Intra-arterial Chemotherapy for Retinoblastoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Jyostna Chouturi, M.B.B.S [2]

Overview

Intra-arterial chemotherapy is an emerging therapy and represents a significant advance in the treatment of intraocular retinoblastoma, also referred to as superselective intra-arterial chemotherapy and chemosurgery, is a new treatment regimen that is gaining popularity, particularly for advanced cases. Its preliminary success is recognized worldwide, and it is currently being performed in over 31 countries. Further reports from other centers will add to the growing body of literature, and more results will be available for this promising treatment.

History

• Intra-arterial chemotherapy for the treatment of intraocular retinoblastoma was first performed by Algernon B. Reese with direct internal carotid artery (ICA) injection of the alkylating agent triethylene melamine (TEM) in 1954. Other investigators including Kiribuchi in Japan in 1968 experimented with local delivery of drug to the eye comparing ocular tissue concentration of Mitomycin in dogs when treated via the common carotid artery and the external ophthalmic artery by way of the infraorbital artery. The principal motivating factor was to deliver increased local concentration of drug to eyes without excessive systemic toxicity which is not possible with systemic administration.

• The idea of local delivery of chemotherapy for retinoblastoma was later revisited by Yamane & Kaneko in 2004 when they described the technique of ‘selective ophthalmic artery infusion’ (SOAI) where a micro-balloon catheter is positioned by a transfemoral artery approach at the cervical segment of the internal carotid artery just distal to the orifice for the ophthalmic artery. At this point, the balloon catheter is inflated, and chemotherapy is injected with flow thereby directed into the ophthalmic artery. The authors of this study noted there are several small, but nevertheless important, branches proximal to the origin of the ophthalmic artery (i.e. cavernous branches of the ICA) into which infused chemotherapy could flow, and concluded, “Therefore, strictly speaking, our infusion method is not truly selective.”

• The Japanese technique of ‘selective ophthalmic artery infusion’ was further developed into ‘direct intra-arterial (ophthalmic artery) infusion’ under the pioneering work of Abramson and Gobin in New York, NY at Memorial Sloan-Kettering Cancer Center and New York-Presbyterian Hospital/Weill Cornell Medical Center under an institutional review board approved-protocol that began in May 2006. Abramson’s initial report on the technique was seminal as it was the first truly selective delivery by direct catheterization of the ophthalmic artery which could be performed reliably, quickly, efficiently and safely in young children with intraocular retinoblastoma.

Indications

• It is important to note intra-arterial treatment is intended for intraocular retinoblastoma and not for disease with extra-ocular involvement which requires consultation with a pediatric oncologist.
• Studies have demonstrated that the direct ophthalmic artery catheterization technique can be used successfully as primary therapy (i.e. naïve eyes that have received no previous treatment), especially with advanced disease (Reese Ellsworth [RE] Group IV/V, International Classification of Retinoblastoma [ICRB] Group D/E), in bilateral cases (treating both eyes, ‘tandem therapy’) and in eyes that have previously failed conventional management including external beam radiation and systemic chemotherapy.
• Although many different treatment strategies can be used to treat intraocular retinoblastoma, a clinical dilemma exists when approaching the treatment of eyes with advanced intraocular disease (Reese Ellsworth [RE] Group IV/V, International Classification of Retinoblastoma [ICRB] Group D/E). Current conventional therapy, most commonly external beam radiation (EBR) or systemic chemotherapy followed by local therapy also known as ‘chemoreduction’, for advanced eyes produces universally poor results. Only approximately 20-25% of Reese Ellsworth [RE] Group V eyes avoided enucleation with external beam irradiation as described by Reese et al, and the best results for advanced Reese Ellsworth [RE] Group V eyes treated with chemoreduction published by Shields et al. report that 47% required external beam radiation (EBR) and 53% required enucleation at 5 years. This highlights the inadequacy of these treatment modalities for eyes with advanced disease.
• Seeding of any type (vitreous or subretinal) is a poor prognostic indicator; however, a recent study with 2 year results shows that unlike external beam radiation (EBR) or chemoreduction, intra-arterial chemotherapy can more often prevent enucleation in naïve eyes with intraocular retinoblastoma, especially with subretinal seeds.
• Initial reports also indicate that eyes with advanced intraocular disease presenting with retinal detachment treated with intra-arterial therapy appear to have a better prognosis than eyes without retinal detachment even if subretinal seeds are present. Moreover, intra-arterial treatment can resolve partial retinal detachment in 100% of cases and total retinal detachment in 43-75%.

