT. All patients were treated to a dose of 56 GyE in four fractions. The authors reviewed and replanned all 79 macular melanoma cases with superimposition of pretreatment and post-treatment fundus imaging in the new EYEPLAN software. For patients with no local failure, the authors analyzed whether fundus photograph fusion accurately depicted and confirmed tumor volumes as outlined in the original treatment plan. For patients with local failure, the authors determined whether the addition of the fundus photograph might have benefited in terms of more accurate tumor volume delineation. RESULTS: The mean follow-up of patients was 33.6 +/- 23 months. Tumor growth was seen in six eyes of the 79 macular lesions. All six patients were marginal failures or tumor miss in the region of dose fall-off, including one patient with both in-field recurrence as well as marginal. Among the six recurrences, three were managed by enucleation and one underwent retreatment with proton therapy. Three patients developed distant metastasis and all three patients have since died. The replanning of six patients with their original fundus photograph superimposed showed that in four cases, the treatment field adequately covered the tumor volume. In the other two patients, the overlaid fundus photographs indicated the area of marginal miss. The replanning with the fundus photograph showed improved tumor coverage in these two macular lesions. For the remaining patients without local failure, replanning with fundus photograph superimposition confirmed the tumor volume as drawn in the original treatment plan. CONCLUSIONS: Local control was excellent in patients receiving 56 GyE of PBRT for uveal melanomas in the macular region, which traditionally can be more difficult to control. Posterior lesions are better defined with the additional use of fundus image since they can be difficult to mark surgically. In one-third of treatment failing patients, the superposition of the fundus photograph would have clearly allowed improved localization of tumor. The current practice standard is to use the superimposition of the fundus photograph in addition to the surgeon's clinical and clip mapping of the tumor and ultrasound measurement to draw the tumor volume.

A new noninvasive monitoring system for fixing the eye has been developed to treat orbital and choroidal tumors with CyberKnife-based radiotherapy. This device monitors the eye during CT/MRI scanning and during treatment. The results of this study demonstrate the feasibility of the fixation light system for CyberKnife-based treatments of orbital and choroidal tumors and supports the idea that larger choroidal melanomas and choroidal metastases could be treated with CyberKnife without implanting fiducial markers.

In order to reduce the dose to surrounding critical tissues and also minimize the probability of recurrence of the tumor the placement of radiation fields relative to patient anatomy is very essential in proton beam therapy of ocular tumors. To achieve this objective, patient setup and field placement have been verified before treatment by analyzing the portal images obtained with Polaroid film-camera system. The Polaroid films are becoming expensive and obsolete, making new methods of verifying the patient treatment position essential. The objective of this study was to implement an orthogonal flat panel digital imaging (FPDI) system as a tool to image-guided radiation therapy (IGRT) on the UC Davis cyclotron proton beam therapy line and to use the system for patient setup verification. The image quality of the system is sufficient to see an air hole with a diameter of 0.5 mm at a depth of 9 mm, in a 10 cm Lucite phantom. The subject contrast of the FPDI system varied from 16% to 29% by varying the size of the air hole in the phantom from 1 to 5 mm and changing the depth from 9 to 15 mm. The subject contrast for 0.5 mm air hole was 11%. The comparison of the setup variations as measured from Polaroid port films and FPDI was 0.1±0.7 mm in the X -direction, 0.2±0.2 mm in the Y -direction and 0.04±0.1 mm in Z -direction, respectively. The day-to-day positional variations in-patient set-ups were studied for 30 patients using the FPDI system. The patient position set-up on first day of treatment [defined by the X , Y , Z coordinates of the chair and head holder] was registered as the reference image. The comparison of day-to-day patient position with reference image indicated net translation along the three orthogonal axes as 0.3±1.88 mm in right–left direction, −0.3±1.78 in superior–inferior direction and −0.6±2.8 mm in anterior–posterior direction. The image quality of the FPDI system was sufficient to clearly reveal the radio-opaque markers on the digital image. In conclusion a FPDI system can accurately replace the Polaroid system and will facilitate daily portal alignment and true electronic IGRT verification of patient position and tumor location relative to the proton beam.

