Treatment Of Ocular Melanoma Research Articles

Monte Carlo dosimetry of Y-90 and Ru-106 /Rh-106 disk sources for ocular melanoma treatment: beta dose falloff study

Monte Carlo dosimetry of Y-90 and Ru-106 /Rh-106 disk sources for ocular melanoma treatment: beta dose falloff study

P 14 - Ocular melanoma treatment on a spot-scanning system

P 14 - Ocular melanoma treatment on a spot-scanning system

P 25 - Utilization of fundus image for target delineation and contouring for treatment of ocular melanoma

P 25 - Utilization of fundus image for target delineation and contouring for treatment of ocular melanoma

A multi-dimensional reality: Carol Lally Shields.

A multi-dimensional reality: Carol Lally Shields.

Design and characterization of an aperture system and spot configuration for ocular treatments with a gantry-based spot scanning proton beam.

Proton therapy is a key modality used in the treatment of ocular melanoma. Traditionally ocular sites are treated using a dedicated eyeline with a passively scattered proton beam and a brass aperture. This work aims to design and characterize a beam-collimating aperture to treat ocular targets with a gantry-based spot scanning proton beam. A plastic aperture system that slides into the gantry nozzle of a spot scanning proton beam was designed and constructed. It consists of an intermediate scraper layer to attenuate stray protons and a 3D-printed patient-specific aperture positioned 5.7cm from the surface of the eye. The aperture system was modeled in TOPAS and Monte Carlo simulations were validated with film measurements. Two different spot configurations were investigated for treatment planning and characterized based on lateral penumbra, central axis (CAX) dose and relative efficiency. Alignment and leakage were investigated through experimental film measurements. Range was verified using a multi-layer ionization chamber. Reference dose measurements were made with a PinPoint 3D ion chamber. Neutron dose was evaluated through Monte Carlo simulations. Aperture alignment with radiation isocenter was determined to be within 0.31mm at a gantry angle of 0°. A single-spot configuration with a 10mm diameter aperture yielded film-measured lateral penumbras of 1mm to 1.25mm, depending on depth in the spread-out Bragg peak. TOPAS simulations found that a single spot configuration results in a flat dose distribution for a 10mm diameter aperture and provides a CAX dose of less than 106% for apertures less than 14mm in diameter. For larger targets, adding four corner spots to fill in the dose distribution is beneficial. Trade-offs between lateral penumbra, CAX dose and relative efficiency were characterized for different spot configurations and can be used for future clinical decision-making. The aperture was experimentally determined to not affect proton beam range, and no concerning leakage radiation or neutron dose was identified. Reference dose measurements with a PinPoint ion chamber were within 2.1% of Monte Carlo calculated doses. The aperture system developed in this work provides a method of treating ocular sites on a gantry-based spot scanning proton system. Additional work to develop compatible gaze tracking and gating infrastructure is ongoing.

Microdosimetry with a mini-TEPC in the spread-out Bragg peak of 148 MeV protons

A new miniaturized Tissue Equivalent Proportional Counter (mini‒TEPC) with cylindrical sensitive volume of 1.0 mm in diameter and height, and with external diameter of 1.53 cm, has been developed to work without gas flow. With this mini counter we have measured the radiation quality of the 148 MeV energy-modulated proton beam at the radiobiological research line of the Trento Proton Therapy Centre. The irradiation field had a diameter of about 6 cm, a modulation width of 2.5 cm and a range of about 13.5 cm. At four specific depths, the response function of the new microdosimeter has also been compared to that of a commercial spherical microdosimeter, the LET-1/2” Spherical TEPC produced by Far West Technology. Afterwards, measurements were performed with the mini‒TEPC at nine precise positions across the Spread-Out Bragg Peak (SOBP).From the microdosimetric spectra the frequency and the dose‒mean lineal energy values, y‾F and y‾D, were derived for both detectors. Afterwards, microdosimetric assessment of Relative Biological Effectiveness (RBEμ) has been performed by weighting the dose distribution of the lineal energy, d(y), with the Loncol’s biological weighting function r(y).RBEμ has been used to calculate the RBEμD at different dose levels D. In the distal fall-off region the RBEμD(d) increases significantly, up to a factor 3. Finally, the RBEμD-weighted dose was calculated and compared to that obtained with a fixed RBE = 1.1. The use of a variable RBE to weight the physical dose leads to a biological range extension evaluated at R80 of about 2.0 mm, with respect to the R80 obtained with a fixed RBE = 1.1.The use of a mini‒TEPC in proton therapy has been so far limited to 60 MeV proton beams, used for the treatment of ocular melanoma. This is the first time that a mini-TEPC was used with an higher energy proton beam of 148 MeV, and the spectra measured with the mini-TEPC were compared to those measured with the commercial FWT LET1/2 counter for the first time.These new results corroborate the usability of mini-TEPCs in proton therapy.

