Kimberly J. Chin

Local Recurrence Significantly Increases the Risk of Metastatic Uveal Melanoma

PURPOSEnTo assess of the effect of local recurrence of uveal melanoma on metastasis using a multicenter international tumor registry.nnnDESIGNnRetrospective study using an online tumor registry.nnnPARTICIPANTSnPatients with uveal melanoma diagnosed between 2001 andxa02011.nnnMETHODSnA committee was formed to create uveal melanoma patient-specific data fields. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma and adequate records to allow tumor staging by American Joint Committee on Cancer (AJCC) criteria and follow-up for metastatic melanoma.nnnMAIN OUTCOME MEASURESnLocal tumor recurrence and metastatic uveal melanoma.nnnRESULTSnOf 3809 total entries, 3217 patients with ciliary body and choroidal (CBC) melanoma and 160 with iris melanoma were evaluated. There was a median follow-up of 3.7 years (95% confidence interval [CI], 3.5-3.8). One hundred fifty-two patients (4.7%) with CBC melanoma experienced local recurrence, with a cumulative incidence of 11%. Kaplan-Meier point estimates for remaining free of local recurrence were 99% (95% CI, 99-99) at 1 year, 93% (95% CI, 92-94) at 5 years, and 89% (95% CI, 86-91) at 10 years. Five- and 10-year metastasis-free Kaplan-Meier estimates for the recurrence-free group were 87% (95% CI, 86-89) and 82% (95% CI, 79-84), and those for the local recurrence group were 71% (95% CI, 62-78) and 62% (95% CI, 49-72). The difference between these 2 groups was statistically significant (P < 0.001). Furthermore, local tumor recurrence increased the risk of metastasis by a hazard ratio (HR) of 6.28 (95% CI, 4.4-8.9; P < 0.001). Local recurrence was detected up to 9.8 years after treatment. Extrascleral extension also was associated with local recurrence (HR, 3.2; 95% CI, 1.5-6.7; Pxa0= 0.003), but higher AJCC T-size category was not (Pxa0= 0.63). Five patients (nxa0= 5/161 [3.1%]) with iris melanoma demonstrated local recurrence and 1 metastasized.nnnCONCLUSIONSnInternational multicenter data sharing was used to evaluate the effect of local tumor recurrence on metastatic rate. In that local tumor recurrence was associated with a significantly higher risk of systemic metastasis, effective initial treatment and long-term surveillance of treated uveal melanoma patients is necessary.

International Validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma.