Peripheral radiation can have deleterious effects on normal tissues throughout the body, including secondary cancer induction and cataractogenesis. The aim of this study is to evaluate the peripheral dose received by various regions of the body after ocular treatment delivered with the Model C Gamma Knife, proton radiotherapy with a dedicated ocular beam employing no passive-scattering system, or a CyberKnife unit before and after supplemental shielding was introduced. TLDs were used for stray gamma and x-ray dosimetry, whereas CR-39 dosimeters were used to measure neutron contamination in the proton experiments. Doses to the contralateral eye, neck, thorax and abdomen were measured on our anthropomorphic phantom for a 56 Gy treatment to a 588 mm(3) posterior ocular lesion. Gamma Knife (without collimator blocking) delivered the highest dose in the contralateral eye, with 402-2380 mSv, as compared with 118-234 mSv for CyberKnife pre-shielding, 46-255 mSv for CyberKnife post-shielding and 9-12 mSv for proton radiotherapy. Gamma Knife and post-shielding CyberKnife delivered comparable doses proximal to the treatment site, with 190 versus 196 mSv at the thyroid, whereas protons doses at these locations were less than 10 mSv. Gamma Knife doses decreased dramatically with distance from the treatment site, delivering only 13 mSv at the lower pelvis, comparable to the proton result of 4 to 7 mSv in this region. In contrast, CyberKnife delivered between 117 and 132 mSv to the lower pelvis. In conclusion, for ocular melanoma treatments, a proton beam employing no double scattering system delivers the lowest peripheral doses proximally to the contralateral eye and thyroid when compared to radiosurgery with the Model C Gamma Knife or CyberKnife. At distal locations in the pelvis, peripheral doses delivered with proton and Gamma Knife are of an order of magnitude smaller than those delivered with CyberKnife.

The aim of this study is to (1) compare the delineation of the tumor volume for ocular melanoma on high-resolution three-dimensional (3D) T2-weighted fast spin echo magnetic resonance imaging (MRI) images with conventional techniques of A- and B-scan ultrasound, transcleral illumination, and placement of tantalum markers around tumor base and (2) to evaluate whether the surgically placed marker ring tumor delineation can be replaced by 3D MRI based tumor delineation. High-resolution 3D T2-weighted fast spin echo (3D FSE) MRI scans were obtained for 60 consecutive ocular melanoma patients using a 1.5 T MRI (GE Medical Systems, Milwaukee, WI), in a standard head coil. These patients were subsequently treated with proton beam therapy at the UC Davis Cyclotron, Davis, CA. The tumor was delineated by placement of tantalum rings (radio-opaque markers) around the tumor periphery as defined by pupillary transillumination during surgery. A point light source, placed against the sclera, was also used to confirm ring agreement with indirect ophthalmoscopy. When necessary, intraoperative ultrasound was also performed. The patients were planned using EYEPLAN software and the tumor volumes were obtained. For analysis, the tumors were divided into four categories based on tumor height and basal diameter. In order to assess the impact of high-resolution 3D T2 FSE MRI, the tumor volumes were outlined on the MRI scans by two independent observers and the tumor volumes calculated for each patient. Six (10%) of 60 patients had tumors, which were not visible on 3D MRI images. These six patients had tumors with tumor heights < or = 3 mm. A small intraobserver variation with a mean of (-0.22 +/- 4)% was seen in tumor volumes delineated by 3D T2 FSE MR images. The ratio of tumor volumes measured on MRI to EYEPLAN for the largest to the smallest tumor volumes varied between 0.993 and 1.02 for 54 patients. The tumor volumes measured directly on 3D T2 FSE MRI ranged from 4.03 to 0.075 cm3. with a mean of 0.87 +/- 0.84 cm3. The tumor shapes obtained from 3D T2 FSE MR images were comparable to the tumor shapes obtained using EYEPLAN software. The demonstration of intraocular tumor volumes with the high-resolution 3D fast spin echo T2 weighted MRI is excellent and provides additional information on tumor shape. We found a high degree of accuracy for tumor volumes with direct MRI volumetric measurements in uveal melanoma patients. In some patients with extra large tumors, the tumor base and shape was modified, because of the additional information obtained from 3D T2 FSE MR images.

Relevant clinical data are needed given the increasing national interest in charged particle radiation therapy (CPT) programs. Here we report long-term outcomes from the only randomized, stratified trial comparing CPT with iodine-125 plaque therapy for choroidal and ciliary body melanoma.From 1985 to 1991, 184 patients met eligibility criteria and were randomized to receive particle (86 patients) or plaque therapy (98 patients). Patients were stratified by tumor diameter, thickness, distance to disc/fovea, anterior extension, and visual acuity. Tumors close to the optic disc were included. Local tumor control, as well as eye preservation, metastases due to melanoma, and survival were evaluated.Median follow-up times for particle and plaque arm patients were 14.6 years and 12.3 years, respectively (P=.22), and for those alive at last follow-up, 18.5 and 16.5 years, respectively (P=.81). Local control (LC) for particle versus plaque treatment was 100% versus 84% at 5 years, and 98% versus 79% at 12 years, respectively (log rank: P=.0006). If patients with tumors close to the disc (2 mm) were excluded, CPT still resulted in significantly improved LC: 100% versus 90% at 5 years and 98% versus 86% at 12 years, respectively (log rank: P=.048). Enucleation rate was lower after CPT: 11% versus 22% at 5 years and 17% versus 37% at 12 years, respectively (log rank: P=.01). Using Cox regression model, likelihood ratio test, treatment was the most important predictor of LC (P=.0002) and eye preservation (P=.01). CPT was a significant predictor of prolonged disease-free survival (log rank: P=.001).Particle therapy resulted in significantly improved local control, eye preservation, and disease-free survival as confirmed by long-term outcomes from the only randomized study available to date comparing radiation modalities in choroidal and ciliary body melanoma.

