Evaluation of retinal and systemic toxicity of intravitreal Melphalan in rabbits for potential treatment of retinoblastoma.

Abstract

Purpose: Despite currently use of intravitreal melphalan (MPL) in retinoblastoma treatment, scarce information is still available about potential ocular toxicity. The aim of this work was to evaluate the retinal and systemic toxicity of intravitreal administration of MPL in an animal model.

Methods: 12 New Zealand/Dutch Belt pigmented rabbits (1.8 to 2.2 kg) were assigned to 3 groups, named A, B and C (n=4 in each group). Animals in groups A (acute toxicity) and B (subacute toxicity) received 3 weekly intravitreal injections of 15 μg of MPL and group C the same volume (0.1 ml) of vehicle into the right eye. All left eyes were left untreated. Animals were evaluated weekly for clinical, and hematological values and ocular evaluations were performed with an inverse ophthalmoscope. Weekly controls included MPL assay in plasma of all rabbits. Electroretinograms were recorded in all eyes during the study period. One week after the last injection in group A and one month after the last dose in group B, animals were euthanized and samples for retinal histology were obtained.

Results: No significant change in body weight or the hematological values during the studied interval for both MPL-treated groups (acute and subacute toxicity) and vehicle-treated animals were detected (p>0.05). Evident fundus changes were observed after 1 week of the 2nd dose while no change was observed in contralateral eyes or in vehicle-treated eyes. Control eyes of groups A, B and C, between control and vehicle-treated eyes of animals belonging to group C showed no significant differences throughout the entire follow-up period (p>0.05). A statistically significant change in a- and b-wave amplitude was observed in melphalan-treated eyes from groups A and B after 1 week of the 2nd dose compared to vehicle-treated eyes (p<0.05) with no recovery in a or b-wave amplitude after completion of the study period. Hystopathological findings reveal massive retinal damage in MPL treated eyes.

Conclusions: Significant retinal toxicity was evident in rabbits after 3 weekly doses of intravitreal MPL in a schedule and dose fashion that resembles the current clinical treatment of patients with retinoblastoma. No systemic toxicity was evident in the animals. The present study alerts for potential toxicity that retinoblastoma patients may be undergoing in current treatment with intravitreal MPL.

Keywords: 703 retinoblastoma • 688 retina