IMPORTANCEnAlthough an accurate uveal melanoma staging system is needed to improve research and patient care, the evaluation of eye cancer staging systems requires international multicenter data sharing to acquire a statistically significant analysis.nnnOBJECTIVEnTo assess patient mortality outcomes associated with uveal melanoma staging according to the 7th edition of the American Joint Committee on Cancers AJCC Cancer Staging Manual.nnnDESIGN, SETTING, PARTICIPANTSnA committee was formed to create patient-specific data fields for patients with uveal melanoma. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma from April 1, 2001, to April 1, 2011, adequate records to allow tumor staging by the AJCC criteria, and follow-up for metastatic melanoma.nnnINTERVENTIONSnPrimary treatments included local resection, radiation therapy, and enucleation.nnnMAIN OUTCOMES AND MEASURESnMetastasis after initial tumor staging with 5- and 10-year Kaplan-Meier metastasis-free point estimates, depending on AJCC prognostic stages I through IV, tumor size category, and subclassification (defined by the presence of ciliary body involvement and/or extrascleral extension).nnnRESULTSnA total of 3809 patients were entered into the database. Of these, 3377 records (88.7%) were complete. Primary ciliary body and choroidal melanoma was the diagnosis for 3217, and 160 had primary iris melanoma. Tumor size categories were T1 in 1115 (34.7%) of the 3217 patients, T2 in 1128 patients (35.1%), T3 in 789 patients (24.5%), and T4 in 185 patients (5.8%). The 5- and 10-year Kaplan-Meier metastasis-free point estimates by tumor size categories were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for T1 tumors, 85% (95% CI, 82%-88%) and 80% (95% CI, 75%-84%) for T2 tumors, 77% (95% CI, 73%-80%) and 68% (95% CI, 60%-74%) for T3 tumors, and 61% (95% CI, 49%-71%) (5-year only) for T4 tumors, respectively. Increasing tumor size was consistent with increased metastasis risk (P <xa0.001). Subclassifications were significantly associated with increased risk of metastasis (P < .001). The AJCC prognostic and anatomical groupings were as follows: stage I, 1030 (32.0%); stage IIA, 1095 (34.0%); stage IIB, 710 (22.1%); stage IIIA, 282 (8.8%); stage IIIB, 79 (2.5%); and stage IIIC, 21 (0.7%). The 5- and 10-year Kaplan-Meier metastasis-free estimates for prognostic stages were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for stage I, 89% (95% CI, 86%-91%) and 84% (95% CI, 80%-88%) for stage IIA, 79% (95% CI, 75%-83%) and 70% (95% CI, 62%-76%) for stage IIB, 67% (95% CI, 59%-73%) and 60% (95% CI, 51%-68%) for stage IIIA, 50% (95% CI, 33%-65%) and 50% (95% CI, 33%-65%) for stage IIIB, and 25% (95% CI, 4%-53%) (5-year only) for stage IIIC, respectively. The 160 iris melanomas were too few for subgroup analysis.nnnCONCLUSIONS AND RELEVANCEnMulticenter, worldwide, Internet-based data sharing was used to study a heterogenous patient population in ophthalmic oncology. Our results support the continued use of the 7th edition of the AJCCCancer Staging Manual for uveal melanoma.

ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR BEVACIZUMAB FOR RADIATION OPTIC NEUROPATHY: SECONDARY TO PLAQUE RADIOTHERAPY

PURPOSEnTo evaluate the intravitreal antivascular endothelial growth factor, bevacizumab, for treatment of radiation optic neuropathy (RON).nnnMETHODS AND MATERIALSnA prospective interventional clinical case series was performed of 14 patients with RON related to plaque radiotherapy for choroidal melanoma. The RON was characterized by optic disc edema, hemorrhages, microangiopathy, and neovascularization. The entry criteria included a subjective or objective loss of vision, coupled with findings of RON. The study subjects received a minimum of two initial injections of intravitreal bevacizumab (1.25 mg in 0.05 mL) every 6-8 weeks. The primary objectives included safety and tolerability. The secondary objectives included the efficacy as measured using the Early Treatment Diabetic Retinopathy Study chart for visual acuity, fundus photography, angiography, and optical coherence tomography/scanning laser ophthalmoscopy.nnnRESULTSnReductions in optic disc hemorrhage and edema were noted in all patients. The visual acuity was stable or improved in 9 (64%) of the 14 patients. Of the 5 patients who had lost vision, 2 had relatively large posterior tumors, 1 had had the vision decrease because of intraocular hemorrhage, and 1 had developed optic atrophy. The fifth patient who lost vision was noncompliant. No treatment-related ocular or systemic side effects were observed.nnnCONCLUSIONSnIntravitreal antivascular endothelial growth factor bevacizumab was tolerated and generally associated with improved vision, reduced papillary hemorrhage, and resolution of optic disc edema. Persistent optic disc neovascularization and fluorescein angiographic leakage were invariably noted. The results of the present study support additional evaluation of antivascular endothelial growth factor medications as treatment of RON.

Initial PET/CT staging for choroidal melanoma: AJCC correlation and second nonocular primaries in 333 patients.

