Brian P. Marr

Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.

OBJECTIVE To determine whether intra-arterial chemotherapy is safe and effective in advanced intraocular retinoblastoma. Retinoblastoma often presents with advanced intraocular disease and, despite conventional treatment with intravenous chemotherapy and external beam radiation therapy, may still require enucleation. DESIGN Single-arm, prospective registry from May 30, 2006, to May 30, 2010, at an ophthalmic oncology referral center with ambulatory care. A total of 95 eyes of 78 patients with unilateral or bilateral retinoblastoma were treated. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy, usually melphalan with or without topotecan. Drug dosage was determined by age and angioanatomy. The main outcome measures were procedural success, event-free (enucleation or radiotherapy) ocular survival, and ocular and extraocular complications. RESULTS Catheterization succeeded in 98.5% of procedures. There were 289 chemotherapy injections (median, 3 per eye). The Kaplan-Meier estimates of ocular event-free survival rates at 2 years were 70.0% (95% confidence interval, 57.9%-82.2%) for all eyes, 81.7% (95% confidence interval, 66.8%-96.6%) for eyes that received intra-arterial chemotherapy as primary treatment, and 58.4% (95% confidence interval, 39.5%-77.2%) for eyes that had previous treatment failure with intravenous chemotherapy and/or external beam radiation therapy. There were no permanent extraocular complications. CONCLUSION Our experience suggests that intra-arterial chemotherapy is safe and effective in the treatment of advanced intraocular retinoblastoma.

Effect of Selumetinib vs Chemotherapy on Progression-Free Survival in Uveal Melanoma A Randomized Clinical Trial

IMPORTANCE Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01143402.

Superselective Ophthalmic Artery Chemotherapy as Primary Treatment for Retinoblastoma (Chemosurgery)

PURPOSE To report on our 3-year experience with the use of superselective ophthalmic artery infusion of chemotherapy as initial, primary treatment for intraocular retinoblastoma. DESIGN Prospective, institutional review board-approved clinical trial. PARTICIPANTS Twenty-eight eyes of 23 newly diagnosed retinoblastoma patients (Reese-Ellsworth [RE] group V, 25 eyes; RE IV, 1 eye; RE III, 1 eye; RE II, 1 eye), ages 3-88 months (mean, 22; median, 11) followed for 3-37 months (mean, 15; median, 14). METHODS Cannulation of 1 or both ophthalmic arteries in young children with retinoblastoma was performed via the femoral artery under general anesthesia on an outpatient basis and chemotherapy (melphalan [n = 12], melphalan plus topotecan [n = 7], melphalan plus topotecan and carboplatin [n = 3], or melphalan plus carboplatin [n = 1]) infused. MAIN OUTCOME MEASURES Patient survival, eye survival, systemic toxicity, complete blood counts, ophthalmic examination, retinal photography, and electroretinograms. RESULTS We treated 23 newly diagnosed retinoblastoma patients initially with 75 separate intra-arterial chemotherapy infusions (range, 1-6 treatments; mean, 3.2) over a 3-year period. All children survived. Only 1 of the 28 eyes came to enucleation (for progressive disease). No eye was enucleated for ocular complications of the procedure and the only adverse ophthalmic findings were occasional transient lid edema, forehead hyperemia, and loss of nasal lashes. Kaplan-Meier enucleation free was 100% at 12 months and 89% at 2 years (95% confidence interval, 43%-98%). There were no deaths, strokes, or transfusions of any blood products; no effect on red cell count; 9 cycles of grade 3 and 1 cycle of grade 4 neutropenia; and no hospitalizations, episodes of fever/neutropenia, or complications at the site of femoral artery puncture. CONCLUSIONS The ophthalmic artery(s) of children can safely be repeatedly canulated in very young children and high concentrations (but low doses) of chemotherapy infused on an outpatient basis. When used as initial therapy superselective chemotherapy delivered through the ophthalmic artery prevented enucleation, primary radiation or the use of systemic chemotherapy in 27 of 28 eyes.

Intra-arterial chemotherapy for retinoblastoma in eyes with vitreous and/or subretinal seeding: 2-year results

Background/aims To review the effectiveness of intra-arterial chemotherapy for advanced intra-ocular retinoblastoma with vitreous and/or subretinal seeds in naive (untreated) and previously treated eyes. Methods Retrospective study, approved by the institutional review board, of 76 eyes of 67 patients with retinoblastoma with subretinal and/or vitreous seeding treated with intra-arterial chemotherapy at Memorial Sloan-Kettering Cancer Center between May 2006 and August 2010. Results Despite advanced intraocular disease with seeding, the majority (56/76) of eyes were saved; 20/76 eyes were enucleated. Among treatment-naive eyes, the 2-year probability of ocular salvage was 83% (95% CI 27% to 97%) for eyes with subretinal seeding only, 64% (95% CI 24% to 87%) for eyes with vitreous seeding only, and 80% (95% CI 40% to 95%) for eyes with both. Among eyes that received previous treatment and had progressed, the 2-year probability of ocular salvage was 50% (95% CI 15% to 78%) for eyes with only subretinal seeding, 76% (95% CI 48% to 91%) for eyes with vitreous seeding only, and 54% (95% CI 20% to 79%) for eyes with both. Nine of 29 naive eyes (31%) were cured with intra-arterial (super-selective ophthalmic artery infusion of chemotherapy) chemotherapy alone. Conclusion Unlike radiation or systemic chemotherapy, intra-arterial chemotherapy can usually prevent the need for enucleation in naive eyes with advanced intraocular retinoblastoma with seeding—especially if the seeding is subretinal. Treatment appears to be less effective in previously treated eyes when subretinal seeding is present (50% at 2 years), but may be more effective in eyes that failed to respond to previous systemic chemotherapy and have only vitreous seeding.

