Proton Therapy For Uveal Melanoma Research Articles

Clinical Outcomes in AYAs (Adolescents and Young Adults) Treated with Proton Therapy for Uveal Melanoma: A Comparative Matching Study with Elder Adults.

The aim of this study was to compare the clinical outcomes of adolescents and young adults (AYAs) with those of elder adult patients treated with proton therapy (PT) for uveal melanoma (UM). A retrospective, comparative study was conducted in UM patients who underwent PT at the Ocular Oncology Unit of the Jules-Gonin Eye Hospital (University of Lausanne, Lausanne, Switzerland) and the Paul Scherrer Institute (PSI); (Villigen, Switzerland) between January 1997 and December 2007. Propensity score matching (PSM) was used to select for each AYA (between 15-39 years old) an elder adult patient (≥40 years) with similar characteristics. We assessed ocular follow-up, local tumor control, metastasis incidence, and overall and relative survival (OS and RS). Non-terminal outcomes were then compared between the two groups using competing risk survival analysis. Out of a total of 2261 consecutive UM patients, after excluding 4 children (<15 years) and 6 patients who were metastatic at presentation, we identified 272 AYA patients and matched 270 of them with 270 elder adult patients. Before PSM, the AYA patients had a higher incidence of primary iris melanoma (4.0% vs. 1.4%; p = 0.005), while the elder patients were more likely to have other neoplastic diseases at presentation (9% vs. 3.7%; p = 0.004). Ocular outcomes and local tumor control were similar in both groups. Cumulative metastasis incidence for the AYA and elder adult groups was 13% and 7.9% at 5 years and 19.7% and 12.7% at 10 years, respectively, which was not significantly different between the groups (p = 0.214). The OS was similar in the two groups (p = 0.602), with estimates in the AYA and elder adult groups of 95.5% and 96.6% at 5 years and 94.6% and 91.4% at 10 years, respectively. However, the relative survival (RS) estimation was worse in the AYA group than the elder group (p = 0.036). While AYAs treated with PT for UM have similar ocular outcomes and present the same metastasis incidence and OS as elder adults, their RS is worse than that in elder adults, when compared with the population in general.

Inter-Observer Variability in MR-Based Target Volume Delineation of Uveal Melanoma

Several efforts are being undertaken toward MRI-based treatment planning for ocular proton therapy for uveal melanoma (UM). The interobserver variability of the gross target volume (GTV) on magnetic resonance imaging (MRI) is one of the important parameters to design safety margins for a reliable treatment. Therefore, this study assessed the interobserver variation in GTV delineation of UM on MRI. Six observers delineated the GTV in 10 different patients using the Big Brother contouring software. Patients were scanned at 3T MRI with a surface coil, and tumors were delineated separately on contrast enhanced 3DT1 (T1gd) and 3DT2-weighted scans with an isotropic acquisition resolution of 0.8 mm. Volume difference and overall local variation (median standard deviation of the distance between the delineated contours and the median contour) were analyzed for each GTV. Additionally, the local variation was analyzed for 4 interfaces: sclera, vitreous, retinal detachment, and tumor-choroid interface. The average GTV was significantly larger on T1gd (0.57cm3) compared with T2 (0.51cm3, P=.01). A not significant higher interobserver variation was found on T1gd (0.41 mm) compared with T2 (0.35 mm). The largest variations were found at the tumor-choroid interface due to peritumoral enhancement (T1gd, 0.62 mm; T2, 0.52 mm). As a result, a larger part of this tumor-choroid interface appeared to be included on T1gd-based GTVs compared with T2, explaining the smaller volumes on T2. The interobserver variation of 0.4 mm on MRI are low with respect to the voxel size of 0.8 mm, enabling small treatment margins. We recommend delineation based on the T1gd-weighted scans, as choroidal tumor extensions might be missed.