Purpose To report on whole body positron emission tomography/computed tomography (PET/CT) screening for metastasis at diagnosis of primary uveal melanoma. Methods Since August 2003, 333 consecutive patients were diagnosed with uveal melanoma and underwent whole body screening for metastatic disease with PET/CT along with liver function tests and physical examination. Abnormal findings prompted further biopsies, blood tests, imaging, or clinical evaluations for confirmation. The presence of metastatic disease and second cancers were evaluated. Results Using the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) 7th edition criteria, 104 tumors were classified T1 (31%), 162 T2 (49%), 37 T3 (11%), and 30 T4 (9%). Seven of 333 (2.1%; 95% confidence interval [CI] 0.8-4.3) patients had metastatic melanoma. One tumor was a T3 and 6 were T4. Thus, 3% of T3 and 20% of T4 melanomas were found to have metastases at the time of initial diagnosis. Ten patients (3.3%; 95% CI 0.9-5.5) had synchronous second cancers and 28 (8.4%) concurrent benign lesions. The most common metastatic sites were liver (7/7) and bone (2/7). Discussion This study suggests that PET/CT improves the yield of detecting both extrahepatic metastases, especially from tumors defined as AJCC-T4, and synchronous primary cancers, irrespective of the size of the uveal melanoma. With respect to liver metastases, PET/CT demonstrated high sensitivity and positive predictive values, indicating an overall better performance than conventional screening procedures.

Risk Factors for Cataract After Palladium-103 Ophthalmic Plaque Radiation Therapy

PURPOSEnTo examine how tumor characteristics and dose affect cataract development after plaque radiation therapy.nnnMETHODS AND MATERIALSnThree hundred and eighty-four patients were diagnosed with uveal melanoma and treated with palladium-103 ((103)Pd) plaque radiation therapy. Of these, 282 (74%) inclusion met exclusion criteria for follow-up time, tumor location, and phakic status. Then patient-, ophthalmic-, and radiation-specific factors (patient age, diabetes, hypertension, tumor location, tumor dimensions, and lens dose) were examined (by a Cox proportional regression model) as predictors for the development of radiation-related cataract.nnnRESULTSnRadiation cataract developed in 76 (24%) of patients at a mean follow-up of 39.8 months (range, 1-192). Patients with anteriorly located tumors were noted to have a higher incidence of cataract at 43.0% (43 of 100 patients) vs. 18.1% (33 cataracts per 182 patients) for posteriorly located tumors (p <0.0001). However, multivariate Cox proportional modeling showed that increasing patient age at time of treatment (p for trend = 0.0003) and higher lens dose (p for trend = 0.001) were the best predictors (biomarkers) for radiation cataract.nnnCONCLUSIONSnAlthough anterior tumor location, greater tumor height, and increased patient age (at treatment) were associated with significantly greater risk for radiation cataract, dose to lens was the most significant factor.

Refractory squamous cell carcinoma of the conjunctiva treated with subconjunctival ranibizumab (Lucentis): a two-year study.

Purpose: To test the safety, tolerability, and efficacy of subconjunctival ranibizumab (Lucentis [Genentech, Inc.]) for squamous cell carcinoma of the conjunctiva and cornea. Methods: Five patients with recurrent squamous cell carcinoma of the conjunctiva and cornea enrolled in this nonrandomized, single center, phase I pilot study as an alternative to radiation or exenteration. Subconjunctival ranibizumab (0.5 mg) was given on a monthly or twice monthly basis. Patients were examined for safety, tolerability, and efficacy using visual acuity, blood pressure, urinalysis, comparative slit lamp biomicroscopy with photography, and high frequency ultrasound imaging. Results: Five male patients with biopsy-proven squamous conjunctival carcinoma were found to have recurrent disease. Each patient had been initially treated with combinations of primary excision (n = 1) or excision and cryotherapy (n = 4), and all (n = 5) had failed separate courses of both topical interferon &agr; and mitomycin 0.02%. Tumors were multifocal and involved between 8 and 12 clock hours of the limbus. A median of 22 injections (range 12–27) was given over a mean 19 months (range 6–24). Three patients had a complete response (no clinically apparent disease) during the 2-year study, while 2 failed treatment despite demonstrating an initial partial response. Treatment was well-tolerated, as 4 patients demonstrated stable or improved visual acuity, and none had significant systemic or ocular side effects. Conclusions: This 2-year study demonstrated that subconjunctival ranibizumab induced regression of squamous cell carcinoma of the conjunctiva and cornea. Therefore, antivascular endothelial growth factor chemotherapy may offer a new strategy, complement excision and cryotherapy, or provide an alternative to radiation and/or exenteration. Further, larger investigations utilizing a larger group of patients are needed to determine the ideal dose, route of drug delivery, and case selection.

