Treatment of retinoblastoma is strategic and multifaceted, with options including enucleation, external and plaque radiotherapy, cryotherapy, laser photocoagulation, transpupillary thermotherapy, and various methods of chemotherapy.1 Currently, intravenous chemotherapy is most frequently used and remarkably effective.1 Intra-arterial chemotherapy is a novel modality shown to be equal to or more effective with advanced retinoblastoma compared to intravenous chemotherapy.1 Both methods allow tumor control for solid retinoblastoma and subretinal seeds, but less control for vitreous seeds.
Intravenous and intra-arterial chemotherapy depend on adequate vascular supply for effective drug delivery; hence, these routes are less effective for vitreous seeds because of the lack of vascular source. For this reason, vitreous seeds are recognized as a poor prognostic sign for globe salvage because of their inadequate response to standard treatment methods. In recent years, intravitreal chemotherapy has gained popularity for tumor control of vitreous seeds following failure of other therapies.1–6 We report a dramatic case of retinoblastoma with extensive vitreous seeds recurrent following intravenous and intra-arterial chemotherapy, and successfully managed with combination intravitreal chemotherapy.
A 4-year-old girl was referred with bilateral retinoblastoma with recurrent vitreous seeds in the right eye. Previous treatment elsewhere included chemotherapy for the right eye and enucleation of the left eye. The right eye received 24 cycles of systemic intravenous chemotherapy and consolidation with focal laser and cryotherapy, four cycles of intra-arterial chemotherapy with melphalan and topotecan, and sequential intra-vitreal injections with carboplatin and topotecan.
Visual acuity at presentation of the right eye was fix-and-follow and intraocular pressure was normal. Fundus examination showed a single retinoblastoma with type I calcified regression and no subretinal seeds. There was extensive vitreous seeding involving the entire vitreous cavity with a coalescent premacular film of seeds (Figure 1). There was no view of the underlying fovea and only a partial view of the optic nerve. Ultrasonography confirmed a single calcified retinal tumor without subretinal fluid. The enucleated socket of the left eye was unremarkable.
A 4-year-old girl with massive, recurrent vitreous seeds from retinoblastoma in her only remaining eye following extensive intravenous and intra-arterial chemotherapy. The right eye shows a coalescent film of vitreous seeds in the (A) premacular region and additional extensive seeds throughout the (B) entire vitreous cavity. (C, D) Photograph of the same region as in A and B demonstrating dramatic resolution of vitreous seeds and no sign of active tumor after four intravitreal injections of combination melphalan and topotecan.
Treatment options included enucleation of the only remaining eye, external beam radiotherapy, or intravitreal chemotherapy. After discussion of the risks and benefits of each treatment, a decision was made to proceed with intravitreal injections of melphalan and topotecan, given bi-weekly. The patient initially started with intravitreal injections of 20-µg melphalan and 20-µg topotecan, using techniques previously described.4–6 After the first injection, there was minimal regression of vitreous seeds and subsequent injections were increased to 25-µg melphalan and 20-µg of topotecan. After three more intravitreal injections, there was complete regression of vitreous seeds and dissipation of the premacular film, allowing visualization of the macula and documentation of normal foveal anatomy with minute overlying vitreous seeds on optical coherence tomography. At final examination, all vitreous seeds were regressed to disappearance or to calcified or fibrotic appearance (Figures 1C–1D). At the 3-month follow-up visit, LEA symbol visual acuity measured 20/100 and there was no retinal toxicity clinically or by imaging with fluorescein angiography and optical coherence tomography.
Intravitreal injection is a powerful tool initially used to treat endophthalmitis, but has shown recent applications in macular degeneration and other retinal diseases. Intravitreal chemotherapy was first used for retinoblastoma in 1960 when Ericson and Rosengren injected thiotepa using a needle with an outer diameter of 0.8 mm (currently equivalent to a 21-gauge needle) through the ciliary body but was abandoned for safety reasons until decades later.7 Inomata and Kaneko later investigated chemosensitivity of retinoblastoma to various agents and found it was most sensitive to melphalan.8 They later determined that intravitreal melphalan injections of 10 µg showed no electrophysiologic retinal changes in rabbit eyes, moderate changes after 20 µg, and severe deterioration after 90 µg.9 Their magnificent work formed the foundation for the interest in intravitreal chemotherapy and spawned the popularity of this novel treatment method. Based on their work8,9 and that of Ghassemi and Shields,4 it is known that intravitreal melphalan has a high efficacy, but with narrow therapeutic index of vitreous seed control in eyes with retinoblastoma.
