Preclinical Acute Ocular Safety Study of Combined Intravitreal Carboplatin and Etoposide Phosphate for Retinoblastoma.

To describe the ocular toxicity of intravitreal carboplatin and etoposide phosphate (VP16P) in Dutch-Belted rabbits.

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.

Groups 2 through 8 demonstrated a statistically 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. Fundoscopic toxicity consisted of slight-to-moderate attenuation of vessels in rabbits receiving doses above carbo 4 µg/VP16P 50 µg. Histopathologic retinal toxicity (Cohort 2) was dose-dependent, ranging from full-thickness atrophy in rabbits receiving the highest dose to normal in rabbits receiving carbo 2 µg/VP16P 25 µg.

Combined carboplatin and VP16P may be compatible for intravitreal injection therapy, 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.].