The aim of this study was to evaluate high-frequency ultrasound imaging (HFUI) as an aid in localizing anterior margins of tumours of the eye for proton therapy. Proton irradiation of ocular melanoma requires an accurate assessment of all tumour margins. The tumour is marked surgically by suturing to the sclera four or five tantalum rings on the borders of the tumour defined by transillumination. In order to evaluate the clinical usefulness of high-frequency ultrasound imaging, four and five rings were surgically placed in a patient with an iris/ciliary body melanoma and in a patient with ciliochoroidal melanoma using transillumination to localize the tumour margins. Subsequently margins were verified by HFUI. In the first patient, the distances between the rings and the limbus were measured using calipers during surgery and were compared with HFUI measurements and measurements from planning software. The distances were comparable within 0.5 mm. In the second patient the treatment was planned in two different ways using EYEPLAN software. In the first scenario the shape of the tumour and its relation to the rings were obtained from the surgeon's mapping, the fundus drawing using a transilluminating point light source, and the HFUI. In the second scenario, the shape of the tumour was deduced from the ring positions only. It was observed that the maximum difference between the tumour edge as seen on high-frequency ultrasound images and the rings was 2.6 mm. The tumour volume was underestimated by 39% when tumour shape was obtained from ring positions only. During the past year we have utilized HFUI in 18 patients having tumours involving the anterior segment of the eye, among which four were treated with proton therapy. In conclusion, we believe that high-frequency ultrasound imaging provides additional information with respect to the location of tumour margins in ciliary body and anterior uveal melanoma. Occult extension of the tumour within the ciliary body or posterior iris may not be appreciated by transillumination alone.

Background and purpose : A new protocol for calibration of proton beams was established by the ICRU in report 59 on proton dosimetry. In this paper we report the results of an international proton dosimetry intercomparison, which was held at Loma Linda University Medical Center. The goals of the intercomparison were, first, to estimate the level of consistency in absorbed dose delivered to patients if proton beams at various clinics were calibrated with the new ICRU protocol, and second, to evaluate the differences in absorbed dose determination due to differences in 60 Co-based ionization chamber calibration factors. Materials and methods : Eleven institutions participated in the intercomparison. Measurements were performed in a polystyrene phantom at a depth of 10.27 cm water equivalent thickness in a 6-cm modulated proton beam with an accelerator energy of 155 MeV and an incident energy of approximately 135 MeV. Most participants used ionization chambers calibrated in terms of exposure or air kerma. Four ionization chambers had 60 Co -based calibration in terms of absorbed dose-to-water. Two chambers were calibrated in a 60 Co beam at the NIST both in terms of air kerma and absorbed dose-to-water to provide a comparison of ionization chambers with different calibrations. Results : The intercomparison showed that use of the ICRU report 59 protocol would result in absorbed doses being delivered to patients at their participating institutions to within ±0.9% (one standard deviation). The maximum difference between doses determined by the participants was found to be 2.9%. Differences between proton doses derived from the measurements with ionization chambers with N K -, or N W - calibration type depended on chamber type. Conclusions : Using ionization chambers with 60 Co calibration factors traceable to standard laboratories and the ICRU report 59 protocol, a distribution of stated proton absorbed dose is achieved with a difference less than 3%. The ICRU protocol should be adopted for clinical proton beam calibration. A comparison of proton doses derived from measurements with different chambers indicates that the difference in results cannot be explained only by differences in 60 Co calibration factors.

To determine neovascular glaucoma (NVG) incidence and identify contributing tumor and dosing factors in uveal melanoma patients treated with proton beam radiation therapy (PBRT).A total of 704 PBRT patients treated by a single surgeon (DHC) for uveal melanoma (1996-2010) were reviewed for NVG in our prospectively maintained database. All patients received 56 GyE in 4 fractions. Median follow-up was 58.3 months. Analyses included the Kaplan-Meier method to estimate NVG distributions, univariate log-rank tests, and Cox's proportional hazards multivariate analysis using likelihood ratio tests to identify independent risk factors of NVG among patient, tumor, and dose-volume histogram parameters.The 5-year PBRT NVG rate was 12.7% (95% confidence interval [CI] 10.2%-15.9%). The 5-year rate of enucleation due to NVG was 4.9% (95% CI 3.4%-7.2%). Univariately, the NVG rate increased significantly with larger tumor diameter (P.0001), greater height (P.0001), higher T stage (P.0001), and closer proximity to the disc (P=.002). Dose-volume histogram analysis revealed that if30% of the lens or ciliary body received ≥50% dose (≥28 GyE), there was a higher probability of NVG (P.0001 for both). Furthermore, if 100% of the disc or macula received ≥28 GyE, the NVG rate was higher (P.0001 and P=.03, respectively). If both anterior and posterior doses were above specified cut points, NVG risk was highest (P.0001). Multivariate analysis confirmed significant independent risk factors to include tumor height (P.0001), age (P.0001), %disc treated to ≥50% Dose (100% vs 100%) (P=.0007), larger tumor diameter (P=.01), %lens treated to ≥90% Dose (0 vs0%-30% vs30%) (P=.01), and optic nerve length treated to ≥90% Dose (≤1 mm vs1 mm) (P=.02).Our current PBRT patients experience a low rate of NVG and resultant enucleation compared with historical data. The present analysis shows that tumor height, diameter, and anterior as well as posterior critical structure dose-volume parameters may be used to predict NVG risk.