Inter‐Observer variability in MRI‐based target volume delineation of uveal melanoma

AbstractPurpose: Several efforts are being undertaken towards MRI‐based treatment planning for ocular proton therapy for uveal melanoma (UM). The inter‐observer variability of the gross target volume (GTV) on MRI is one of the important parameters to design safety margins for a reliable treatment. Therefore, this study assessed the inter‐observer variation in tumour delineation of UM on MRI.Methods: Six observers delineated the tumour in 10 different UM patients using the Big Brother contouring software. Patients were scanned at 3 T MRI with a surface coil and tumours were delineated separately on contrast enhanced 3DT1 (T1gd) and 3DT2‐weighted scans with a resolution of 0.8 mm isotropic for the acquisition voxels (1). Volume difference and overall local variation were analysed for each patient. Additionally the local variation was analysed for four interfaces: sclera, vitreous, retinal detachment, and tumour‐choroid interface.Results: The average tumour contour was significantly larger on T1gd (0.57 cm3) compared to T2 (0.51cm3, p = 0.01). A not significant higher interobserver variation was found on T1gd (0.4 1 mm) compared to T2 (0.35 mm). The largest variations were found at the tumour‐choroid interface, due to peritumoral enhancement (T1gd: 0.62 mm and T2: 0.5 2 mm). As a result, a larger part of this tumour‐choroid interface appeared to be included on T1gd based GTVs compared to T2, explaining the smaller volumes on T2.Conclusions: The interobserver variation of 0.4 mm on MRI are low with respect to the voxel size of 0.8 mm. We recommend to delineate based on the T1gd‐weighted scans, as choroidal tumour extensions might be missed.Reference1. Ferreira, et al. MR imaging characteristics of uveal melanoma with histopathological validation. Neuroradiology. 2022; 64:171. doi: 10.1007/s00234‐021‐02825‐5.

Proton Therapy for Uveal Melanoma: A Single-Institution Experience

<h3>Purpose/Objective(s)</h3> Uveal melanoma (UM) is the most common intraocular malignancy in adults. Eye-preserving approaches like episcleral plaque brachytherapy are common but limited in patients (pts) with large tumors or those adjacent to the optic nerve. Proton therapy (PT) offers an alternative eye-preserving treatment option. We report a single-institution experience utilizing PT to treat UM. We hypothesized that PT would provide excellent local control (LC) and eye preservation (EP) with acceptable toxicity and visual outcomes across all patients, including those with large tumors in adverse locations. <h3>Materials/Methods</h3> We reviewed the records of treatment-naive pts who received PT for non-metastatic UM between June 2012 and December 2020. All pts had ≥ 6 months of follow-up. Treatment planning was performed in EyePlan (Clatterbridge, UK) based on eye/tumor measurements and 3-4 implanted scleral fiducial markers, registered fundus photographs, and confirmed by CT/MRI. Pts were set-up in a seated position with gaze fixation and real-time image guidance using a single en face beam to a total 50-60 Gy RBE in 4-5 consecutive daily fractions. We estimated disease control and survival, including LC, EP, distant metastasis-free survival (DMFS), cause-specific survival (CSS), overall survival (OS), and grade 3+ toxicity as defined by CTCAEv5 using the cumulative incidence method. Regression of multiple variables simultaneously was accomplished with competing-risks Cox regression. <h3>Results</h3> 120 pts met inclusion criteria; 33 had a biopsy of their lesion; 9.2% were class 2. Moreover, 47.5% had COMS medium while 35.8% had large tumors. Median tumor thickness was 5.0 mm (0.5 – 13.0) and median basal dimension was 13.0 mm (4.0 – 25.0). Median distance to the fovea and optic disc was 3.5 mm. 38% had retinal detachment with 47% having significantly impaired visual acuity at baseline (worse than Snellen 20/40). 98.3% received 60 Gy RBE over 4 daily fractions. Median follow-up was 31 months (6 – 104). The 2-year estimates (95% CI) for LC, EP, DMFS, CSS, and OS were 94% (88-97%), 95% (90-98%), 88% (81-93%), 94% (88-97%), and 90% (83-95%), respectively. 9 pts underwent enucleation following PT (5 for recurrent/persistent disease). Retinopathy (5%), neovascular glaucoma (3.3%), and optic nerve disorder (2.5%) were the most common severe toxicities. 60% of toxicity resolved during follow-up. 38% had functional vision (20/40 or better) at last follow-up. Pretreatment visual acuity had a substantial impact on post-treatment vision. Tumor size was an independent prognostic factor for OS (p=0.01), CSS (p<0.01), EP (p=0.02), and DMFS (p<0.01). No prognostic factor was associated with LC. <h3>Conclusion</h3> Our experience using PT for UM is consistent with previously reported outcomes demonstrating high rates of LC and EP with acceptable toxicity despite a significant percentage of patients with large tumors and/or adverse location near the optic nerve.