Efficacy of immunotherapy and sequencing of checkpoint inhibition for metastatic ocular melanoma.

e21526 Background: Ocular melanoma (OM) is the most common intraocular tumor in adults. However, it is still rare as compared to other subtypes of melanoma. Treatment of primary OM is certainly successful, but most therapies assessed in treatment of metastatic OM have not shown promise. Immunotherapy (IO), which has otherwise held prospect for durable remissions in other metastatic melanoma has shown no evidence in metastatic OM. Our study aims at narrowing the gap in knowledge in the treatment of OM with IO. Methods: We conducted a retrospective cohort study of patients with metastatic OM treated during the period 2017-2021 at the University of Louisville. Patients aged 18 years or more with treatment-naïve metastatic (Stage IV) OM were included. Data was censored according to date of last recorded clinical follow up or death. The primary outcome of interest was overall survival (OS). Subgroup analysis was done to examine survival based on initial treatment with dual versus single checkpoint inhibition. After progression on initial therapy, patients previously on dual inhibition went on to receive single inhibition, and vice versa. Kaplan-Meier survival analyses were generated using all-cause mortality as the competing outcome event and log-rank testing to evaluate differences between groups with alpha set at 0.05 for significance. Results: A total of 21 patients with Stage IV OM were identified with 4 excluded due to lack of data. The majority were male (10/17) and median age was 66 years, ranging from 30 to 89 years. More than half (10/17) received dual checkpoint inhibition as initial IO, with ipilimumab and nivolumab. The remainder received pembrolizumab or Nivolumab monotherapy (7/17). IO was well tolerated with no treatment related mortality and incidence of immune-related adverse effects similar to cutaneous melanoma. The median follow-up time overall was 56 months using the reverse Kaplan-Meier method with a median OS of 15 months. Estimated 2-year OS was 41%. No significant difference was found between single and dual checkpoint inhibition as the initial treatment regimen. Conclusions: While IO has markedly improved survival in advanced melanomas, OM continues to have inferior survival. Consistent with the literature by Zimmer et al, survival in this cohort is better than that reported with ipilimumab monotherapy. The median survival of 15 months is consistent with that reported by Heppt et al in the German multicenter study. IO for Stage IV OM was well tolerated, resulting in median survival of 15 months and 2-year OS of 41%. There was no survival advantage to initial treatment with single versus dual checkpoint inhibition, allowing for crossover at progression. Further research with novel agents and enrollment in clinical trials are needed in ocular melanoma.

Comparison between dose distribution from 103Pd, 131Cs, and 125I plaques in a real human eye model with different tumor size

Knowledge of the energy deposition in different eye components is a critical decision-making to the overall effectivity of ocular melanoma treatment with plaques loaded with low-energy sources. The aim of this study is using the GATE 8.2 Monte Carlo code to calculate the 3D dose distribution in a realistic eye model. At first, we validated the GATE simulation for 125I, 103Pd, and 131Cs seeds by calculating the dose rate constant, radial dose function, and anisotropy function of the three radioactive sources. Then, a 12-mm Collaborative Ocular Melanoma Study (COMS) eye plaque was simulated in the eye phantoms to evaluate dose distribution due to low-energy gamma emitters on the three simulated medium-sized tumors. The findings of this study indicate that the estimated doses received by different eye substructures strongly depend on the source type. The results show that the type of seeds used in the plaque, as well as the size of the eye tumor, have significant effects on the dose deposition in the different structures of the eye and dose deposition uniformity. Moreover, comparing different radionuclides showed that the COMS plaque fully loaded with 103Pd presents a higher dose delivery to the tumor and a lower one to the critical structures for medium-sized tumors, while the plaque fully loaded with 131Cs produces the most uniform dose distribution in the tumor.

