Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma.
carboplatin
fundus imaging and optical coherence tomography
intravitreal injection
melphalan
retinoblastoma
topotecan
Journal
Clinical & experimental ophthalmology
ISSN: 1442-9071
Titre abrégé: Clin Exp Ophthalmol
Pays: Australia
ID NLM: 100896531
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
26
08
2019
revised:
05
12
2019
accepted:
18
12
2019
pubmed:
25
12
2019
medline:
1
9
2021
entrez:
25
12
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Substances chimiques
Carboplatin
BG3F62OND5
Melphalan
Q41OR9510P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
500-511Informations de copyright
© 2019 Royal Australian and New Zealand College of Ophthalmologists.
Références
Lumbroso-Le Rouic L, Aerts I, Levy-Gabriel C, et al. Conservative treatments of intraocular retinoblastoma. Ophthalmology. 2008;115:1405-1410. e1-2.
Soliman SE, D'Silva CN, Dimaras H, Dzneladze I, Chan H, Gallie BL. Clinical and genetic associations for carboplatin-related ototoxicity in children treated for retinoblastoma: a retrospective noncomparative single-institute experience. Pediatr Blood Cancer. 2018;65:e26931.
Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al. Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma. Pediatr Blood Cancer. 2009;52:637-643.
Gunduz K, Gunalp I, Yalcindag N, et al. Causes of chemoreduction failure in retinoblastoma and analysis of associated factors leading to eventual treatment with external beam radiotherapy and enucleation. Ophthalmology. 2004;111:1917-1924.
Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology. 1999;106:1947-1950.
Schmack I, Hubbard GB, Kang SJ, Aaberg TM Jr, Grossniklaus HE. Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma. Am J Ophthalmol. 2006;142:310-315.
Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115:1398-1404.e1.
Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no. 2, treatment complications. Arch Ophthalmol. 2011;129:1407-1415.
Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no. 1, control of retinal tumors, subretinal seeds, and vitreous seeds. Arch Ophthalmol. 2011;129:1399-1406.
Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol. 2012;96:1078-1083.
Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol. 2012;130:1268-1271.
Yanik O, Gunduz K, Yavuz K, Tacyildiz N, Unal E. Chemotherapy in retinoblastoma: current approaches. Turk J Ophthalmol. 2015;45:259-267.
Francis JH, Brodie SE, Marr B, Zabor EC, Mondesire-Crump I, Abramson DH. Efficacy and toxicity of intravitreous chemotherapy for retinoblastoma: four-year experience. Ophthalmology. 2017;124:488-495.
Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human retinoblastoma cells in a human tumor clonogenic assay. Jpn J Cancer Res. 1987;78:858-868.
Ueda M, Tanabe J, Inomata M, Kaneko A, Kimura T. [Study on conservative treatment of retinoblastoma-effect of intravitreal injection of melphalan on the rabbit retina]. Nippon Ganka Gakkai Zasshi. 1995;99:1230-1235.
Buitrago E, Winter U, Williams G, Asprea M, Chantada G, Schaiquevich P. Pharmacokinetics of melphalan after intravitreal injection in a rabbit model. J Ocul Pharmacol Ther. 2016;32:230-235.
Suzuki S, Aihara Y, Fujiwara M, Sano S, Kaneko A. Intravitreal injection of melphalan for intraocular retinoblastoma. Jpn J Ophthalmol. 2015;59:164-172.
Ghassemi F, Amoli FA. Pathological findings in enucleated eyes after intravitreal melphalan injection. Int Ophthalmol. 2014;34:533-540.
Windle JJ, Albert DM, O'Brien JM, et al. Retinoblastoma in transgenic mice. Nature. 1990;343:665-669.
Windle JJ, Weiner RI, Mellon PL. Cell lines of the pituitary gonadotrope lineage derived by targeted oncogenesis in transgenic mice. Mol Endocrinol. 1990;4:597-603.
Pajovic S, Corson TW, Spencer C, et al. The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated Muller glia with progenitor properties. Invest Ophthalmol Vis Sci. 2011;52:7618-7624.
Harbour JW, Murray TG, Hamasaki D, et al. Local carboplatin therapy in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci. 1996;37:1892-1898.
Shah NV, Pham DG, Murray TG, et al. Intravitreal and subconjunctival melphalan for retinoblastoma in transgenic mice. J Ophthalmol. 2014;2014:829879.
O'Brien JM, Marcus DM, Bernards R, et al. A transgenic mouse model for trilateral retinoblastoma. Arch Ophthalmol. 1990;108:1145-1151.
Wenzel AA, O'Hare MN, Shadmand M, Corson TW. Optical coherence tomography enables imaging of tumor initiation in the TAg-RB mouse model of retinoblastoma. Mol Vis. 2015;21:515-522.
Laurie NA, Gray JK, Zhang J, et al. Topotecan combination chemotherapy in two new rodent models of retinoblastoma. Clin Cancer Res. 2005;11:7569-7578.
Fassberg J, Stella VJ. A kinetic and mechanistic study of the hydrolysis of camptothecin and some analogues. J Pharm Sci. 1992;81:676-684.
Craig SB, Bhatt UH, Patel K. Stability and compatibility of topotecan hydrochloride for injection with common infusion solutions and containers. J Pharm Biomed Anal. 1997;16:199-205.
Ghassemi F, Shields CL, Ghadimi H, Khodabandeh A, Roohipoor R. Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. JAMA Ophthalmol. 2014;132:936-941.
Lawson BM, Saktanasate J, Say EA, Shields CL. Intravitreal chemotherapy provides control for massive vitreous seeding from retinoblastoma. J Pediatr Ophthalmol Strabismus. 2014;51:e92-e94.
Rao R, Honavar SG, Sharma V, Reddy VAP. Intravitreal topotecan in the management of refractory and recurrent vitreous seeds in retinoblastoma. Br J Ophthalmol. 2018;102:490-495.
Francis JH, Schaiquevich P, Buitrago E, et al. Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study. Ophthalmology. 2014;121:1810-1817.
Lemaitre S, Poyer F, Marco S, et al. Looking for the most suitable orthotopic retinoblastoma mouse model in order to characterize the tumoral development. Invest Ophthalmol Vis Sci. 2017;58:3055-3064.
Francis JH, Abramson DH, Gobin YP, et al. Electroretinogram monitoring of dose-dependent toxicity after ophthalmic artery chemosurgery in retinoblastoma eyes: six year review. PLoS One. 2014;9:e84247.
Susskind D, Hagemann U, Schrader M, Januschowski K, Schnichels S, Aisenbrey S. Toxic effects of melphalan, topotecan and carboplatin on retinal pigment epithelial cells. Acta Ophthalmol. 2016;94:471-478.