Intra-Arterial Chemotherapy (Ophthalmic Artery Infusion of Chemotherapy)

Direct delivery of chemotherapy into the eye via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage when performed at high-volume centers that have specialized services of an interventional radiologist skilled in this area and a pediatric anesthesiologist. The Children’s Oncology Group conducted a multi-institutional study (ARET12P1 [NCT02097134]) to evaluate the feasibility of administering intra-arterial therapy to newly diagnosed patients with Group D retinoblastoma. The study failed to meet the feasibility goals, highlighting the importance of referring patients to high-volume institutions that have expertise in the procedure.[20] Responses to chemotherapy using this approach can be further consolidated with local control measures, as described above.

Melphalan is the most common and most effective agent used for intra-arterial chemotherapy. It is often combined with topotecan or carboplatin when responses are suboptimal or there is very advanced intraocular disease.[21,22]

Outcome after intra-arterial chemotherapy correlates with the extent of intraocular burden, as follows:

The role of intra-arterial chemotherapy in ocular salvage has been further clarified in a multicenter randomized clinical trial. This trial compared intra-arterial chemotherapy with systemic chemotherapy for children with unilateral advanced (Group D or E) retinoblastoma. Patients were randomly assigned to receive either four cycles of intra-arterial melphalan combination chemotherapy (two cycles with carboplatin and two cycles with topotecan) or six cycles of systemic chemotherapy with vincristine, carboplatin, and etoposide. Local control was performed based on standard practice. The 2-year progression-free ocular salvage rates were 53% for patients in the intra-arterial chemotherapy group and 27% for patients in the intravenous chemotherapy group. The ocular salvage rates were 71% for patients who received intra-arterial chemotherapy and 51% for patients who received intravenous chemotherapy.[26]

Patients with bilateral disease can undergo tandem intra-arterial chemotherapy administration.[27] In those circumstances, patients are at higher risk of systemic toxicity caused by melphalan exposure,[28] and single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure.[29] For neonates and very young infants in whom the cannulization of the ophthalmic artery is not feasible, bridge treatment with single-agent systemic carboplatin until the infant is aged 3 months or weighs 6 kg, followed by consolidation with intra-arterial chemotherapy, has been shown to be very effective. In one study, the 1-year radiation-free ocular survival rate was 95%.[30]

In a study of 39 infants younger than 3 months with advanced intraocular retinoblastoma (Group D and E eyes), patients received intra-arterial chemotherapy as primary treatment (29 eyes) or secondary treatment (13 eyes previously treated with intravenous chemotherapy) using a microcatheterization procedure. The middle meningeal artery was used when the ophthalmic artery could not be catheterized.[31]

The addition of intravitreal chemotherapy to intra-arterial chemotherapy appears to markedly improve the overall effectiveness in eyes with vitreous seeds, especially those with vitreous seed clouds.[21,32,33] For more information, see the Intravitreal Chemotherapy section.

In patients presenting with total retinal detachment, ophthalmic artery chemosurgery has been shown to promote retinal reattachment.[34]

Complications related to intra-arterial chemotherapy include the following:[22,26,35]

Major vascular complications related to the procedure are very rare. Strokes or significant acute neurological events have not been reported by the most experienced groups.[21,22,37] However, stenosis of the ophthalmic artery and occlusion of the retinal artery have been documented.[35,37] The risk of thrombosis is significantly increased in children with thrombophilia.[38] In a large series of 196 patients who were treated with 682 infusions of intra-arterial chemotherapy, ophthalmic vascular events were reported in 17% of the treated eyes.[35]

The impact of the intraocular vascular changes on vision has not been fully assessed because of the young age of the first cohorts of patients treated. Most patients do not have substantial electroretinographic changes,[39] and preservation of central vision has been reported.[40] A proportion of patients with abnormal electroretinograms (ERGs) with or without retinal detachment may have improved ERGs in the years after intra-arterial chemotherapy.[41] However, in patients with heavily pretreated eyes, intensive intra-arterial chemotherapy may result in worsening of retinal function.[25]

Another risk associated with intra-arterial chemotherapy is the exposure to ionizing radiation during fluoroscopy. Mean total radiation doses of 42.3 mGy have been reported in very experienced centers.[42] After multiple procedures, cumulative doses can reach 0.1 to 0.2 Gy, which can be cataractogenic and potentially carcinogenic in this susceptible population.[43] There has been no increase in the incidence of second malignancies.[44,45] However, longer follow-up is required to fully ascertain the risks associated with the procedure.

The risk of metastatic progression with direct ocular delivery of chemotherapy appears to be very low.[2] However, up to 20 cases of patients treated with intra-arterial chemotherapy who subsequently developed metastases have been reported.[22]