A rare case of mucosal metastases 14 years after resolution of a primary uveal melanoma

Uveal melanoma has a high metastasis rate. Following the initial diagnosis, up to 50% of patients are affected by late recurrence and gastrointestinal metastasis is found to be one of the least frequent. We report the case of a 47-year-old woman who underwent proton therapy for uveal melanoma. Fourteen years after the initial diagnosis, she presented to the hospital complaining of an enduring gas in stomach. Dark colored, metastatic lesions were discovered in gastric mucosa during endoscopy and hyperintense hepatic lesions were spotted in T1 weighted MR imaging. Long term metastasis is commonly seen in patients with uveal melanoma and its management is more difficult when compared to other melanoma types, hence regular follow-ups are crucial for patient well-being. Keywords: uveal melanoma; gastric metastases; mucosal metastases; gastric mucosa; intraocular tumors.

Physiopathology of neovascular glauoma and preventive Anti VEGF injections

AbstractNeovascular glaucoma is a major complication after proton therapy of uveal melanomas, and is provoked by vasoproliferative agents produced by the tumor or ischemic retina. Risk factors for the presence of an ischemic retina at presentation are largest tumor diameter (LTD) tumor height and the extent of retinal detachment. In a prospective study the efficacy of preventive anti VEGF treatment was estimated following Proton Beam radiotherapy of uveal Melanomas associated with an ischemic retinal detachment. None of the treated cases and 32% of the controlled group developped an neovascular glaucoma. The anti VEGF treatment was completed with and extensive laser photocoagulation of the ischemic retina. Anti VEGF treatment associated to retina photocoagulation appears as valuable therapeutic modality in selected cases of uveal Melanomas following Protom Beam radiotherapy.

Prophylactic Use of Bevacizumab to Avoid Anterior Segment Neovascularization Following Proton Therapy for Uveal Melanoma

To investigate whether the prophylactic use of bevacizumab reduces the rate of rubeosis after proton therapy for uveal melanoma and improves the possibility to treat ischemic, reapplicated retina with laser photocoagulation. Comparative retrospective case series. Uveal melanoma patients with ischemic retinal detachment and treated with proton therapy were included in this institutional study. Twenty-four eyes received prophylactic intravitreal bevacizumab injections and were compared with a control group of 44 eyes without bevacizumab treatment. Bevacizumab injections were performed at the time of tantalum clip insertion and were repeated every 2 months during 6 months, and every 3 months thereafter. Ultra-widefield angiography allowed determination of the extent of retinal ischemia, which was treated with laser photocoagulation after retinal reapplication. Main outcome measures were the time to rubeosis, the time to retinal reattachment, and the time to laser photocoagulation of ischemic retina. Baseline characteristics were balanced between the groups, except for thicker tumors and larger retinal detachments in the bevacizumab group, potentially to the disadvantage of the study group. Nevertheless, bevacizumab prophylaxis significantly reduced the rate of iris rubeosis from 36% to 4% (log-rank test P = .02) and tended to shorten the time to retinal reapplication until laser photocoagulation of the nonperfusion areas could be performed. Prophylactic intravitreal bevacizumab in patients treated with proton therapy for uveal melanoma with ischemic retinal detachment prevented anterior segment neovascularization, until laser photocoagulation to the reapplied retina could be performed.

