Paul T. Finger

Radiation therapy for choroidal melanoma

Radiotherapy offers patients with malignant melanoma of the choroid an eye and a vision-sparing alternative to enucleation. The most commonly used forms of radiotherapy are ophthalmic plaque brachytherapy and charged-particle (external beam) radiotherapy. Unfortunately, after all forms of radiotherapy for choroidal melanoma many patients experience sight-limiting side effects, and an average of 16.3% of patients treated with radiotherapy subsequently require enucleation because of tumor regrowth or uncontrollable neovascular glaucoma. The severity, location, and incidence of radiation-induced complications are related to the type of radiation used, its method of delivery, amount of radiation delivered to normal ocular structures, the size and location of the tumor, as well as its response to irradiation. Current research is directed toward developing methods to reduce the amount of radiation delivered to normal structures, e.g., adding heat to radiotherapy. The true viability and metastatic potential of irradiated uveal melanoma cells has not been established, although clinical studies have reported local control of choroidal melanoma in 81-100% (mean = 92.8%) of cases. The purpose of this review is to present the worlds experience with radiotherapy for choroidal melanoma, information that will contribute to patient education and informed consent.

The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19.

OBJECTIVE To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I(125)) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial. DESIGN Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial. PARTICIPANTS Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension. METHODS I(125) brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis. MAIN OUTCOME MEASURES Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation. RESULTS As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS Local treatment failure and enucleation were relatively infrequent events after I(125) brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe.

The American Brachytherapy Society recommendations for brachytherapy of uveal melanomas

PURPOSE This article presents the American Brachytherapy Society (ABS) guidelines for the use of brachytherapy for patients with choroidal melanomas. METHODS Members of the ABS with expertise in choroidal melanoma formulated brachytherapy guidelines based upon their clinical experience and a review of the literature. The Board of Directors of the ABS approved the final report. RESULTS Episcleral plaque brachytherapy is a complex procedure and should only be undertaken in specialized medical centers with expertise in this sophisticated treatment program. Recommendations were made for patient selection, techniques, dose rates, and dosages. Most patients with very small uveal melanomas (<2.5 mm height and <10 mm in largest basal dimension) should be observed for tumor growth before treatment. Patients with a clinical diagnosis of medium-sized choroidal melanoma (between 2.5 and 10 mm in height and <16 mm basal diameter) are candidates for episcleral plaques if the patient is otherwise healthy and without metastatic disease. A histopathologic verification is not required. Small melanomas may be candidates if there is documented growth; some patients with large melanomas (>10 mm height or >16 mm basal diameter) may also be candidates. Patients with large tumors or with tumors at peripapillary and macular locations have a poorer visual outcome and lower local control that must be taken into account in the patient decision-making process. Patients with gross extrascleral extension, ring melanoma, and tumor involvement of more than half of the ciliary body are not suitable for plaque therapy. For plaque fabrication, the ophthalmologist must provide the tumor size (including basal diameters and tumor height) and a detailed fundus diagram. The ABS recommends a minimum tumor (125)I dose of 85 Gy at a dose rate of 0.60-1.05 Gy/h using AAPM TG-43 formalism for the calculation of dose. NRC or state licensing guidelines regarding procedures for handling of radioisotopes must be followed. CONCLUSIONS Brachytherapy represents an effective means of treating patients with choroidal melanomas. Guidelines are established for the use of brachytherapy in the treatment of choroidal melanomas. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose reporting policies. These guidelines will be modified as further clinical results become available.

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN Prospective, multicenter study. PARTICIPANTS A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES Patients were managed for their primary tumor and monitored for metastasis. RESULTS The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Long-term Results of Iodine 125 Irradiation of Uveal Melanoma

The authors report on 64 of the first 65 patients treated with iodine 125. The mean follow-up was 64.9 months. After treatment, 29 patients (45.3%) retained visual acuity of 20/100 or better, and 18 patients (28.1%) retained visual acuity within two lines of visual acuity before irradiation. Eleven patients (17.2%) died of metastasis, and 5 patients (7.8%) had local recurrence. Cataract developed in 29 (45.3%) patients; keratitis developed in only 2 (3.1%) patients, and dry eye developed in none. Neovascular glaucoma developed in 7 (10.9%) patients, and 15 (23.4%) patients had radiation retinopathy. Eleven patients (17.2%) required enucleation for either tumor growth or neovascular glaucoma. These results show the increasing number of radiation complications seen with long-term observation and the frequently seen adverse visual outcome.

Conjunctival melanoma: is it increasing in the United States?

PURPOSE While the incidence of cutaneous melanoma has been found to have increased over time, the evidence for conjunctival melanoma is not as clear. We applied a large cancer registry database to determine whether any changes had occurred in the incidence of conjunctival melanoma. DESIGN Descriptive epidemiologic analysis. METHOD Using population-based registry data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI), we identified 206 newly diagnosed patients with conjunctival melanoma from 1973 to 1999. For analysis purposes, we calculated age-adjusted incidence rates and described temporal changes, using joinpoint regression model. RESULTS Overall estimated biannual percent change (EBAPC) was 5.5 (95% confidence interval [CI] = 2.3, 8.8; P <.001). The significant elevated trend was observed for white men (EBAPC = 11.2; 95% CI = 6.3, 16.3; P <.001) but not for white women (EBAPC = 0.3; 95% CI = -4.1, 4.9; P >.05). In white men, the incidence rate increased 295% within the 27 years. Our analysis also showed a significant upward trend in the age group aged 60 years or more (EBAPC = 7.6; 95% CI = 3.9, 11.3; P <.001). Incidence tended to rise in the group aged 40 to 59 years, but it was not statistically significant (EBAPC = 4.4; 95% CI = -2.3, 11.6; P =.1536). CONCLUSIONS Substantial temporal changes in the incidence of conjunctival melanoma have occurred in the United States in recent years. The changing incidence patterns coincide with those seen in cutaneous melanoma, suggesting a possible link to a sunlight-related etiology.