A new facility has been constructed at the Crocker Nuclear Laboratory at University of California Davis for the purpose of treating ocular tumors using the 67.5 MeV protons from the 76-in. isochronous cyclotron. Beam line design, commissioning, control system, beam characteristics, dosimetry, patient positioner and system performance are discussed. The unmodulated Bragg peak has a penetration of 29 mm in tissue at the isocenter with a peak to plateau ratio of 3.8:1 and a width of 5 mm (FWHM measured in water). The delivered dose is monitored by two transmission ionization chambers which are calibrated against a thimble ionization chamber with an NIST-traceable 60 Co calibration factor. The Bragg peak is spread across the target volume by the use of range modulators. The residual range is varied by means of a variable water column. Daily variation in patient dosimetry is within ±3%. The beam penumbra (defined here as the distance between the 90% and 10% isodose levels) is 1.5 mm for a range-modulated beam at a collimator-to-isocenter distance of 50 mm. The beam flatness in a 25 mm diameter beam is within ±2% and the beam symmetry is ±1%. In the first 18 months, 50 patients have been treated with an average field size of 16.8 × 16.6 mm 2 . The residual range varied between 13.0 mm to 29.2 mm with an average value of 22.4 mm, and the range modulation varied between 16 mm to 24 mm with an average value of 20 mm. The tumor thickness (height) ranged between 1.2 to 11.5 mm with mean of 5.2 mm. The age of the patients ranged from 25 to 88 yr.

Proton beam radiotherapy of uveal melanoma and other malignant and benign ocular tumors has shown tremendous development and success over the past four decades. Proton beam is associated with the lowest overall risk of local tumor recurrence in uveal melanoma, compared with other eye-conserving forms of primary treatment. Proton beam is also utilized for other malignant and benign tumors as primary, salvage, or adjuvant treatment with combined modality therapy. The physical characteristics of proton therapy allows for uniform dose distribution, minimal scatter, and sharp dose fall off making it an ideal therapy for ocular tumors in which critical structures lay in close proximity to the tumor. High radiation doses can be delivered to tumors with relative sparing of adjacent tissues from collateral damage. Proton beam therapy for ocular tumors has resulted in overall excellent chances for tumor control, ocular conservation, and visual preservation.

A method is described for imaging integrated density along the beam path in phantoms that makes use of high energy proton beams. An application of the technique is in the positioning of patients in a proton therapy radiation facility. It makes use of a proton range telescope for density variation and X - Y detectors for planar positioning. The principle of the method was tested at a proton energy of 66 MeV. Good visual quality is seen in the tests. The measurements are compared with detailed Monte Carlo simulations, and good agreement is found. We apply the simulations to high energy proton beams (245 MeV) and show that the method should provide good visual quality and sensitivity for positioning at the higher energies necessary for whole body therapy.

Background To investigate the safety and tolerability of ranibizumab combined with proton beam irradiation in treating exudative age-related macular degeneration. Methods Six eyes (6 subjects) with exudative age-related macular degeneration (4 newly diagnosed; 2 previous treated with ranibizumab) were treated with 4 monthly ranibizumab and 24 GyE proton beam irradiation (2 fractions, 24 hours apart) and seen monthly thereafter and retreated with ranibizumab for decrease in best-corrected visual acuity of ≥2 lines, new macular hemorrhage or fluid noted on optical coherence tomography. Results Follow-up ranged from 12 months to 36 months (mean, 28 months). Baseline best-corrected visual acuity ranged from 20/40 to 20/250. Final best-corrected visual acuity ranged from 20/25 to 20/400. No radiation retinopathy was noted in any eye. Calculated radiation distribution dose curves indicate that ≤10% of retina received ≥90% of radiation dose in all eyes. Two subjects lost ≥3 lines of best-corrected visual acuity during follow-up, 1 subject in both eyes from enlarging geographic atrophy and the other from worsening fibrovascular pigment epithelial detachment, which was refractory to multiple ranibizumab treatments before enrollment. Among 4 eyes with newly diagnosed exudative age-related macular degeneration, 3 had no fluid on optical coherence tomography at month 12 without further treatment. Conclusion No safety concerns were noted after 3 years in eyes with exudative age-related macular degeneration treated with ranibizumab combined with proton beam irradiation in this small pilot study. A larger randomized prospective study is under way to further evaluate this combination therapy.

