OSLI Retina

February 2017

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■ E X P E R I M E N T A L S C I E N C E ■ February 2017 · Vol. 48, No. 2 151 Preclinical Acute Ocular Safety Study of Combined Intravitreal Carboplatin and Etoposide Phosphate for Retinoblastoma Brian G. Mohney, MD; Victor M. Elner, MD, PhD; Andrew B. Smith, BS; J. William Harbour, MD; Brian D. Smith, MD; David C. Musch, PhD, MPH; Stephen J. Smith, MD BACKGROUND AND OBJECTIVE: To describe the ocu- lar toxicity of intravitreal carboplatin and etopo- side phosphate (VP16P) in Dutch-Belted rabbits. MATERIALS AND METHODS: Twenty-two adult male Dutch-Belted rabbits (Cohort 1) each received a single, bilateral intravitreal injection (0.05 mL). For Cohort 1, safety was assessed via electroretinograms (ERGs) and ocular examination. Of nine total groups in Cohort 1, the first five received the following single agents: Group 1: normal saline; Group 2: VP16P 75 µg; Group 3: VP16P 100 µg; Group 4: carboplatin 4 µg; and Group 5: carboplatin 8 µg. Groups 6 through 9 received the following combination of carboplatin/ VP16P, respectively: Group 6: 8 µg/75 µg, Group 7: 8 µg/50 µg, Group 8: 4 µg/50 µg, and Group 9: 2 µg/25 µg. Cohort 2 consisted of 15 Dutch-Belted rabbits in seven groups (Groups 10 through 16), each receiving a single, bilateral intravitreal injection. For Cohort 2, safety was assessed via histopathology. RESULTS: Groups 2 through 8 demonstrated a statis- tically significant decrease (relative to Group 1) in at least one ERG waveform amplitude obtained 4 weeks postinjection (P < .05). Group 9 (carbo 2 µg/ VP16P 25 µg) did not manifest ERG toxicity. Fun- doscopic toxicity consisted of slight-to-moderate attenuation of vessels in rabbits receiving doses above carbo 4 µg/VP16P 50 µg. Histopathologic ret- inal toxicity (Cohort 2) was dose-dependent, rang- ing from full-thickness atrophy in rabbits receiv- ing the highest dose to normal in rabbits receiving carbo 2 µg/VP16P 25 µg. CONCLUSIONS: Combined carboplatin and VP16P may be compatible for intravitreal injection ther- apy, and a single dose of 2 µg/25 µg appears to be safe in a rabbit model. These agents may be a safer alternative to intravitreal melphalan (Alkeran; GlaxoSmithKline, Brentford, United Kingdom) for the treatment of vitreous seeds in retinoblastoma. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:151-159.] INTRODUCTION Treatment outcomes for retinoblastoma (RB) have dramatically improved during the last two decades, with an increasing focus on salvaging the affected eye, even eyes with vitreous seeds. Injecting an an- tineoplastic agent directly into the vitreous, as pio- neered by Erickson and Rosengren 1,2 in 1962, is an ideal method for delivering therapy to the avascular vitreous humor to treat vitreous extension of tumor cells. Intravitreal injection therapy (IViT) was largely avoided for 40 years due to concerns of extraocular tumor spread following penetration of the ocular wall. 3 However, IViT has been widely used in Japan for more than two decades due cultural beliefs that cause resistance to enucleation. In 2013, Smith and Smith summarized published data on tumor spread following IViT and found the percentage of confirmed tumor spread to be 0.35%. 4 This and other reports encouraged a wider adoption of this therapy around the world, with published reports showing an 85% to 100% success rate in treating vitreous tumor exten- sion. 5-7 Although the risk of tumor spread due to IViT is extremely low, the pharmacologic ocular morbidity of IViT can be severe, including chorioretinal atrophy, iris atrophy, retinal detachment, and phthisis bulbi, From the Department of Ophthalmology, Mayo Clinic and Mayo Founda- tion, Rochester, MN (BGM); the Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Health System, Ann Arbor, MI (VME, DCM); the Department of Pathology, University of Michigan Health System, Ann Arbor, MI (VME); the State University of New York – Brockport, Brockport, NY (ABS); the Department of Ophthalmol- ogy, Bascom Palmer Eye Institute, University of Miami, Miami (JWH); the Department of Medicine, Hematology/Oncology, University of Rochester, Rochester, NY (BDS); the Department of Epidemiology, University of Michi- gan, Ann Arbor, MI (DCM); and the Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA (SJS). Originally submitted October 18, 2016. Revision received November 5, 2016. Accepted for publication November 29, 2016. This study was supported by a Michigan Ophthalmology Career Develop- ment Award (SJS) with matching funds from Mayo Clinic via a Research to Prevent Blindness unrestricted grant (BGM). The authors report no relevant financial disclosures. Address correspondence to Stephen J. Smith, MD, Stanford University, Byers Eye Institute, 2452 Watson Court, Palo Alto, CA 94303; email: smith. stephenj1@gmail.com. doi: 10.3928/23258160-20170130-09

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