Proton Therapy for Uveal Melanoma in 43 Juvenile Patients

To examine the metastatic and survival rates, eye retention probability, and the visual outcomes of juvenile patients after proton beam radiotherapy (PBRT) for uveal melanoma (UM). Retrospective case-factor matched control study. Forty-three patients younger than 21 years treated with PBRT for UM were compared with 129 matched adult control patients. Information on patient demographics and clinical characteristics were recorded before and after treatment from patients' files. The control group was composed of adult patients (>21 years) matched for tumor size (largest tumor diameter, ±2 mm; height, ±2 mm) and anterior margin location (iris, ciliary body, pre-equatorial or postequatorial choroid). For each juvenile patient, 3 adults were selected. Comparing outcomes of juvenile and adult patients in terms of metastatic and eye retention rates using the log-rank statistic, relative survival using the Hakulinen method, as well as their visual outcomes. Forty-three juvenile and 129 control cases were reviewed. The metastatic rate at 10 years was significantly lower in juvenile UM patients than in adult controls (11% vs. 34%; P <0.01), with an associated relative survival rate of 93% versus 65% (P= 0.02). Six juvenile patients (14%) demonstrated metastases. One patient underwent enucleation because of a presumed local tumor recurrence and 4 additional patients underwent enucleation because of complications (9.3%). In the adult control group, 27% (n= 35) of matched patients demonstrated metastases, there were 2 cases of local recurrence, and 16% (n= 21) underwent enucleation because of complications. A visual acuity of more than 0.10 was maintained in most cases, without any significant differences before or after treatment observed between both groups. After PBRT, metastatic and survival rates are significantly better for juvenile than for adult patients with UM. Clinically, juvenile and adult eyes react similarly to PBRT, with patients having a comparable eye retention probability and maintaining a useful level of vision in most cases. This is the largest case-control study of proton therapy in juvenile eyes to date and further validates PBRT as an appropriate conservative treatment for UM in patients younger than 21 years.

ROLE OF VITREORETINAL SURGERY IN MAXIMIZING TREATMENT OUTCOME FOLLOWING COMPLICATIONS AFTER PROTON THERAPY FOR UVEAL MELANOMA

To assess the role of vitreoretinal surgery in maximizing treatment outcome following complications after proton therapy for uveal melanoma and to evaluate its safety. Retrospective chart study on 21 patients (2% of a total of 1,005 treated by proton therapy between January 2003 and August 2007) who had developed a complication requiring vitreoretinal surgery. Mean/median total follow-up after irradiation was 43/43 months (range, 12-70 months). Indications for surgery included vitreous hemorrhage (n = 13), epimacular membrane (n = 5), rhegmatogenous retinal detachment (n = 1), combined vitreous hemorrhage with total serous retinal detachment (n = 1), and vitritis (n = 1). Mean/median interval for vitreoretinal surgery after irradiation was 21/20 months (range, 4-45 months), and mean/median follow-up after pars plana vitrectomy was 22/23 months (range, 2-56 months). Pars plana vitrectomy was combined with retinal photocoagulation (n = 5), air/gas (n = 5), or silicone oil tamponade (n = 1). Mean Snellen visual acuity was 20/200 (0-20/40) before and 20/100 (0-20/25) after pars plana vitrectomy. A transient postoperative rise in intraocular pressure was measured in seven patients. Four patients developed phthisis bulbi. Vitreoretinal surgery was efficient in maximizing treatment outcome after proton therapy, as it allowed a better oncologic follow-up. Pars plana vitrectomy permitted panretinal photocoagulation to avoid neovascular glaucoma or retinal detachment repair. Macular surgery improved visual acuity, especially in anterior melanoma, whereas repeated surgery may increase the risk of enucleation.

The influence of silicone oil used in ophthalmology on the proton therapy of uveal melanomas

In ocular proton therapy the important parameters range and modulation of the proton field are calculated by a simple geometric ray tracking. Due to the assumed homogeneous eye tissue, the relative-to-water proton stopping power is nearly constant within the radiation field. In cases when silicone oil tamponades are used, this will no longer hold. CT-data which are necessary to estimate the path length of protons within the oil show bigger attenuation of x-rays then in eye tissue. The use of a CT-calibration curve to deduce the relative-to-water electron density for proton stopping power calculation would be misleading giving a value of 1.05 and thus a higher proton stopping power. In reality the relative-to-water electron density is smaller, namely 0.95, leading to a proton range prolonged by about 11% of the path length within the silicone oil, if the demand for the range adjustment would not be recognized (missing information from ophthalmologists or no CT data). This finding is congruent in analytical and Monte Carlo calculations as well as in experimental investigations, being presented here. The misleading result of the CT calibration curve is explained and therapeutic consequences are demonstrated. Multiple Coulomb scattering in silicone oil does not affect the size of the planed irradiation field.