The purpose of this study is to evaluate a novel approach for treatment planning using digital fundus image fusion in EYEPLAN for proton beam radiation therapy (PBRT) planning for ocular melanoma. The authors used a prototype version of EYEPLAN software, which allows for digital registration of high-resolution fundus photographs. The authors examined the improvement in tumor localization by replanning with the addition of fundus photo superimposition in patients with macular area tumors.The new version of EYEPLAN (v3.05) software allows for the registration of fundus photographs as a background image. This is then used in conjunction with clinical examination, tantalum marker clips, surgeon's mapping, and ultrasound to draw the tumor contour accurately. In order to determine if the fundus image superimposition helps in tumor delineation and treatment planning, the authors identified 79 patients with choroidal melanoma in the macular location that were treated with PBRT. All patients were treated to a dose of 56 GyE in four fractions. The authors reviewed and replanned all 79 macular melanoma cases with superimposition of pretreatment and post-treatment fundus imaging in the new EYEPLAN software. For patients with no local failure, the authors analyzed whether fundus photograph fusion accurately depicted and confirmed tumor volumes as outlined in the original treatment plan. For patients with local failure, the authors determined whether the addition of the fundus photograph might have benefited in terms of more accurate tumor volume delineation.The mean follow-up of patients was 33.6 +/- 23 months. Tumor growth was seen in six eyes of the 79 macular lesions. All six patients were marginal failures or tumor miss in the region of dose fall-off, including one patient with both in-field recurrence as well as marginal. Among the six recurrences, three were managed by enucleation and one underwent retreatment with proton therapy. Three patients developed distant metastasis and all three patients have since died. The replanning of six patients with their original fundus photograph superimposed showed that in four cases, the treatment field adequately covered the tumor volume. In the other two patients, the overlaid fundus photographs indicated the area of marginal miss. The replanning with the fundus photograph showed improved tumor coverage in these two macular lesions. For the remaining patients without local failure, replanning with fundus photograph superimposition confirmed the tumor volume as drawn in the original treatment plan.Local control was excellent in patients receiving 56 GyE of PBRT for uveal melanomas in the macular region, which traditionally can be more difficult to control. Posterior lesions are better defined with the additional use of fundus image since they can be difficult to mark surgically. In one-third of treatment failing patients, the superposition of the fundus photograph would have clearly allowed improved localization of tumor. The current practice standard is to use the superimposition of the fundus photograph in addition to the surgeon's clinical and clip mapping of the tumor and ultrasound measurement to draw the tumor volume.

The Philips SL25 accelerator is a multimodality machine offering asymmetric collimator jaws and a new type of beam bending and transport system. It produces photon beams, nominally at 6 and 25 MV, and a scattered electron beam with nine selectable energies between 4 and 22 MeV. Dosimetric characteristics for the 6- and 25-MV photon beams are presented with respect to field flatness, surface and depth dose characteristics, isodose distribution, field size factors for both open and wedged fields, and narrow beam transmission data in different materials.

Objective To assess outcomes of proton beam radiotherapy for the treatment of extra-large uveal melanomas in patients specifically referred to the University of California, San Francisco, for ocular conservation therapy. Series patients uniformly refused enucleation both at an outside institution and again as a treatment option after extensive discussion at the University of California, San Francisco. Design In a retrospective, nonrandomized cohort study, 21 patients with extra-large choroidal or ciliochoroidal melanomas measuring at least 10 mm in maximum thickness or 20 mm in maximum basal diameter or tumors located within 3 mm of the optic nerve measuring at least 8 mm in maximum thickness or 16 mm in maximum basal diameter met inclusion criteria. Main outcome measures were frequency of (1) anterior segment complications (lash loss, keratopathy, cataract, and neovascular glaucoma), (2) posterior segment complications (vitreous hemorrhage, radiation retinopathy, and radiation papillopathy), (3) treatment failure (tumor growth, enucleation, or metastases), and (4) final visual acuity. Results Median follow-up was 28 months. Mean age at treatment was 58.3 years. The frequencies of hypertension and diabetes mellitus were 14.3% and 9.5%, respectively. Mean tumor thickness and mean basal diameter were 8.6 mm and 18.7 mm, respectively. Lash loss occurred in 52.4%; dry eye, in 23.8%; cataract, in 28.6%; neovascular glaucoma, in 38.1% (100% in patients with diabetes mellitus); radiation retinopathy, in 9.5%; and radiation papillopathy, in 9.5%. No patient developed radiation-associated scleral necrosis or vitreous hemorrhage. The 2-year Kaplan-Meier estimate of local tumor growth after treatment was 33%, and the rate of distant metastasis was 10%. Visual acuity of 20/200 or better was preserved in 25% of patients, including 4 patients (19%) who experienced an average of 4 lines of Snellen visual acuity improvement. Development of neovascular glaucoma was associated with tumors in close proximity to the optic nerve ( P = .04), while cataract ( P = .03) and lash loss ( P = .02) occurred with more anteriorly located tumors. Proton beam radiotherapy provided a 67% probability of local control and 90% probability of clinically discernible metastases-free survival at 24 months after treatment. Conclusion Proton beam radiotherapy is an ocular-conserving option that may be considered for the treatment of extra-large uveal melanoma in carefully selected patients.