Intravitreal triamcinolone acetonide for radiation maculopathy after plaque radiotherapy for choroidal melanoma.

Objective: To evaluate the effect of intravitreal triamcinolone acetonide on patients with visually symptomatic radiation-induced maculopathy after plaque radiotherapy for choroidal melanoma. Design: In this prospective, nonrandomized, single-center case series of 31 patients with visually symptomatic radiation-induced maculopathy after plaque radiotherapy for choroidal melanoma at the Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, triamcinolone acetonide (4 mg/1 mL) was injected through the pars plana into the vitreous cavity using sterile technique. Status of radiation maculopathy and final visual acuity were the main outcome measures. Results: At the time of diagnosis of choroidal melanoma, visual acuity was 20/20 to 20/50 in 90% (n = 28), 20/60 to 20/200 in 10% (n = 3), and 20/400 or worse in none of the patients. The mean radiation dose to the foveola was 5,122 cGy (median, 3,280 cGy; range, 1,000–16,100 cGy). Radiation maculopathy developed at a mean of 22 months (median, 16 months; range, 6–96 months) after plaque radiotherapy. In all cases, the choroidal melanoma was regressed, and there was no retinal detachment or neovascularization of the retina, optic disk, or iris. At the time of diagnosis of radiation maculopathy, visual acuity was 20/20 to 20/50 in 19% (6/31), 20/60 to 20/200 in 58% (18/31), and 20/400 or worse in 23% (7/31) of patients. After intravitreal injection of triamcinolone acetonide, visual acuity was stable or improved in 91% (20/22) of patients by 1 month and 45% (14/31) by 6 months. Mean foveal thickness by optical coherence tomography was 417 μm at injection and 207 μm at 1 month and 292 μm at 6 months after injection. Conclusions: Intravitreal triamcinolone acetonide can stabilize or improve visual acuity in some patients with radiation-induced maculopathy, but its effect might not be lasting.

Optical coherence tomography of choroidal nevus in 120 patients.

Objective: To describe the optical coherence tomography (OCT) findings of choroidal nevi. Methods: Retrospective, single-center case series of 120 eyes of 120 consecutive patients with choroidal nevi who were evaluated by OCT. Diagnostic imaging was performed with a Zeiss StratusOCT Model 3000 (Carl Zeiss Ophthalmic Systems, Dublin, CA) using scan acquisition protocols of 6 radial lines and retinal thickness analysis overlying the nevus. Results: The mean patient age was 59 years (median, 60 years; range, 14–87 years). The choroidal nevus was a mean of 5.2 mm in basal dimension and 1.7 mm in thickness and was located a mean of 2.7 mm from the optic disk and 2.5 mm from the foveola. Related retinal findings by ophthalmoscopic evaluation included overlying retina edema (3%), subretinal fluid (16%), retinal thinning (0%), drusen (58%), and retinal pigment epithelium (RPE) detachment (2%). In comparison, related retinal findings at the site of the nevus by OCT included overlying retina edema (15%), subretinal fluid (26%), retinal thinning (22%), drusen (41%), and RPE detachment (12%). Furthermore, OCT permitted classification of the overlying retinal edema as focal cystoid (3%), diffuse cystoid (8%), coalescent cystoid (3%), and noncystoid edema (1%). By OCT, the overlying retina was normal thickness (32%), thinned (22%), or thickened (45%), and photoreceptor loss or attenuation was noted in 51% of cases. Specific OCT findings of the choroidal nevus were limited to its anterior surface with minimal penetration into the mass. These findings included increased thickness of the RPE/choriocapillaris layer (68%) and optical qualities within the anterior portion of the nevus of hyporeflectivity (62%), isoreflectivity (29%), and hyperreflectivity (9%). Hyporeflectivity was observed in 68% of pigmented nevi and 18% of nonpigmented nevi. When comparing OCT with clinical examination, OCT was more sensitive in the detection of related retinal edema, subretinal fluid, retinal thinning, photoreceptor attenuation, and RPE detachment. Conclusions: OCT is a useful diagnostic modality for imaging the retina overlying a choroidal nevus. Numerous overlying changes such as subretinal fluid, retinal edema, retinal thinning, and photoreceptor attenuation are visible by OCT.

