Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma

Abstract

Background: Retinoblastoma is a rare intraocular malignancy in children. Current treatments have many adverse effects. New therapeutic approaches like intravitreal injections of chemotherapies are currently being developed but their toxicities need to be evaluated on animal models. This study compares the efficacy and toxicity of intravitreal melphalan, topotecan and carboplatin, alone or in combination (sequential administration), in the LHBetaTag retinoblastoma mice. Methods: Mice were divided into nine groups: control, carboplatin 1.5 and 4 μg, melphalan 0.1 and 1 μg, topotecan 0.1 and 1 μg, carboplatin 4 μg/ topotecan 0.1 μg and melphalan 1 μg/topotecan 0.1 μg. The follow-up was performed using fundus imaging and optical coherence tomography combined with histopathological analysis. Absence of tumour and presence of calcified tumours were the criteria for therapeutic response assessment. Ocular complications were assessed after four weekly injections. Retinal toxicity was defined by the decrease of retinal thickness and of the number of retinal layers.Results: Topotecan was inactive on retinal tumours. Melphalan (1 μg) led to a complete tumour control in 91.7% of eyes. Carboplatin strongly decreased the tumour burden (85.7-93.8% of eyes without retinal tumour). The intravitreal injection itself led to ocular complications (25% of media opacities and 45.7% of retinal detachment). Only melphalan at 1 μg showed a strong retinal toxicity. The two combinations showed a good efficacy in reducing the number of eyes with retinal tumours with a reduced retinal toxicity.Conclusions: This preclinical study suggests that intravitreal injection of carboplatin has a low toxicity and could be evaluated in clinical practice to treat patients suffering from retinoblastoma. K E Y W O R D Scarboplatin, fundus imaging and optical coherence tomography, intravitreal injection, melphalan, retinoblastoma, topotecan

Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits

“…Recently Lemaître et al 28 evaluated the effectiveness and safety of intravitreal injection of Melphalan, Topotecan, and Carboplatin, alone or in combination in the animal model of LHBetaTag retinoblastoma mice. They found that weekly intravitreal Carboplatin, either 1.5 or 4 μg could reduce tumor burden significantly (80%).…”

“…For the Carboplatin group, the dose chosen dose was close to the maximum tolerated dose to achieve the most effective concentration (1 µg), based on previous investigations. 28 , 30 , 31 , 32 For the Digoxin group, the dosage was chosen based on the amount of Digoxin that could result in pharmacologically active amounts in the vitreous of a rabbit (1.5 ml) for at least 4 h after injection, as well as a low systemic exposure as a proxy of cardiac toxicity for its direct impact in the translation to clinics, which was the end goal of these studies. 40 …”

“… 24 , 25 Moreover, a second chemotherapeutic agent is usually required to reduce the number of injections, and serve as an alternative in cases with intravitreal melphalan resistance. 19 Thiotepa , 26 Methotrexate , 27 Topotecan , 10 , 19 Etoposide , 2 Carboplatin , 18 , 28 and Digoxin 29 were evaluated as other intravitreal chemotherapeutics in retinoblastoma. Among these alternatives the in vivo safety studies on repeated intravitreal injection of Digoxin and Carboplatin, as available agents especially in developing countries, is limited.…”

“… 2 There are several studies that show the effectiveness of intravitreal injection of Carboplatin, 12 , 18 , 30 however, there are limited data regarding the ocular safety and possible toxicity after repeated intravitreal injections. 28 , 31 , 32 …”

“…The adverse eye effects of Melphalan, such as toxicity to the posterior and anterior segments, 20–23 prompted researchers to look for other possible chemotherapeutic agents for intravitreal injection 24,25 . Moreover, a second chemotherapeutic agent is usually required to reduce the number of injections, and serve as an alternative in cases with intravitreal melphalan resistance 19 Thiotepa, 26 Methotrexate, 27 Topotecan, 10,19 Etoposide, 2 Carboplatin, 18,28 . and Digoxin 29 were evaluated as other intravitreal chemotherapeutics in retinoblastoma.…”