A Five-Year Study of Slotted Eye Plaque Radiation Therapy for Choroidal Melanoma: Near, Touching, or Surrounding the Optic Nerve

OBJECTIVEnTo evaluate slotted eye plaque radiation therapy for choroidal melanomas near the optic disc.nnnDESIGNnA clinical case series.nnnPARTICIPANTSnTwenty-four consecutive patients with uveal melanomas that were near, touching, or surrounding the optic disc.nnnINTERVENTIONnSlotted eye plaque radiation therapy.nnnMAIN OUTCOME MEASURESnRecorded characteristics were related to patient, clinical, and ophthalmic imaging. Data included change in visual acuity, tumor size, recurrence, eye retention, and metastasis.nnnRESULTSnFrom 2005 to 2010, 24 consecutive patients were treated with custom-sized plaques with 8-mm-wide, variable-depth slots. Radiation doses ranged from 69.3 to 163.8 Gy (mean, 85.0 Gy) based on delivering a minimum tumor dose of 85 Gy. All treatments were continuously delivered over 5 to 7 days. Mean patient age at presentation was 57 years. Tumors were within 1.5 mm of the optic nerve (n = 3, 13%), juxtapapillary (n = 6, 25%), touching ≥180 degrees (n = 7, 29%), or circumpapillary (n = 8, 33%). Ultrasound revealed dome-shaped tumors in 79% of patients, collar-button tumors in 17% of patients, irregular tumor in 1 patient (4%), and intraneural invasion in 2 patients. Mean initial largest basal dimension was 11.0 mm (standard deviation [SD] ± 3.5 mm; median, 11.4 mm; range, 5.9-16.4 mm). Mean initial tumor thickness was 3.5 mm (SD ± 1.7 mm; median, 3.0 mm; range, 1.4-6.9 mm). Initial visual acuities were a median 20/25 (range, 20/20 to hand motions) and decreased to a median 20/40 (range, 20/20 to no light perception). At a mean follow-up of 23 months, 12 patients required periodic intravitreal bevacizumab to suppress radiation optic neuropathy (RON) or maculopathy. To date, there has been a 100% local control rate. No patients have required secondary enucleation for recurrence or neovascular glaucoma. No patients have developed metastasis.nnnCONCLUSIONSnSlotted plaque radiation therapy allows peripapillary, juxtapapilary, and circumpapillary choroidal melanomas (and a safety margin) to be included in the radiation targeted zone. Normalization of the plaque position beneath the tumor appears to increase RON and improve local control.

Ocular manifestations of multiple myeloma: Three cases and a review of the literature

BACKGROUNDnMultiple myeloma is the most common plasma cell tumor; however, ocular plasmacytomas are rare and can appear in almost any structure of the eye. We present 3 cases, including 2 with unique ophthalmic ultrasound images of ocular plasmacytoma.nnnCASE REPORTSnThree patients with ocular manifestations of multiple myeloma are described. All were noted to have known synchronous systemic disease. In this study, patients presented with epibulbar (n = 2), iridociliary (n = 1), and orbital (n = 2) plasmacytomas. Presenting signs included clinically visible tumor (n = 2), blurred vision (n = 2), diplopia (n = 2), and glaucoma (n = 1). The iridociliary plasmacytoma was defined by high-frequency 35-MHz ultrasonography that revealed 360° of anterior chamber involvement, secondary angle-closure, and extent of iridociliary invasion. In another case, low-frequency B-scan ultrasonography found multiple myeloma of the orbit. Ocular manifestations of multiple myeloma, histopathology, treatment, and prognosis are described.nnnCONCLUSIONnOcular manifestations of plasma cell neoplasms are rare. In multiple myeloma, plasmacytomas can present as a solitary tumor, as an initial sign of systemic disease, or as recurrence. This study presents 3 cases in which epibulbar, orbital, and iridociliary plasmacytoma with secondary glaucoma were presenting signs of uncontrolled multiple myeloma.