The Clinical Feature and Treatment Outcome of Ocular Melanoma: A 34-Year Experience in a Tertiary Referral Center

Simple SummaryAlthough uncommonly encountered, ocular melanoma may threaten the vision and even the life of a patient. The clinical feature and long-term results of ocular melanoma have rarely been described in the Asian population, as it has a low incidence for non-Caucasians. Therefore, we investigated the epidemiology, clinical manifestation, treatment strategy, and long-term outcome of ocular melanoma in a tertiary referral center in Taiwan.Malignant melanoma can arise from melanocytes in various structures of the eye, orbit, and ocular adnexa. We reviewed the clinical features and long-term results of all subjects with histologically proved melanoma originating from any of the ocular and periocular structures in a tertiary referral center. Overall, 88 patients including 47 men were recruited. The tumor was primarily located in the uvea, followed by the conjunctiva, orbit, eyelid, and lacrimal sac. Patients with uveal melanoma were diagnosed at a relatively younger age (47.0 years), while those with orbital and eyelid melanomas were older at presentation (79.5 years and 78.5 years, respectively). The overall local recurrence rate was 9% at a median follow-up of 41.0 months, among which orbital and eyelid melanomas recurred most commonly. The overall mortality rate was 41% in a median duration of 27.2 months (IQR, 13–58 months) from diagnosis, with the highest for lacrimal sac melanoma, followed by melanoma of the orbit, uveal, conjunctiva, and eyelid. Despite prompt local control, the risk for metastasis and mortality was high. Therefore, efficient modalities for early diagnosis and treatment of ocular melanoma are necessary.

Intensity modulated high dose rate ocular brachytherapy using Se-75

PurposeWe propose an alternative to LDR brachytherapy for the treatment of ocular melanomas by coupling intensity modulation, through the use of a gold shielded ring applicator, with a middle energy HDR brachytherapy source, Se-75. In this study, we computationally test this proposed design using MCNP6. Methods and MaterialsAn array of discrete Se-75 sources is formed into a ring configuration within a gold shielded applicator, which collimates the beam to a conical shape. Varying this angle of collimation allows for the prescription dose to be delivered to the apex of various sized targets. Simulations in MCNP6 were performed to calculate the dosimetric output of the Se-75 ring source for various sized applicators, collimators, and target sizes. ResultsThe prescription dose was delivered to a range of target apex depths 3.5−8 mm in the eye covering targets 10-15 mm in diameter by using various sized applicators and collimators. For a 16 mm applicator with a collimator opening that delivers the prescription dose to a depth of 5 mm in the eye, the maximum percent dose rate to critical structures was 30.5% to the cornea, 35.7% to the posterior lens, 33.3% to the iris, 20.1% to the optic nerve, 278.0% to the sclera, and 267.3% to the tumor. ConclusionsWhen using Se-75 in combination with the proposed gold shielded ring applicator, dose distributions are appropriate for ocular brachytherapy. The use of a collimator allows for the dose to more easily conform to the tumor volume. This method also reduces treatment time and cost, and it eliminates hand dose to the surgeon through the use of a remote afterloader device.

Evaluation of eye melanoma treatments in rabbits: A systematic review.

Melanomas are the most common cancer of the eye in canines, felines and humans. The treatment approaches vary, since no gold standard exists. Therefore, this systematic review aimed to compare the treatment modalities in ocular melanoma in rabbits. Medline/PubMed, Cochrane Library, Web of Science and Embase were searched for articles published until 21 April 2021 in English, Portuguese or Spanish, reporting animal studies evaluating photodynamic therapy (PDT), laser, radiotherapy or surgical excision. Twenty-seven articles were included for the qualitative synthesis, with publication dates from 1970 to 2018. Of the selected studies, 19 used PDT, six used radiotherapy and two used laser as treatment. No studies regarding surgical therapy that met the inclusion criteria were obtained. The tumour therapy results were evaluated in a heterogeneous manner for different periods and various methods, including microscopy, angiographic, histological examination, fundoscopy, ultrasound exam and electroretinogram. The treatment modalities analysed successfully treated the ocular melanoma, with tumour necrosis being commonly observed. Despite the therapeutic efficacy shown, side effects have been reported for all the therapies. The studies showed high heterogeneity, and therefore, in the future, new studies should be carried out to increase knowledge about ocular melanoma treatment. The analysed therapies can be used successfully in the treatment of ocular melanoma, with more conservative options such as PDT presenting great potential.