The aim of this study is to (1) compare the delineation of the tumor volume for ocular melanoma on high-resolution three-dimensional (3D) T2-weighted fast spin echo magnetic resonance imaging (MRI) images with conventional techniques of A- and B-scan ultrasound, transcleral illumination, and placement of tantalum markers around tumor base and (2) to evaluate whether the surgically placed marker ring tumor delineation can be replaced by 3D MRI based tumor delineation. High-resolution 3D T2-weighted fast spin echo (3D FSE) MRI scans were obtained for 60 consecutive ocular melanoma patients using a 1.5 T MRI (GE Medical Systems, Milwaukee, WI), in a standard head coil. These patients were subsequently treated with proton beam therapy at the UC Davis Cyclotron, Davis, CA. The tumor was delineated by placement of tantalum rings (radio-opaque markers) around the tumor periphery as defined by pupillary transillumination during surgery. A point light source, placed against the sclera, was also used to confirm ring agreement with indirect ophthalmoscopy. When necessary, intraoperative ultrasound was also performed. The patients were planned using EYEPLAN software and the tumor volumes were obtained. For analysis, the tumors were divided into four categories based on tumor height and basal diameter. In order to assess the impact of high-resolution 3D T2 FSE MRI, the tumor volumes were outlined on the MRI scans by two independent observers and the tumor volumes calculated for each patient. Six (10%) of 60 patients had tumors, which were not visible on 3D MRI images. These six patients had tumors with tumor heightsor = 3 mm. A small intraobserver variation with a mean of (-0.22 +/- 4)% was seen in tumor volumes delineated by 3D T2 FSE MR images. The ratio of tumor volumes measured on MRI to EYEPLAN for the largest to the smallest tumor volumes varied between 0.993 and 1.02 for 54 patients. The tumor volumes measured directly on 3D T2 FSE MRI ranged from 4.03 to 0.075 cm3. with a mean of 0.87 +/- 0.84 cm3. The tumor shapes obtained from 3D T2 FSE MR images were comparable to the tumor shapes obtained using EYEPLAN software. The demonstration of intraocular tumor volumes with the high-resolution 3D fast spin echo T2 weighted MRI is excellent and provides additional information on tumor shape. We found a high degree of accuracy for tumor volumes with direct MRI volumetric measurements in uveal melanoma patients. In some patients with extra large tumors, the tumor base and shape was modified, because of the additional information obtained from 3D T2 FSE MR images.

The optimal treatment of uveal melanoma would destroy the intraocular tumor, retain good vision, and avoid the development of metastatic disease. Unfortunately, inherent limitations make the development of such an optimal therapy unlikely in the near future.1 One, approximately two thirds of choroid

Purpose/Objective(s): To present long-term follow-up for patients with intraocular vascular tumors treated with proton beam radiation therapy (PBRT). Materials/Methods: We performed a review of our prospectively maintained database for all patients with intraocular vascular tumors treated with PBRT at our institution between 1994 and 2012. We report patient demographics, tumor characteristics, dose schemes, treatment responses, and complications. Patients with at least 6 months of follow-up data were included in the study. Results: Our review identified 29 evaluable patients (29 eyes) with vascular tumors of the eye, with the most common diagnosis being choroidal hemangioma (n Z 22). Additionally, three diffuse choroidal hemangiomas associated with Sturge-Weber syndrome, three retinal angiomas, and one hemangioblastoma associated with von Hippel-Lindau syndrome were also identified. The main analysis hereafter focuses on the choroidal hemangioma patients (n Z 22), with mean follow-up time of 78.5 months (range 12-177 months, median 69.2 months). Median age at diagnosis was 48.3 years (range 17-72). All 22 patients were symptomatic at the time of diagnosis. Initial tumor thickness, as measured by ultrasonography, ranged from 2.0 mm to 7.2 mm (mean 3.8 mm). All patients except one had the anterior tumor border located posterior to the equator. Patients were treated using total doses between 18 and 24 Cobalt Gray Equivalent (CGE) in four fractions. Best corrected visual acuity improved or remained stable in 20 of 22 eyes (91%). Of the 16 eyes initially presenting with retinal detachment, 15 experienced reattachment (94%). Cystoid macular edema was initially documented in 16 eyes and completely resolved in 13 eyes (81%). Subretinal fluid was initially present in 17 eyes and resolved in 16 eyes (94%). Tumor thickness decreased in all eyes as of last examination. Notable complications occurred in five patients, with the most common being radiation retinopathy and atrophy; anti-VEGF therapy was used for treatment. Nine patients received full dose to the disc and macula (range 18-24 CGE), none of whom had significant worsening of vision. The additional seven intraocular vascular tumors with variable histologies have also demonstrated tumor response after PBRT at mean follow-up of 29.5 months (median 24.4 months) with stable or improved visual acuity. Conclusions: This series demonstrates consistent and long-term tumor response and visual preservation in patients with benign vascular tumors of the eye, including choroidal hemangiomas, diffuse hemangiomas with Sturge-Weber syndrome, retinal angiomas, and hemangioblastoma related to von Hippel-Lindau syndrome. The data presented represents the longest available follow-up in the literature to date for choroidal hemangiomas treated with PBRT. Author Disclosure: E.M. Chang: None. D.H. Char: None. D. Jusufbegovic: None. I.K. Daftari: None. T.B. Cole: None. J.M. Quivey: None. T.L. Phillips: None. K.K. Mishra: None.

