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Perspectives

Chemotherapy for Retinoblastoma: Impact of Intravitreal Chemotherapy

Raval, Vishal MD; Bowen, R. Christopher MD, MS; Soto, Hansell MD; Singh, Arun MD

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Asia-Pacific Journal of Ophthalmology: March-April 2021 - Volume 10 - Issue 2 - p 200-202
doi: 10.1097/APO.0000000000000322
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Abstract

INTRODUCTION

In the last 3 decades, management of retinoblastoma has come a long way from preserving patient's life to preserving eye and vision with minimizing complications of treatment.1,2 Intraocular retinoblastoma can be managed by enucleation, external beam radiation therapy, chemotherapy, and focal therapies including cryotherapy, laser therapy, and brachytherapy.3–5 The extent of disease, as indicated by its International Classification of Retinoblastoma classification, is one major factor driving the choice of treatment modality employed. In the last 2 decades, primary chemoreduction via intravenous chemotherapy, aimed at reducing tumor bulk before focal therapies, has been the mainstay of therapy for retinoblastoma;6,7 in recent years, chemotherapy delivered via alternative routes such as intra-arterial and intravitreal administration has emerged as a promising option for managing advanced or refractory retinoblastoma.

REVIEW

Intravenous Chemotherapy

Till the end of last decade (2010), intravenous chemotherapy (IVC), commonly involving a 3-drug regimen of vincristine, etoposide, and carboplatin, was the most widely utilized first-line therapy for intraocular retinoblastoma. The main aim of IVC was of tumor reduction so that focal therapies like laser or cryotherapy can be subsequently employed, with the primary goal of eye conservation. Various studies have shown excellent results in salvaging nearly 100% of group A, B, and C eyes when coupled with adjunctive laser therapy and cryotherapy.7–9 Advanced group D eyes with diffuse vitreous and subretinal seeds and group E eyes, however, carried a modest prognosis for eye salvage with IVC ranging from 24.3% to 59.1% as reported in various studies.10

Intra-arterial Chemotherapy

With the advent of IAC in this decade (2011–2019), there is a shift in the treatment choices for retinoblastoma. Intra-arterial chemotherapy is very efficacious similar to IVC in achieving tumor control in early retinoblastoma (groups A, B, and C; International Classification of Retinoblastoma) with 100% treatment success in the majority of studies.11–14 Reported outcomes for advanced retinoblastomas (groups D and E eyes) are more favorable after intra-arterial chemotherapy compared to IV chemotherapy. Success rates for group D eyes range from 36% to 100%,11,12,14 whereas that of group E eyes range from 17% to 87%.11,12,15 Of note, using a 3-drug intra-arterial regimen drastically enhanced treatment success of group E eyes, from 17% to 50% to 87%.16 A separate study by Abramson et al17 reported probabilities of ocular salvage at 50% to 83% after intra-arterial chemotherapy in advanced intraocular retinoblastoma with vitreous and/or subretinal seedings, suggesting that intra-arterial chemotherapy can be effective against seeding, especially if the seeding is subretinal.

Intravitreal Chemotherapy

In particular, tumor seeding has been demonstrated to be one of the major predictive factors for failure of systemic chemotherapy,18 necessitating treatment modalities that would be more effective toward tumors presenting with vitreous and/or subretinal seeds. IVitC, a targeted approach that would deliver the highest concentration of drug in the vitreous cavity while minimizing systemic drug concentration, has emerged in recent years as an effective treatment for refractory or persistent vitreous seeding. Since IVitC is indicated for vitreous seeding, the majority of cases studied were of group C or higher. Munier et al, with the largest case series up to date, demonstrated complete regression of vitreous seeds in all group C eyes, and 82% of group D eyes, after up to 8 weekly intravitreal melphalan treatments.19 Similarly, Shields et al reported 100% regression in cases treated with monthly injections of intravitreal melphalan for persistent or recurrent vitreous seeds.14

Adverse Effects of Local Chemotherapeutic Drugs

Intra-arterial chemotherapy is safe with fewer systemic side effects compared to IVC; however, local transient side effects consist of redness, eyelid edema, loss of eyelashes, ptosis which usually resolves within 2 to 3 months,20 whereas permanent vision threatening intraocular vascular complications like choroidal occlusive vasculopathy, vitreous hemorrhage, and ophthalmic artery occlusion remain a concern.21 Intravitreal injections as compared to IAC have fewer local adverse effects and no known systemic toxicity.22 Shields et al23 in one of the largest series of 192 intravitreous treatments for retinoblastoma have reported local side effects such as retinal pigment epithelial mottling (32%), focal cataract (25%), transient vitreous hemorrhage (13%), hypotony (8%), optic disc edema (3%), and hemorrhagic retinal necrosis (3%). Similarly, anterior segment toxicity in form of iris depigmentation and atrophy after multiple melphalan injections has been reported.24 In pigmented fundus, topotecan seems to be safer than melphalan. Rao et al in a study of 17 patients showed 100% regression of vitreous seeds with no known ocular or systemic side effects.25

COMMENTS

Several important aspects are overlooked when results from various studies are grouped to generate averages or even ranges to calculate outcome measures. First, the reported studies lack uniform inclusion criteria; therefore, results are not directly comparable between the studies, such as primary versus secondary application of IAC. Secondly, variations in classification systems used in each study can upgrade or downgrade eyes with groups D and E eyes making it impossible to compare outcomes between studies.26 Most of the studies reviewed herein have used International Classification of Retinoblastoma, hence we used the same system in this perspective. Thirdly, confounding variables like prior, concomitant, or subsequent treatment in management of groups D and E tumors are impossible to adjust for, as each eye may have received many forms of local therapy.

The role of concomitant and subsequent therapies is an important consideration, particularly the use of IVitC, which is used increasingly for intravitreal seeding. The combination of IAC (for the primary tumor control) and use of IVitC (for the vitreous seeding) is almost always necessary for treatment of groups D and E tumors. Hence the contributory role of IVitC in reporting high control rates with IAC cannot be ignored. As IVitC (2012) became acceptable during the era of IAC (2012),19 we could only identify 4 IAC studies without IVitC in contrast to 14 studies with IVitC. Most of the patients treated previously with IVC (17 studies) did not receive IVitC6 (Fig. 1); however, recent publications on use of concurrent or subsequent administration of IVitC27–29 for vitreous seed recurrence have improved the overall globe salvage rate supporting our perspective that some of the IVC failures in the pre-IvitC era could have been avoided with the use of IVitC.

FIGURE 1
FIGURE 1:
Practice patterns of chemotherapy for retinoblastoma. The timeline represents best approximation. A literature search done using search engine (Google, PubMed) to identify all the studies related to primary intravenous and intraarterial chemotherapy for treatment of retinoblastoma from year 1992 to 2012 and 2012 to 2019 in English language. Studies were excluded if the number of cases in the series was <40 or the details of treatment were not mentioned. IAC indicates intra-arterial chemotherapy; IVC, intravenous chemotherapy, IVitC, intravitreal chemotherapy.

At present, both IVC and IAC are first-line treatments for retinoblastoma based upon local availability. Although IAC has been shown to have excellent therapeutic effects, whether it can replace IVC remains controversial. Published data are skewed by evolving practice patterns that project enhanced efficacy of IAC when compared with historic control rates achieved with IVC. In absence of better-quality data or randomized controlled trials, it is hard to establish superiority of one treatment over the other.

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Keywords:

intra-arterial chemotherapy; intravenous chemotherapy; intravitreal chemotherapy; retinoblastoma

Copyright © 2020 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.