In-field and out-of-field microdosimetric characterisation of a 62 MeV proton beam at CATANA.

A 5 and 10 μm thin silicon on insulator (SOI) 3D mushroom microdosimeter was used to characterize both the in-field and out-of-field of a 62 MeV proton beam. The SOI mushroom microdosimeter consisted of an array of cylindrical sensitive volumes (SVs), developed by the Centre for Medical Radiation Physics, University of Wollongong, was irradiated with 62 MeV protons at the CATANA (Centro di AdroTerapia Applicazioni Nucleari Avanzate) facility in Catania, Italy, a facility dedicated to the radiation treatment of ocular melanomas. Dose mean lineal energy, ( ), values were obtained at various depths in PMMA along a pristine and spread out Bragg peak (SOBP). The measured microdosimetric spectra at each position were then used as inputs into the modified Microdosimetric Kinetic Model (MKM) to derive the RBE for absorbed dose in a middle of the SOBP 2Gy (RBED ). Microdosimetric spectra were obtained with both the 5 and 10 μm 3D SOI microdosimeters, with a focus on the distal part of the BP. The in-field and out-of-field measurement configurations along the Bragg curve were modeled in Geant4 for comparison with experimental results. Lateral out-of-field measurements were performed to study secondary particles' contribution to normal tissue's dose, up to 12 mm from the edge of the beam field, and quality factor and dose equivalent results were obtained. Comparison between experimental and simulation results showed good agreement between one another for both the pristine and SOBP beams in terms of and RBED. Though a small discrepancy between experiment and simulation was seen at the entrance of the Bragg curve, where experimental results were slightly lower than Geant4. The dose equivalent value measured 12 mm from the edge of the target volume was 1.27 ± 0.15 mSv/Gy with a value of 2.52 ± 0.30, both of which agree within uncertainty with Geant4 simulation. These results demonstrate that SOI microdosimeters are an effective tool to predict RBED in-field as well as dose equivalent monitoring out-of-field to provide insight to probability of second cancer generation.

Proton beam therapy

Proton beam therapy (PBT) is an advanced type of radiotherapy that shows a dosimetric advantage over photon beam therapy and provides superior dose distribution. PBT may improve patient survival by improving the local disease control while reducing toxicity to normal organs, which may result in fewer treatment-related complications. During the last decade, technological progress has opened up new possibilities in the planning and conducting of PBT, so indications have gradually expanded to different cancers. However, many biological aspects of PBT are still unclear, and its role in clinical settings is controversial. Proton therapy is considered to be safe and effective for different types of pediatric cancers, and suitable in treatment of ocular melanomas, chordomas, and chondrosarcomas. Future research and more prospective clinical studies with long-term follow-up are required in order to clearly determine the benefits and proper indications for PBT.

Bioresorbable, Miniaturized Porous Silicon Needles on a Flexible Water-Soluble Backing for Unobtrusive, Sustained Delivery of Chemotherapy.

Conventional melanoma therapies suffer from the toxicity and side effects of repeated treatments due to the aggressive and recurrent nature of melanoma cells. Less-invasive topical chemotherapies by utilizing polymeric microneedles have emerged as an alternative, but the sustained, long-lasting release of drug cargos remains challenging. In addition, the size of the microneedles is relatively bulky for the small, curvilinear, and exceptionally sensitive cornea for the treatment of ocular melanoma. Here, we report a design of bioresorbable, miniaturized porous-silicon (p-Si) needles with covalently linked drug cargos at doses comparable to those of conventional polymeric microneedles. The p-Si needles are built on a water-soluble film as a temporary flexible holder that can be intimately interfaced with the irregular surface of living tissues, followed by complete dissolution with saline solution within 1 min. Consequently, the p-Si needles remain embedded inside tissues and then undergo gradual degradation, allowing for sustained release of the drug cargos. Its utility in unobtrusive topical delivery of chemotherapy with minimal side effects is demonstrated in a murine melanoma model.