The purpose of this study is to explore the use of GafChromic MD-55 (RC) film for 67.5 MeV clinical proton beam dosimetry at the Crocker Nuclear Laboratory, University of California, Davis. Several strips of RC film 6 cm x 6 cm in dimension were irradiated at a depth of 18.2 mm corresponding to the middle of a 24 mm spread-out Bragg peak (SOBP). The films were irradiated to a proton dose in the range of 0.5 Gy to 100 Gy. The beam profiles were also measured at the middle of the 24 mm SOBP. The Bragg peak was measured by using a wedge shaped phantom made of Lucite. The Bragg peak measured with RC film was compared with diode and ionization chamber measurements. After background subtraction, the calibration of the dose response of RC film showed, to a maximum deviation of 10%, a linear increase of optical density (OD) with dose from 0.5 to 100 Gy. The uniformity of OD over a single sheet of film showed a variation of +/-6%. The distal-fall off between 90% and 20% measured with GafChromic film for the Bragg peak was 1.3 mm as compared to 1.1 mm for a diode measurement and 1.4 mm for an ionization chamber measurement. The FWHM of the Bragg peak was 7.5 mm when measured with GafChromic film, 5.3 mm when measured with a diode and 8.1 mm as measured by an ionization chamber. The peak/plateau ratio with GafChromic film was 3.3 as compared to 3.7 with a diode and 3.2 with an ionization chamber. In conclusion, GafChromic MD-55 film may be a useful and convenient detector for dose measurement and quality assurance programmes of proton beams.

PURPOSE: The purpose of this investigation is to delineate the risk factors in the development of neovascular glaucoma (NVG) after helium-ion irradiation of uveal melanoma patients and to propose treatment technique that may reduce this risk. METHODS AND MATERIALS: 347 uveal melanoma patients were treated with helium-ions using a single-port treatment technique. Using univariate and multivariate statistics, the NVG complication rate was analyzed according to the percent of anterior chamber in the radiation field, tumor size, tumor location, sex, age, dose, and other risk factors. Several University of California San Francisco-Lawrence Berkeley National Laboratory (LBNL) patients in each size category (medium, large, and extralarge) were retrospectively replanned using two ports instead of a single port. By using appropriate polar and azimuthal gaze angles or by treating patients with two ports, the maximum dose to the anterior segment of the eye can often be reduced. Although a larger volume of anterior chamber may receive a lower dose by using two ports than a single port treatment. We hypothesize that this could reduce the level of complications that result from the irradiation of the anterior chamber of the eye. Dose-volume histograms were calculated for the lens, and compared for the single and two-port techniques. RESULTS: NVG developed in 121 (35%) patients. The risk of NVG peaked between 1 and 2.5 years posttreatment. By univariate and multivariate analysis, the percent of lens in the field was strongly correlated with the development of NVG. Other contributing factors were tumor height, history of diabetes, and vitreous hemorrhage. Dose-volume histogram analysis of single-port vs. two-port techniques demonstrate that for some patients in the medium and large category tumor groups, a significant decrease in dose to the structures in the anterior segment of the eye could have been achieved with the use of two ports. CONCLUSION: The development of NVG after helium-ion irradiation is correlated to the amount of lens, anterior chamber in the treatment field, tumor height, proximity to the fovea, history of diabetes, and the development of vitreous hemorrhage. Although the influence of the higher LET deposition of helium-ions is unclear, this study suggests that by reducing the dose to the anterior segment of the eye may reduce the NVG complications. Based on this retrospective analysis of LBNL patients, we have implemented techniques to reduce the amount of the anterior segment receiving a high dose in our new series of patients treated with protons using the cyclotron at the UC Davis Crocker Nuclear Laboratory (CNL).