Shields et al. published intravitreal injection of melphalan through the pars plana using a 31-gauge needle with immediate cryotherapy.5 In their series of 11 eyes with vitreous seeds, complete regression and globe salvage was achieved in all cases, with an average of five injections given at a median interval of 1 month.5 Munier et al. reported complete regression of vitreous seeds using intravitreal melphalan, with an average of 5.3 total weekly injections and globe salvage in 87%.6 In both series, there was no reported extraocular spread and the optimum dose was deemed to be approximately 20 to 30 µg to enable tumor control while limiting adverse reactions.5,6 These reactions can occur in low doses but are more frequent with higher amounts and include retinal pigment epithelium mottling, hypotony, hemorrhage, cataract, vasculitis, keratopathy, optic neuropathy, decreased electroretinographic response, and phthisis.4–6,10 It should be realized that these can occasionally lead to enucleation and, histologically, higher doses of melphalan have been reported to cause ischemic retinal necrosis.11
The narrow therapeutic index and repetitive injections with melphalan monotherapy can be a limiting factor in achieving tumor control while limiting toxicity. Ghassemi et al. introduced combined melphalan and topotecan injections for extensive vitreous seeding and showed complete response after a mean of two injections.3 Combination therapy allows maximization of treatment response with lower doses of melphalan by adding another agent. Our case illustrates the capacity for control of massive vitreous seeding using combination therapy when higher doses of melphalan can achieve similar control, but with more extensive side effects. It also highlights its potential for globe salvage in eyes that would have otherwise been enucleated or exposed to external beam radiation. We believe that after visual rehabilitation from sensory deficit from the macular film of vitreous seeds, the patient could have improved visual outcome.
Intravitreal chemotherapy can achieve vitreous seed control in retinoblastoma after failure with other methods. Although intravitreal melphalan monotherapy can be effective in many cases, the addition of topotecan can allow regression of vitreous seeds while limiting toxicity of high-dose melphalan.
- Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye (Lond). 2012;27:253–264. doi:10.1038/eye.2012.175 [CrossRef]
- Munier FL, Gaillard M, Balmer A, Beck-Popovic M. Intravitreal chemotherapy for vitreous seeding in retinoblastoma: recent advances and perspectives. Saudi J Ophthalmol. 2013;27:147–150. doi:10.1016/j.sjopt.2013.06.003 [CrossRef]
- Ghassemi F, Shields CL, Ghadimi H, et al. Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. JAMA Ophthalmol. 2014;132:936–941. doi:10.1001/jamaophthalmol.2014.414 [CrossRef]
- Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol. 2012;130:1268–1271. doi:10.1001/archophthalmol.2012.1983 [CrossRef]
- Shields CL, Manjandavida FP, Arepalli S, Kaliki S, Lally SE, Shields JA. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol. 2014;132:319–325. doi:10.1001/jamaophthalmol.2013.7666 [CrossRef]
- 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. doi:10.1136/bjophthalmol-2011-301450 [CrossRef]
- Ericson LA, Rosengren BH. Present therapeutic resources in retinoblastoma. Acta Ophthalmol. 1961;39:569–576. doi:10.1111/j.1755-3768.1961.tb00269.x [CrossRef]
- 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. Nihon Ganka Gakkai Zasshi. 1995;99:1230–1235.
- 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. doi:10.1016/j.ophtha.2014.03.028 [CrossRef]
- Ghassemi F, Amoli FA. Pathological findings in enucleated eyes after intravitreal melphalan injection. Int Ophthalmol. 2013;34:533–540. doi:10.1007/s10792-013-9851-2 [CrossRef]