Local and Systemic Toxicity of Intravitreal Melphalan for Vitreous Seeding in Retinoblastoma: A Preclinical and Clinical Study

PURPOSE Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model. DESIGN Clinical and preclinical, prospective, cohort study. PARTICIPANTS In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 μg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 μg of intravitreal melphalan or vehicle to the right eye. METHODS Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated. MAIN OUTCOME MEASURES For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings. RESULTS By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 μV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina. CONCLUSIONS Weekly injections of 30 μg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.

Distinction of conjunctival melanocytic nevi from melanomas by fluorescence in situ hybridization

A conjunctival melanocytic nevus may on occasion be difficult to distinguish from melanoma both clinically and histopathologically. An unambiguous correct diagnosis is critical because of major differences in management and prognosis. We evaluated a fluorescence in situ hybridization (FISH) assay, which has previously been shown to be of value for the diagnosis of melanocytic nevi and melanomas of the skin, using probes targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1) and centromere 6 (CEP6), for its potential to assist in the distinction of conjunctival melanocytic nevi from melanomas. Four melanocytic nevi and eight melanomas of the conjunctiva were analyzed. Two of the melanomas were diagnostically problematic because of suboptimal histopathology. None of the conjunctival melanocytic nevi showed a level of chromosomal aberrations that met FISH criteria for a diagnosis of melanoma. All eight conjunctival melanomas (six unequivocal and two suspicious lesions) met FISH criteria for melanoma. Thus, results from FISH assay targeting 6p25, 6q23, 11q13 and centromere 6 correlated well with the histopathologic diagnoses and supported the histopathologic suspicion in two problem cases. The findings encourage further exploration of this technique as an ancillary method for the work‐up of conjunctival melanocytic proliferations.

Congenital simple hamartoma of the retinal pigment epithelium: A study of five cases☆

PURPOSE To report 5 patients with presumed congenital, simple hamartoma of the retinal pigment epithelium (RPE). DESIGN Retrospective, observational small case series. PARTICIPANTS Five patients with a black macular tumor of the RPE. MAIN OUTCOME MEASURES Initial tumor features, initial associated fundus features, tumor course on follow-up, and visual acuity outcome. RESULTS In all 5 cases, the tumor involved the macula and the mean distance to the foveola was 0.4 mm (median, 0.2 mm; range, 0.2-1.2 mm). In all cases, the tumor was darkly pigmented, with full-thickness retinal and RPE involvement and minimal protrusion into the vitreous cavity. The mean ultrasonographic tumor thickness was 1.6 mm (median, 1.4 mm; range, 1.1-2.5 mm). Associated features included minimally dilated retinal feeding artery and draining vein (100%), surrounding mild retinal traction (80%), retinal exudation (20%), and vitreous pigmented cells (20%). None of the lesions had associated subretinal fluid, macular edema, or macular hole. Visual acuity was 20/20 in 3 cases and slightly decreased in the other 2 cases because of foveal traction. The findings remained stable in 3 patients who had adequate follow-up. We chose to classify this lesion as congenital simple hamartoma of the RPE to differentiate it from combined hamartoma of the retina and RPE, congenital hypertrophy of the RPE, adenoma or adenocarcinoma of the RPE, and acquired hyperplasia of the RPE, which are different clinical entities. CONCLUSIONS Congenital hamartoma of the RPE is typically a black, full-thickness retinal mass, often adjacent to the foveola. Despite such location, the visual acuity was affected minimally.

Three-drug intra-arterial chemotherapy using simultaneous carboplatin, topotecan and melphalan for intraocular retinoblastoma: preliminary results

Aims To report outcomes with selective intra-arterial chemotherapy (SIAC) using simultaneous carboplatin, topotecan, and melphalan for advanced intraocular retinoblastoma. Methods A retrospective chart review was conducted of patients who received three-drug (melphalan, topotecan, and carboplatin) SIAC during 2006–2011. Results Twenty-six eyes of 25 patients received the three-drug chemotherapy for treatment of advanced retinoblastoma. Reese-Ellsworth group was 5b in 21 eyes, 5a in 2, 4a in 2, and 3a in 1. Seventeen patients (68%) had recurrence after prior intravenous chemotherapy with or without radiotherapy. In the three-drug therapy, dose ranges were 2.5–7.5 mg for melphalan, 0.3–0.6 mg for topotecan, and 25–50 mg for carboplatin, and median infusions per eye was 2 (range 1–4). At a mean follow-up of 14 months (range 1–43 months), all patients are alive and no patient developed metastatic disease. Twenty-three of 26 eyes (88%) survived. Eleven of the 26 eyes (35%) developed recurrent disease and were treated with enucleation (n=3) or with focal therapy (n=8) with or without plaque brachytherapy (n=3). The Kaplan-Meier estimate of ocular survival at 24 months was 75% (95% CI). Electroretinogram showed improvement greater than 25 µV in 4 eyes (15%), loss greater than 25 µV in 12 eyes (46%), and no change greater than 25 µV in 10 eyes (39%). Conclusions Three-drug SIAC has been used successfully to rescue eyes after treatment failure of intravenous chemotherapy and/or single- or double-agent SIAC. Twenty-three of 26 eyes avoided both enucleation and external beam radiotherapy and retained electroretinogram function.