Multifocal Cerebral Infarction and Status Epilepticus as a Result of 3-bromopyruvate Toxicity for Treatment of Ocular Melanoma (P2.6-011)

Multifocal Cerebral Infarction and Status Epilepticus as a Result of 3-bromopyruvate Toxicity for Treatment of Ocular Melanoma (P2.6-011)

9. Commissioning of the first synchrotron-based scanning proton beamline for ocular melanoma treatments

Purpose Around 10 centers worldwide treat ocular tumors with proton therapy, all with dedicated eyelines. Our synchrotron-based facility is equipped with general-purpose fixed beamlines; proton and carbon ion treatments are delivered with pencil beam scanning modality (range in water 3 ÷ 32 cm). Recently, our proton beamline was adapted to treat also ocular diseases. The main dosimetric properties of this new eyeline are described in this work. Methods A 3 cm water-equivalent range shifter (RS) was placed along the beamline to reach shallower penetration depths. In order to achieve steep lateral dose gradients, the position of the RS and patient-specific collimator were simulated using MonteCarlo (MC) FLUKA code. Lateral dose profiles were measured with gafchromic EBT3 films to evaluate lateral penumbra width and dose homogeneity. Several beam scanning patterns were tested. Depth-dose distributions (DDDs) were measured with the Peakfinder system. To obtain uniform dose distributions (Spread-Out Bragg Peaks, SOBPs), the weights of each DDD were optimized simulating different targets. Absorbed doses were then measured in water with an advanced Markus chamber. Neutron dose at the contralateral eye was also evaluated with passive bubble dosimeters. Results MC simulations and experimental results showed that maximizing the distance between RS and collimator reduces the lateral dose penumbra of the collimated beam and increases field transversal dose homogeneity. Therefore, RS and patient-specific collimator were placed at about 98 cm (behind beam monitors) and 6 cm from the isocenter, respectively. The lateral penumbra (distal fall-off) ranged between 1.0 and 1.8 mm (1.0 and 1.6 mm). The measured SOBP doses were in very good agreement with MC simulations, as shown in Fig. 1. The mean neutron dose at the contralateral eye was 68.8 ± 10.2 μSv/Gy. Conclusions Our eyeline satisfied the requirements to treat ocular tumors. The first ocular patient was treated in August 2016. Around 60 patients have been treated so far.

Optimizing radiosurgery with photons for ocular melanoma.

Background and purposePhoton radiotherapy has been established for the treatment of ocular melanoma (OM). Here we investigate the planning qualities of two different planning approaches, a combination of dynamic conformal arcs (DCA) complemented with multiple non-coplanar static intensity-modulated (IMRT) fields (DCA-IMRT), and volumetric modulated arc therapy (VMAT) in combination with automated planning (AP).Materials and methodsThirteen consecutive patients treated for ocular melanoma with curative intent on a Linac-based radiosurgery system were analyzed. Fractionated stereotactic radiosurgery (fSRS) was applied using 50 Gy in 5 fractions using the combination of DCA-IMRT. Plans were reviewed and the thirteen cases were compared to plans obtained with optimized automated VMAT based on a set of 28 distinct patients treated with DCA-IMRT who were selected to generate the AP model for the prediction of dose volume constraints.ResultsOverall, plan quality of DCA-IMRT was superior to AP with VMAT. PTV coverage did not exceed 107% in any case treated with DCA-IMRT, compared to seven patients with VMAT. The median PTV covered by >95% was 98.3% (91.9%–99.7%) with DCA-IMRT, compared to 95.1% (91.5%–97.9%) (p < 0.01) with VMAT. The median mean dose delivered to the treated eye was 22.4 Gy (12.3 Gy–33.3 Gy) with DCA-IMRT compared to 27.2 Gy (15.5 Gy–33.7 Gy) (p < 0.01). Dose to the ipsilateral lacrimal gland and the ipsilateral optic nerve were comparable for DCA-IMRT and VMAT, however, the dose to the lens was lower with DCA-IMRT compared to VMAT.ConclusionsThe combination of multiple arcs complemented with multiple IMRT fields sets the gold standard for fSRS of ocular melanoma for photon therapy.