Risk Factors for Metastasis in Retinoblastoma

Children with retinoblastoma typically survive their cancer due to advances in early diagnosis and treatment. Despite this success, risk factors persist for metastasis that are thought to be related to patient age, sex, laterality, treatment, genetics, histopathology, and extraocular extension. This review has found that invasion of the uvea, orbit, and optic nerve continue to be the most important predictors of metastatic retinoblastoma. Bilaterality and delays in diagnosis are also important factors. We examine molecular and genetic studies that offer the potential of predicting which tumors are likely to metastasize, which will recur within the eye, and which will undergo senescence. In this review, we describe which clinical evaluations, genetic studies, and histopathologic evaluations of retrieved specimens are currently used widely. This review has been performed to help those caring for patients with retinoblastoma and to aid informed consent.

RADIATION RETINOPATHY IS TREATABLE WITH ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR BEVACIZUMAB (AVASTIN)

PURPOSE To report on bevacizumab treatment for radiation retinopathy affecting the macula. PATIENTS AND METHODS Twenty-one patients with radiation retinopathy (edema, hemorrhages, capillary dropout, and neovascularization) and a subjective or objective loss of vision were treated. Treatment involved intravitreal injection of bevacizumab (1.25 mg in 0.05 mL) every 6-12 weeks. Treatment was discontinued at patient request or if there was no measurable response to therapy. Main outcome measures included best corrected visual acuity, ophthalmic examination, retinal photography, and angiography. RESULTS Bevacizumab treatment was followed by reductions in retinal hemorrhage, exudation, and edema. Visual acuities were stable or improved in 86% (n=18). Three patients discontinued therapy. Each was legally blind before treatment (n=1), experienced little to no subjective improvement (n=2), or was poorly compliant (n=2). Three patients (14%) regained 2 or more lines of visual acuity. No ocular or systemic bevacizumab-related side effects were observed. CONCLUSIONS Intravitreal bevacizumab can be used to treat radiation retinopathy. In most cases treatment was associated with decreased vascular leakage, stabilization, or improved vision. An anti-vascular endothelial growth factor strategy may reduce tissue damage associated with radiation vasculopathy and neuropathy.

The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma

PURPOSE To present the American Brachytherapy Society (ABS) guidelines for plaque brachytherapy of choroidal melanoma and retinoblastoma. METHODS AND MATERIALS An international multicenter Ophthalmic Oncology Task Force (OOTF) was assembled to include 47 radiation oncologists, medical physicists, and ophthalmic oncologists from 10 countries. The ABS-OOTF produced collaborative guidelines, based on their eye cancer-specific clinical experience and knowledge of the literature. This work was reviewed and approved by the ABS Board of Directors as well as within the journals peer-reivew process. RESULTS The ABS-OOTF reached consensus that ophthalmic plaque radiation therapy is best performed in subspecialty brachytherapy centers. Quality assurance, methods of plaque construction, and dosimetry should be consistent with the 2012 joint guidelines of the American Association of Physicists in Medicine and ABS. Implantation of plaque sources should be performed by subspecialty-trained surgeons. Although there exist select restrictions related to tumor size and location, the ABS-OOTF agreed that most melanomas of the iris, ciliary body, and choroid could be treated with plaque brachytherapy. The ABS-OOTF reached consensus that tumors with gross orbital extension and blind painful eyes and those with no light perception vision are unsuitable for brachytherapy. In contrast, only select retinoblastomas are eligible for plaque brachytherapy. Prescription doses, dose rates, treatment durations, and clinical methods are described. CONCLUSIONS Plaque brachytherapy is an effective eye and vision-sparing method to treat patients with intraocular tumors. Practitioners are encouraged to use ABS-OOTF guidelines to enhance their practice.

Ophthalmic plaque radiotherapy for age-related macular degeneration associated with subretinal neovascularization

PURPOSE To evaluate ophthalmic plaque radiotherapy for the treatment of subretinal neovascularization associated with age-related macular degeneration. METHODS In a prospective phase I clinical trial, we treated 23 patients (23 eyes) with ophthalmic plaque radiotherapy for subfoveal exudative macular degeneration. Palladium 103 ophthalmic plaque brachytherapy was delivered to a retinal apex dose of 1,250 to 2,362 cGy (rad). Early Treatment Diabetic Retinopathy Study type visual acuity determinations, ophthalmic examinations, and angiography were performed before and after treatment. Clinical evaluations were performed in a nonrandomized and unmasked fashion. RESULTS Patients were followed up for a mean (+/-SD) of 19 +/- 10.7 months (range, 3 to 37 months). Six months after radiation therapy, three (16%) of 19 eyes had lost 3 or more lines of best-corrected visual acuity; 12 months after radiation therapy, four eyes (31% of 13 eyes), and 24 months after radiation therapy, only two (22% of nine eyes) lost 3 or more lines of visual acuity. No eye suffered sudden irreversible loss of central vision. No radiation retinopathy, optic neuropathy, or cataract could be attributed to radiotherapy within this follow-up period. CONCLUSION Ophthalmic plaque radiotherapy can be used to treat neovascular age-related macular degeneration. In contrast to external beam radiotherapy, ophthalmic plaque radiotherapy is a unilateral treatment, which allows a larger dose to be delivered to the macula with less irradiation of normal ocular structures. We have found no sight-limiting complications at the doses, dose rates, and follow-up evaluated in this study.