Intra-arterial agents used to treat retinoblastoma

The three principal chemotherapeutics used intra-arterially are Melphalan, Topotecan and Carboplatin.

The alkylating agent melphalan has been the most extensively used intra-arterial chemotherapeutic agent for the treatment of intraocular retinoblastoma [11]. The rationale for the use of this drug is based on in vitro studies with human cultured retinoblastoma cells using clonogenic assays which showed, compared to other commonly used chemotherapeutic drugs, melphalan had the greatest effect on retinoblastoma cells [18]. Systemic intravenous usage of melphalan is limited by severe myelosuppresion, but when administered intra-arterially is well tolerated at doses less than 0.5 mg/kg [11]. Most commonly, doses of 2.5-7.5 mg are administered intra-arterially to a single affected eye [1], though there is variation in dosing at different centers [9, 10, 19-21].

Topotecan (trade name Hycamtin®), a topoisomerase inhibitor, has been increasingly used intra-arterially for aggressive cases not responsive to single-agent melphalan. Rodent studies showed topotecan with carboplatin compared to vincristine, carboplatin and etoposide most effectively halted retinoblastoma progression in an animal model [22]. Several studies have investigated the use of periocular topotecan in the clinical setting [23, 24]. Lending further support for the use of this agent intra-arterially, is a recent study conducted in a porcine model that compared the vitreous and plasma pharmacokinectics of topotecan delivered intra-arterially via the ophthalmic artery versus periocular injection. Superselective ophthalmic artery infusion of topotecan resulted in a significantly higher vitreous concentration and exposure time with a trend toward lower systemic exposure when compared to periocular injection [23]. Most commonly, doses of 0.3-0.4 mg are administered intra-arterially to a single affected eye [1].

The alkylating agent carboplatin (trade name Paraplatin ®, Paraplatin-AQ®) has been used in three clinical contexts in New York. First, in cases where tumor has failed to respond to melphalan and/or topotecan it can be used intra-arterially as single-agent therapy [11]. Second, more commonly, it can be used in a simultaneous multi-agent triple therapy (melphalan + topotecan + carboplatin) in eyes that have failed single or double agent intra-arterial therapy or systemic intravenous chemotherapy [25]. Third, carboplatin may be used as an additional agent in tandem intra-arterial therapy for bilateral retinoblastoma when infusing melphalan to both eyes during a single treatment session; the dose of melphalan may need to be reduced when administered bilaterally to avoid myelosuppresion [11]. Most commonly doses of 15-30 mg are administered intra-arterially to a single affected eye [1], though there is variation in dosing and indication for use at other centers [9, 10].

Gobin et al. described the dosing regimen of the above three chemotherapeutics in detail [11]. Drug dosage is determined by age, individual angioanatomy with body weight only taken into account for the youngest children receiving bilateral treatment. Extent of disease with particular attending to vitreous and subretinal seeding as well as clinical response to previous intra-arterial treatments also dictates the number and dose of agents used at subsequent IA sessions.

Preclinical studies have demonstrated that cardenolide glycosides such as digoxin have anti-tumor activity against retinoblastoma in vitro and in vivo [26]. A case report indicated oral administration of digoxin was unable to achieve sufficient intraocular levels to be therapeutic, however, there was a modest response with intra-arterial delivery of digoxin [26]. Methotrexate has been reported to be used twice intra-arterially, but ineffective at doses of 6 mg and 12 mg [11].