Abstract ID: 19 Validation of the Monte Carlo GATE platform for the dosimetry of ocular protontherapy

The aim of this work consisted to validate the Monte Carlo GATE platform in dose distributions of a proton beam on a mathematical model of the human eye. As a first step, a recommended 62 MeV proton beam for the treatment of ocular melanoma was simulated with GATE to check its aptitude to reproduce experimental measurements. In the second step, this beam was applied to a mathematical model of the human eye was defined precisely with real dimensions and densities. Depth-dose profile, lateral profile, dosimetric parameters according to international recommendations, and absolute dose in tumor and each organ were calculated and compared to other therapeutic techniques and Monte Carlo codes. A total of 106 incident protons were simulated in 20 min on a single i5 3.2 GHz CPU. Relative comparisons of percentage depth-dose and lateral profiles, performed between measured beam data and the simulated, show an agreement of the order of 2% in dose and 0.1 mm in range accuracy. These comparisons carried out with and without beam-modifying device, yield results compatible to the required precision in ocular melanoma treatments. Doses distributions issued from calculations and measurements were also compared. GATE platform show better results compared to other Monte Carlo codes. Results obtained from this study show that protontherapy is the most suitable treatment for ocular melanoma due to the unique property of its beam (Bragg peak). The ease of use, reproducibility and speed of GATE allows it to be used as an integrated tool for modeling imaging, dosimetry and processing in the same simulation platform. Ocular protontherapy offers excellent levels of eye retention, even in unfavorable cases such as large tumors.

Abstract ID: 169 Monte Carlo calculated correction factors for a proton calorimeter in clinical proton beams

Calorimetry is the only fundamental method for measuring the absorbed dose according to its definition. A calorimeter measures the temperature rise resulting from irradiation in an absorber, assuming all the energy deposited in a material appears as a heat. Unlike other detectors, e.g. ionization chambers, a calorimeter inherently provides a method to measure the energy deposited by radiation directly. In particular, the National Physical Laboratory (NPL) has developed and is now commissioning a graphite calorimeter as a primary standard of absorbed dose for clinical proton beams. To determine the absorbed dose to graphite from calorimeter measurements, different correction factors have to be calculated, including the gap correction factor ( k gap ) and a volume averaging correction factor ( k vol ) [1] . The former is related to the effect due to the presence of vacuum gaps within the calorimeter, the latter converts the mean absorbed dose in the graphite core to the absorbed dose in a point located at the centre of the core. A separate conversion factor is then applied to convert the absorbed dose to graphite in the calorimeter to the absorbed dose at the reference depth in water. Monte Carlo simulations are currently the most precise tool to calculate these corrections in complex experimental configurations. A Monte Carlo application has been developed with the TOPAS platform, based on the Geant4 toolkit to calculate k gap and k vol for monoenergetic proton beams with energies ranging between 60 and 230 MeV [2] . Initial results indicate that k gap ranges from 0.06% above unity at 60 MeV to 0.36% above unity at 230 MeV with k vol being of a similar magnitude at these energies. Moreover, to obtain the corrections in a more realistic environment close to clinical conditions, a typical passive proton therapy beam line for ocular melanoma treatment has been simulated in detail and similar results are being obtained for active scanning systems. The results of the presented work will significantly contribute to the establishment of the NPL calorimeter as a primary standard in proton therapy.

Modelling PET radionuclide production in tissue and external targets using Geant4

The Proton Therapy Facility in TRIUMF provides 74 MeV protons extracted from a 500 MeV H- cyclotron for ocular melanoma treatments. During treatment, positron emitting radionuclides such as 1C, 15O and 13N are produced in patient tissue. Using PET scanners, the isotopic activity distribution can be measured for in-vivo range verification. A second cyclotron, the TR13, provides 13 MeV protons onto liquid targets for the production of PET radionuclides such as 18F, 13N or 68Ga, for medical applications. The aim of this work was to validate Geant4 against FLUKA and experimental measurements for production of the above-mentioned isotopes using the two cyclotrons. The results show variable degrees of agreement. For proton therapy, the proton-range agreement was within 2 mm for 11C activity, whereas 13N disagreed. For liquid targets at the TR13 the average absolute deviation ratio between FLUKA and experiment was 1.9±2.7, whereas the average absolute deviation ratio between Geant4 and experiment was 0. 6±0.4. This is due to the uncertainties present in experimentally determined reaction cross sections.