High-dose (2.0 mg) intravitreal ranibizumab for recalcitrant radiation retinopathy

Purpose To evaluate the safety and tolerability and treatment efficacy of high-dose (2.0 mg) intravitreal ranibizumab for recalcitrant radiation retinopathy. Methods A phase I to II open-label, nonrandomized prospective clinical trial was performed on 10 eyes of 10 patients with recalcitrant radiation retinopathy who were failing standard dose anti–vascular endothelial growth factor (VEGF) therapy. External beam or plaque brachytherapy–associated retinopathy was characterized by persistent macular edema or leakage on optical coherence tomography or fluorescein angiography. Intravitreal 2.0 mg ranibizumab was given monthly up to 12 months and monitored for tolerability and change in best-corrected visual acuity (BCVA), central foveal thickness, and clinical signs of radiation retinopathy. Results Seven patients completed the 1-year study and received all 12 injections; 3 withdrew from the study due to worsening retinopathy (1 after external beam, 2 following plaque). Treatment was well-tolerated with no severe adverse reactions. A total of 70% had stable (n = 3) or improved (n = 4) BCVA. Mean change in BCVA was +3.3 letters at 6 months and +0.7 letters at 1 year. Mean improvement in central foveal thickness (CFT) was −19.3% (range −57 to +15%) at 1 year. Initial mean CFT was 428 μm (range 192–776); final mean CFT was 333 μm (range 190–532). A total of 80% demonstrated a statistically significant (p<0.05) reduction in CFT. Conclusions Regardless of radiation source, intravitreal injections of 2.0 ranibizumab induced significant reductions in macular edema and maintained or improved BCVA in most patients who were failing standard dose anti-VEGF therapy.

Intravitreal anti-VEGF therapy for macular radiation retinopathy: a 10-year study

Purpose To report long-term experience with intravitreal anti–vascular endothelial growth factor treatment for radiation maculopathy. Methods From 2005-2015, 120 consecutive patients underwent intravitreal anti-VEGF therapy for radiation maculopathy. Inclusion criteria included a diagnosis of uveal melanoma treated with plaque radiotherapy and subsequent macular radiation vasculopathy (exudate, retinal hemorrhage, intraretinal microangiopathy, neovascularization, edema). Anti-VEGF therapy involved continuous injections in 4- to 12-week intervals with doses of 1.25 mg/0.05 mL, 2.0 mg/0.08 mL, 2.5 mg/0.1 mL, or 3.0 mg/0.12 mL of bevacizumab as well as 0.5 mg/0.05 mL or 2.0 mg/0.05 mL of ranibizumab. Goals were maintenance of visual acuity and normative macular anatomy. Safety and tolerability (retinal detachment, hemorrhage, infection), visual acuity, central foveal thickness on optical coherence tomography imaging, and clinical features of radiation maculopathy were analyzed. Results Progressive reductions in macular edema, hemorrhages, exudates, cotton-wool spots, and microangiopathy were noted. At last follow-up, 80% remained within 2 lines of their initial visual acuity or better, with a mean treatment interval of 38 months (range 6-108 months). Kaplan-Meier analysis of the probability of remaining within 2 lines of initial visual acuity was 69% at 5 years and 38% at 8 years of anti-VEGF therapy. Discontinuation of therapy was rare. Relatively few acute or long-term side effects were noted, allowing for good long-term patient accrual. Conclusions Continuous intravitreal anti-VEGF therapy in patients with radiation maculopathy was well-tolerated and preserved vision. In most cases, reductions or resolution of retinal hemorrhages, cotton-wool spots, and retinal edema were noted for up to 10 years.