Over the last 3 decades, retinoblastoma (RB) management has evolved, shifting the focus from merely saving the patient’s life to also preserving the eye and vision while reducing treatment-related complications. Although intravenous chemotherapy (IVC) has been pivotal in this shift, targeted therapy in RB, namely intra-arterial chemotherapy (IAC) and intravitreal chemotherapy (IVitC), is becoming increasingly popular.¹ This trend is driven by 2 factors: higher efficacy in advanced stages (ICRB group D and E) and low systemic complications.^1,2 

Vitreous seeding is one of the major predictive factors for the failure of both IVC and IAC.^3-5 The hypoxic vitreous environment and reduced vitreous penetration of drugs delivered through IVC or IAC render these tumor seeds resistant to chemotherapy. This is where IVitC plays a crucial role, delivering the drug as close as possible to the tumor seeds while minimizing systemic toxicity.⁶

Although IVitC was first introduced by Kaneko and Suzuki in 2003,⁷ Munier et al popularized it in RB by demonstrating its safety and efficacy.¹ It is important to control the retinal tumor prior to or in conjunction with treatment of vitreous seeding, because it is the primary tumor that is the source of the seeding. Therefore, IVC is an adjuvant therapy in nonresponsive or recurrent vitreous seeds after IVC or IAC.^8,9

Chemotherapy Agents

Melphalan hydrochloride is the most commonly used and highly effective agent, selected by Inomata and Kaneko for its proven efficacy against retinoblastoma (RB) in
in vitro studies.¹⁰ The major challenge with melphalan is its narrow therapeutic window, meaning the gap between the minimum effective dose for tumor control and the maximum dose that is safe to avoid toxicity.¹¹

The main toxicity associated with melphalan is localized salt-and-pepper retinopathy (18% to 43%), which is linked to its high binding affinity for the retinal pigment epithelium (RPE) with reduced retinal function by electroretinography (ERG).⁵ Anterior segment toxicity in the form of iris depigmentation and atrophy after multiple melphalan injections, as well as uveitis, have also been reported (Figure 1).¹²

Topotecan hydrochloride appears to be a safer alternative because it has a wider therapeutic window.^13,14 Clinical studies have shown no retinal or systemic toxicity with 4 weekly injections of topotecan.^15,16 

In a recent phase 1 clinical trial on the safety and efficacy of intravitreal carboplatin for progressive vitreous seeding, incomplete seed regression was observed with dose-
dependent retinal toxicity.^17,18 Ultimately, the study was terminated in view of the availability of safer alternatives.

Apart from the drug-specific side effects mentioned above, other procedure-related ocular complications include focal lens opacity, vitreous or subretinal hemorrhage, or hemorrhagic retinal necrosis. The risk of extraocular seeding is exceedingly rare.¹⁹ IVitC has no reported systemic side effects.

Injection Technique 

The recommended dose for both drugs is 20 μg to 30 μg (calculated based on patient’s age) every 2 to 4 weeks until complete resolution of vitreous seeds is achieved. Munier et al developed a “safety enhanced” technique for intravitreal injection to minimize this risk, and they addressed 5 major risk factors and successfully administered more than 135 injections without extraocular recurrence or systemic spread.⁶ A careful examination should be performed to rule out any possible contraindications. A 30-gauge needle attached to a tuberculin syringe is used to deliver the drugs under standard aseptic precautions at the chosen site (tumor-free quadrant). Prior to injection, anterior chamber paracentesis is preferred to reduce intraocular pressure. Triple freeze-thaw cryotherapy is performed at the injection site while withdrawing the needle to prevent seeding of RB through the needle tract. The eyeball is then “jiggled” to help disperse the drug evenly throughout the vitreous cavity. Thorough irrigation with a balanced salt solution is performed to remove any residual drug from the ocular surface.

Treatment Outcomes 

Most published data on IVitC were from eyes classified as ICRB group C or higher. Munier et al demonstrated complete regression of vitreous seeds in all group C eyes and 82% of group D eyes with recurrent vitreous seeds, which were treated with weekly melphalan injections.¹ Other studies using melphalan at 20 µg to 30 µg doses have shown excellent efficacy in eliminating vitreous seeds and improving globe salvage in 85% to 100% of cases.²⁰ Overall, incorporation of IVitC as an adjunct chemotherapy significantly enhanced globe salvage rates with IAC, particularly in patients with group E eyes.²¹ Similar benefit of IVitC on ocular survival following IVC seems to be lacking.⁹ There are limited data to substantiate the role of IVitC in treating subretinal seeds and recurrent retinal tumor.²² 

Newer Trends and Pharmacologic Agents

Preclinical studies with targeted inhibition of histone deacetylase inhibitors has shown promising effects against vitreous seeding.²³ In animal studies intravitreal belinostat is an effective alternative to melphalan for treating vitreous seeds, but without exhibiting any ERG-studied retinal toxicity.²⁴ Nanoparticles technology seems to improve bioavailability of topotecan within the vitreous cavity in a rabbit xenograft RB model.²⁵ 

Conclusion

IVitC is a safe and effective treatment for vitreous seeds. As an adjunct to current standards of care (IAC and IVC), IVitC has improved overall globe survival rates. RP

Vishal R. Raval, MD, is a retina specialist with the Operation Eyesight Universal Institute for Eye Cancer of LV Prasad Eye Institute in Hyderabad, India. Dr. Raval reports no relevant disclosures. Reach Dr. Raval at drvishalraval@gmail.com.

Vidhi Bajpai, MS, is a retina fellow at Anant Bajaj Retina Institute of L V Prasad Eye Institute in Hyderabad, India. Ms. Bajpai reports no relevant disclosures.

Arun D. Singh, MD, is director of the department of ophthalmic oncology in the Cole Eye Institute at Cleveland Clinic in Cleveland, Ohio. He reports no relevant disclosures.

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