Severe Periocular Edema after Intraarterial Carboplatin Chemotherapy for Retinoblastoma in a Rabbit (Oryctolagus cuniculus) Model

Abstract

Endovascular microcatheter-based intraarterial (ophthalmic artery) chemotherapy is becoming widely used for the clinical treatment of intraocular retinoblastoma due to its apparent increased efficacy compared with traditional intravenous chemotherapy; however local ocular complications are not uncommon. Carboplatin is a chemotherapeutic agent used in both intravenous and intraarterial chemotherapy. We used rabbits to assess pharmacokinetics and ocular and systemic toxicity after intraarterial carboplatin infusion. Subsequent to unilateral intraarterial administration of carboplatin, severe unilateral or bilateral periocular edema occurred in 6 adult male New Zealand white rabbits. Time to onset varied from less than 4 h after administration (n = 3, 50 mg) to approximately 24 h afterward (n = 3, 25 mg). After becoming symptomatic, 5 of the 6 animals were promptly euthanized, and the remaining animal (25 mg treatment) was medically managed for 4 d before being euthanized due to intractable edema-related lagophthalmos. Globes and orbits from all 6 euthanized rabbits were harvested en bloc; whole-mount sections were prepared for histologic evaluation, which revealed drug-induced vasogenic edema in confined spaces as the main underlying pathogenesis. Transient and self-limiting periocular edema is a common side effect of intraarterial chemotherapy but is thought to occur predominantly with melphalan monotherapy or combination therapy using melphalan, carboplatin, and topotecan. The severity of this adverse consequence in rabbits was unexpected, and its use in the study was subsequently discontinued. Although the definitive cause for this vasotoxicity and striking clinical presentation is unknown, we suspect species-specific anatomic features and sensitivity might have contributed to amplified complications after intraarterial carboplatin chemotherapy of the eye. Due to the adverse effects of intraarterial carboplatin chemotherapy that we observed in 2 experimental cohorts of rabbits, we recommend caution regarding its use in this species.