Ocular and Systemic Safety of Repeated Intravitreal High Doses of Topotecan in Rabbits: Implications in Retinoblastoma Treatment.

DEL SOLE, MARÍA JOSÉ; CLAUSSE, MARÍA; NEJAMKIN, PABLO; CANCELA, BELEN; DEL RÍO, MIRANDA; ZUGBI, SANTIAGO; LAMAS, GABRIELA; LUBIENIECKI, FABIANA; FRANCIS, JASMINE H.; ABRAMSON, DAVID; CHANTADA, GUILLERMO; SCHAIQUEVICH, PAULA SUSANA

Lausanne

Congreso; ISGEDR Joint Meeting; 2021

International Society for Genetic Eye Diseases & Retinoblastoma (ISGEDR)

IntroductionTreatment of vitreous seeds in retinoblastoma may still be challenging in cases of refractory tumors, globe-conserving treatment for the remaining eye in bilateral patients, and poor compliance. An intensive treatment with intravitreal high-dose chemotherapy may be a strategy to control tumor burden in these cases. Since topotecan has proved to be safe after intravitreal injection, protracted schemes of administration showed better tumor control than a single high-dose due to its cell cycle-dependent mechanism of action, prolonged exposure would be desirable to leverage antitumor efficacy. We aimed to evaluate the ocular and systemic safety of high-doses and repeated intravitreal injections of topotecan and vehicle in rabbits as a potential translation to difficult-to-treat retinoblastoma vitreous seeds. Materials and MethodsFifteen New Zealand rabbits (30 eyes) were divided randomly into four groups to receive four weekly injections of three different doses of intravitreal topotecan (n=12; 10ug/dose, 25ug/dose or 50ug/dose yielding human equivalent doses of 20, 50, and 100 ug/dose, respectively), vehicle (n=12, pH 2.5), or normal saline (n=3) in 0.05 ml. Three groups received topotecan in the right eye and vehicle in the contralateral while the fourth group was injected with vehicle in the right eye and saline in the left eye. The maximum dose of topotecan was calculated by means of simulation of vitreous lactone topotecan concentrations in rabbits and the time above the inhibitory concentration determined in primary and topotecan-resistant cell cultures. Animals were clinically evaluated and hematologic values and slit lamp, direct and indirect ophthalmoscopic examination were performed. Electroretinograms (ERGs) were recorded before and one week after each intravitreal injection. One week after the last injection vitreous and plasma samples were collected for drug quantitation by HPLC and thereafter all animals were sacrificed and enucleated, for histological assessment. Analysis was performed by means of two-way repeated measures ANOVA set at p0.05). No statistical differences were observed in all comparisons performed in the individual a- and b-wave amplitude for the topotecan-treated to the vehicle-treated eye of each animal as well as vehicle-treated versus saline-injected eyes (p>0.05).No histologic evidence of damage of the retina was observed in any topotecan or vehicle-treated eye. After one week of the last dose vitreous and plasma topotecan exposure were under the limit of quantitation in all groups of eyes and animals.ConclusionsOur study shows that four weekly intravitreal injection of topotecan up to 50ug in the animal model or 100ug human equivalent dose is not toxic for the rabbit eye throughout the entire follow-up period. No systemic or retinal toxicity according to fundus evaluation, ERG responses and histological examination was found in topotecan-injected or vehicle-treated eyes despite the highly acidity of the solution. High doses of topotecan may show promising translation to treatment of resistant vitreous seeds and special cases of poor retinoblastoma patient compliance.