Scleritis after Proton Therapy in Uveal Melanoma

Sclera is a very radioresistant tissue and scleritis after proton therapy has not been described so far. Four female patients, aged between 31 and 74 years, were treated with proton therapy for uveal melanoma (height range: 2.2 - 3.5 mm), located in the macula, the superior equator and 2 in the ciliary body. All patients had a history of a previous or active inflammatory disease and developed scleritis after radiotherapy. Two patients had infectious scleritis and were treated with adequate antibiotic therapy. After systemic corticotherapy, 3 patients recovered completely; the remaining patient was managed with additional immunosuppressive treatment as well as a conjunctival and scleral graft, but has not become pain free yet. Scleritis is a possible complication after proton therapy, probably on an ischemic basis, where there is a predisposing factor such as inflammatory systemic disease.

Letter by M. Fitzek1 on Höcht S, Bechrakis NE, Nausner M, et al. Proton therapy of uveal melanomas in Berlin: 5 years of experience at the Hahn-Meitner Institut

Letter by M. Fitzek1 on Höcht S, Bechrakis NE, Nausner M, et al. Proton therapy of uveal melanomas in Berlin: 5 years of experience at the Hahn-Meitner Institut

Proton therapy of uveal melanomas in Berlin. 5 years of experience at the Hahn-Meitner Institute.

In June 1998, proton-beam therapy of ocular tumors started at the Hahn-Meitner Institute Berlin, Germany. The purpose of the present study is to evaluate treatment outcome for uveal melanomas. 245 consecutive patients with primary melanoma of the uvea were treated from June 1998 to April 2003 with a 68-MeV proton beam. In 96.2% of all patients, a uniform fractionation scheme was applied: single dose 15 CGE (cobalt gray equivalent), total dose 60 CGE on 4 consecutive days. Follow-up is available in 229 patients. At the time of median follow-up (18.4 months), local control is 96.4% and 95.5% at 3 years. Eye retention rate is 92.6% at 20 months (median follow-up) and 87.5% at 3 years. Proton-beam irradiation of uveal melanomas at the Hahn-Meitner Institute after the first 5 years of its initiation reveals local tumor control and eye retention rates in the range of other centers with larger experience. Delivering high treatment quality in hadron therapy from the beginning has been achieved.

Results of proton therapy of uveal melanomas treated in Nice

Purpose: To present the first results of uveal melanomas treated with the Medicyc Cyclotron 65 MeV proton beam facility in Nice, analyzing the factors that affect the cause-specific survival (CSS), metastatic rate, and reporting the visual outcome. Methods and Materials: This study concerns 538 patients referred by French institutions between June 1991 and December 1996. The eye and tumor parameters were measured using ultrasonography and angiography. Since 1994, CT scans were performed in most patients to help determine the axial length and the shape of the ocular globe. Tantalum clips were inserted around the tumor by the referring ophthalmologist. There were 349 posterior pole tumors (64.9%), 130 equatorial tumors (24.1%), and 59 ciliary body tumors (11%). Two hundred four patients (37.9%) had T1 or T2 tumors, and 334 patients (62.1%) had T3 or T4 tumors. The median tumor diameter was 14.6 mm, and the median tumor height was 5.1 mm. All patients received 52 Gy (57.20 Gy Co-equivalent dose) on 4 consecutive days. The data were analyzed by December 1997. Results: The CSS was 77.4% at 78 months, the overall survival was 73.8% and the local control was 89.0%. The CSS was not influenced by the patient age or the site of the tumor. It was 81.5% for T1 and T2 tumors, versus 75% for T3 and T4 tumors ( P = 0.035). It was found that the tumor diameter, rather than the height, was the most important parameter affecting outcome. The metastatic rate was 8%. It depended on the T stage, tumor diameter and thickness, but not the tumor site. Thirty-eight enucleations were performed, most of them due to tumor progression and/or glaucoma. One-third of the patients in whom visual acuity was adequately scored before and after treatment had a stable, if not improved vision, and half the patients retained useful vision after treatment. Conclusion: The outcome of patients suffering from uveal melanoma and treated with high-energy protons compares favorably with other techniques of treatment. The tumor dimensions affected CSS and metastatic rate. Even though two-thirds of patients had posterior pole tumors, half of them retained useful vision.

Results of protontherapy of uveal melanomas treated in nice

Results of protontherapy of uveal melanomas treated in nice