Purpose: To review the long-term experience of helium iontherapy as a therapeutic alternative to enucleation for uveal melanoma,particularly with respect to survival, local control, and morbidity.Methods and Materials: 347 patients with uveal melanoma were treated withheluim ion RT from 1978-1992. A nonrandomized dose-searching study wasundertaken, with doses progressively reduced from 80 GyE in fivefractionsto 48 GyE in four fractions, given in 3-15 days, mean of 7days. Results: Local control was achieved in 96 percent of patients, withno difference in the rate of local control being seen at 80, 70, 60, or50 GyE in five fractions. At the lowest dose level of 48 GyE in fourfractions, the local control rate fell to 87 percent. Fifteen of 347patients (4 percent) had local regrowth in the eye requiring enucleation(12 patients), laser (1 patient) or reirradiation (2 patients). The timeof appearance of local regrowth ranged from 4 months to 5 yearsposttreatment, with 85 percent occurring within 3 years. Of the 347patients, 208 are alive as of May 1, 1997. The median follow up of allpatients is 8.5 years, range 1-17 years. Kaplan-Maier (K-M) survival is80 percent at 5 years, 76 percent at 10 years, and 72 percent at 15 yearsposttreatment. Patients with tumors notmore » involving the ciliary body have a15-year K-M survival of 80 percent. The results for patients whose tumorsinvolved the ciliary body are poor, with a 15-year K-M survival of 43percent. Seventy-five percent of patients with tumors at least 3.0 mmfrom the fovea and optic nerve, and initial ultrasound height less than6.0 mm, retained vision of 20/200 or better posttreatment. Patients withtumors larger than 6 mm in thickness, or with tumors lying close to theoptic nerve or fovea, have a reduced chance of retaining useful vision.The enucleation rate is 19 percent, 3 percent for local failure and 16percent because of complications of the helium RT, particularlyneovascular glaucoma, which occurred in 35 percent of patients.Conclusions: Local control and retention of the eye are excellent.Complications of therapy reduce vision and eye preservation. Twenty-fourpercent of patients manifested distant metastases 6 to 146 monthsposttreatment, mean of 43 months, median of 36 months. Late-appearingdistant metastases do not appear to be caused by persistent tumor in theeye. The risk of metastases is high for patients with tumors greater than7 mm in initial ultrasound height (37 percent), anterior tumors involvingthe ciliary body (47 percent), and in those with local failure (53percent). Patients with tumors not involving the ciliary body and initialdimensions less than 10 mm had only an 8 percent chance of death frommelanoma. A search for effective adjuvant therapy is needed for patientsat high risk of metastases (large tumors, ciliary body involved, localregrowth in eye).« less

Purpose: High-linear energy transfer (LET) radiation beams have potential applications in the treatment of glioblastoma, but have not yet demonstrated significant improvement in results. However, some patients have had local control of glioblastoma with high-LET irradations such as neutrons and heavy charged particles. Methods and Materials: In this collaborative study, 15 patients were entered into a randomized protocol comparing two dose levels fo 20 and 25 Gy in 4 weeks of neon ion irradiation. This trial was intended to determine the optimal neon dose in terms of survival and effects of radiation. Results: Fourteen patients were evaluable wtih no significatn differences in median survival (13 and 14 months; p = NS) or median time to failure (7 and 9 months; p = NS) between the two dose arms. Three patients died of nontumor-related causes, of whom one (who died 19 months posttreatment) had autopsy confirmation of no tmor on pathological exam. The other two patients had stable magnetic resonance imaging scans at 6 and 22 months posttreatment. Conclusion: Although the results did not demonstrate the optimal high-LET dose level, there is an intriguing effect in that two patients had control of glioblastoma until death at 19 and 22 months. This suggests that better conformation of the high-LET dose to the tumor with neutron capture therapy or dynamic conformal heavy charged particle therapy might control glioblastoma while minimizing brain damage from radiation.

Background and purpose: Methods for determining absorbed dose in clinical proton beams are based on dosimetry protocols provided by the AAPM and the ECHED. Both groups recommend the use of air-filled ionization chambers calibrated in terms of exposure or air kerma in a Co-60 beam when a calorimeter or Faraday cup dosimeter is not available. The set of input data used in the AAPM and the ECHED protocols, especially proton stopping powers and w-value is different. In order to verify inter-institutional uniformity of proton beam calibration, the AAPM and the ECHED recommend periodic dosimetry intercomparisons. In this paper we report the results of an international proton dosimetry intercomparison which was held at Loma Linda University Medical Center. The goal of the intercomparison was two-fold: first, to estimate the consistency of absorbed dose delivered to patients among the participating facilities, and second, to evaluate the differences in absorbed dose determination due to differences in Co-60-based ionization chamber calibration protocols. Materials and methods: Thirteen institutions participated in an international proton dosimetry intercomparison, The measurements were performed in a 15-cm square field at a depth of 10 cm in both an unmodulated beam (nominal accelerator energy of 250 MeV) and a 6-cm modulated beam (nominal accelerator energy of 155 MeV), and also in a circular field of diameter 2.6 cm at a depth of 1.14 cm in a beam with 2.4 cm modulation (nominal accelerator energy of 100 MeV). Results: The results of the intercomparison have shown that using ionization chambers with Co-60 calibration factors traceable to standard laboratories, and institution-specific conversion factors and dose protocols, the absorbed dose specified to the patient would fall within 3% of the mean value. A single measurement using an ionization chamber with a proton chamber factor determined with a Faraday cup calibration differed from the mean by 8%. Conclusion: The adoption of a single ionization chamber dosimetry protocol and uniform conversion factors will establish agreement on proton absorbed dose to approximately 1.5%, consistent with that which has been observed in high-energy photon and electron dosimetry.